|
Inhibition of HIV-1 replication in H9 (human lymphoma) cells.
|
Human immunodeficiency virus 1
|
7.0
ug.mL-1
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Evaluation of tea polyphenols as anti-HIV agents
Year : 1996
Volume : 6
Issue : 6
First Page : 695
Last Page : 700
Authors : Hashimoto F, Kashiwada Y, Nonaka G, Nishioka I, Nohara T, Cosentino L, Lee K
|
Inhibition of uninfected H9 lymphocytic cell growth
|
Homo sapiens
|
8.0
ug.mL-1
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Evaluation of tea polyphenols as anti-HIV agents
Year : 1996
Volume : 6
Issue : 6
First Page : 695
Last Page : 700
Authors : Hashimoto F, Kashiwada Y, Nonaka G, Nishioka I, Nohara T, Cosentino L, Lee K
|
Inhibition of polymerization in wild type HIV-1 RT with poly rC/dG12-18 template primer and [3H]dGTP
|
Human immunodeficiency virus 1
|
730.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Simplified catechin-gallate inhibitors of HIV-1 reverse transcriptase.
Year : 2001
Volume : 11
Issue : 20
First Page : 2763
Last Page : 2767
Authors : Tillekeratne LM, Sherette A, Grossman P, Hupe L, Hupe D, Hudson RA.
Abstract : Systematic simplification of the molecular structures of epicatechin gallate and epigallocatechin gallate to determine the minimum structural characteristics necessary for HIV-1 reverse transcriptase inhibition in vitro resulted in several compounds that strongly inhibited the native as well as the A17 double mutant (K103N Y181C) enzyme, which is normally insensitive to most known nonnucleoside inhibitors.
|
Inhibition against HIV-1 integrase at 1 mM
|
Human immunodeficiency virus 1
|
50.0
%
|
|
Journal : J. Med. Chem.
Title : Developing a dynamic pharmacophore model for HIV-1 integrase.
Year : 2000
Volume : 43
Issue : 11
First Page : 2100
Last Page : 2114
Authors : Carlson HA, Masukawa KM, Rubins K, Bushman FD, Jorgensen WL, Lins RD, Briggs JM, McCammon JA.
Abstract : We present the first receptor-based pharmacophore model for HIV-1 integrase. The development of "dynamic" pharmacophore models is a new method that accounts for the inherent flexibility of the active site and aims to reduce the entropic penalties associated with binding a ligand. Furthermore, this new drug discovery method overcomes the limitation of an incomplete crystal structure of the target protein. A molecular dynamics (MD) simulation describes the flexibility of the uncomplexed protein. Many conformational models of the protein are saved from the MD simulations and used in a series of multi-unit search for interacting conformers (MUSIC) simulations. MUSIC is a multiple-copy minimization method, available in the BOSS program; it is used to determine binding regions for probe molecules containing functional groups that complement the active site. All protein conformations from the MD are overlaid, and conserved binding regions for the probe molecules are identified. Those conserved binding regions define the dynamic pharmacophore model. Here, the dynamic model is compared to known inhibitors of the integrase as well as a three-point, ligand-based pharmacophore model from the literature. Also, a "static" pharmacophore model was determined in the standard fashion, using a single crystal structure. Inhibitors thought to bind in the active site of HIV-1 integrase fit the dynamic model but not the static model. Finally, we have identified a set of compounds from the Available Chemicals Directory that fit the dynamic pharmacophore model, and experimental testing of the compounds has confirmed several new inhibitors.
|
Inhibition against HIV-1 integrase at 200 uM
|
Human immunodeficiency virus 1
|
50.0
%
|
|
Journal : J. Med. Chem.
Title : Developing a dynamic pharmacophore model for HIV-1 integrase.
Year : 2000
Volume : 43
Issue : 11
First Page : 2100
Last Page : 2114
Authors : Carlson HA, Masukawa KM, Rubins K, Bushman FD, Jorgensen WL, Lins RD, Briggs JM, McCammon JA.
Abstract : We present the first receptor-based pharmacophore model for HIV-1 integrase. The development of "dynamic" pharmacophore models is a new method that accounts for the inherent flexibility of the active site and aims to reduce the entropic penalties associated with binding a ligand. Furthermore, this new drug discovery method overcomes the limitation of an incomplete crystal structure of the target protein. A molecular dynamics (MD) simulation describes the flexibility of the uncomplexed protein. Many conformational models of the protein are saved from the MD simulations and used in a series of multi-unit search for interacting conformers (MUSIC) simulations. MUSIC is a multiple-copy minimization method, available in the BOSS program; it is used to determine binding regions for probe molecules containing functional groups that complement the active site. All protein conformations from the MD are overlaid, and conserved binding regions for the probe molecules are identified. Those conserved binding regions define the dynamic pharmacophore model. Here, the dynamic model is compared to known inhibitors of the integrase as well as a three-point, ligand-based pharmacophore model from the literature. Also, a "static" pharmacophore model was determined in the standard fashion, using a single crystal structure. Inhibitors thought to bind in the active site of HIV-1 integrase fit the dynamic model but not the static model. Finally, we have identified a set of compounds from the Available Chemicals Directory that fit the dynamic pharmacophore model, and experimental testing of the compounds has confirmed several new inhibitors.
|
Inhibition against HIV-1 integrase at 25 uM
|
Human immunodeficiency virus 1
|
50.0
%
|
|
Journal : J. Med. Chem.
Title : Developing a dynamic pharmacophore model for HIV-1 integrase.
Year : 2000
Volume : 43
Issue : 11
First Page : 2100
Last Page : 2114
Authors : Carlson HA, Masukawa KM, Rubins K, Bushman FD, Jorgensen WL, Lins RD, Briggs JM, McCammon JA.
Abstract : We present the first receptor-based pharmacophore model for HIV-1 integrase. The development of "dynamic" pharmacophore models is a new method that accounts for the inherent flexibility of the active site and aims to reduce the entropic penalties associated with binding a ligand. Furthermore, this new drug discovery method overcomes the limitation of an incomplete crystal structure of the target protein. A molecular dynamics (MD) simulation describes the flexibility of the uncomplexed protein. Many conformational models of the protein are saved from the MD simulations and used in a series of multi-unit search for interacting conformers (MUSIC) simulations. MUSIC is a multiple-copy minimization method, available in the BOSS program; it is used to determine binding regions for probe molecules containing functional groups that complement the active site. All protein conformations from the MD are overlaid, and conserved binding regions for the probe molecules are identified. Those conserved binding regions define the dynamic pharmacophore model. Here, the dynamic model is compared to known inhibitors of the integrase as well as a three-point, ligand-based pharmacophore model from the literature. Also, a "static" pharmacophore model was determined in the standard fashion, using a single crystal structure. Inhibitors thought to bind in the active site of HIV-1 integrase fit the dynamic model but not the static model. Finally, we have identified a set of compounds from the Available Chemicals Directory that fit the dynamic pharmacophore model, and experimental testing of the compounds has confirmed several new inhibitors.
|
Compound was evaluated for its inhibitory activity against recombinant rat SE(squalene epoxidase)
|
None
|
690.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Inhibition of vertebrate squalene epoxidase by isoprenyl gallates and phenylalkyl gallates.
Year : 2000
Volume : 10
Issue : 22
First Page : 2525
Last Page : 2528
Authors : Abe I, Kashiwagi Y, Noguchi H.
Abstract : Galloy esters with 'substrate-like' isoprenoid or phenylalkyl side chains were newly synthesized and tested for the enzyme inhibition activities toward recombinant rat squalene epoxidase. Isoprenyl gallates (4-6) showed good inhibition (IC50 = 1.5 5.1 microM), as potent as previously reported substrate analogues, while phenylalkyl gallates (7-10) were moderate inhibitors of the enzyme (IC50 = 12-61 microM).
|
Inhibition of FabZ
|
Plasmodium falciparum
|
400.0
nM
|
|
Journal : J. Med. Chem.
Title : Inhibition of Plasmodium falciparum fatty acid biosynthesis: evaluation of FabG, FabZ, and FabI as drug targets for flavonoids.
Year : 2006
Volume : 49
Issue : 11
First Page : 3345
Last Page : 3353
Authors : Tasdemir D, Lack G, Brun R, Rüedi P, Scapozza L, Perozzo R.
Abstract : After the discovery of a potent natural flavonoid glucoside as a potent inhibitor of FabI, a large flavonoid library was screened against three important enzymes (i.e., FabG, FabZ, and FabI) involved in the fatty acid biosynthesis of P. falciparum. Although flavones with a simple hydroxylation pattern (compounds 4-9) showed moderate inhibitory activity toward the enzymes tested (IC50 10-100 microM), the more complex flavonoids (12-16) exhibited strong activity toward all three enzymes (IC50 0.5-8 microM). Isoflavonoids 26-28 showed moderate (IC50 7-30 microM) but selective activity against FabZ. The most active compounds were C-3 gallic acid esters of catechins (32, 33, 37, 38), which are strong inhibitors of all three enzymes (IC50 0.2-1.1 microM). Kinetic analysis using luteolin (12) and (-)-catechin gallate (37) as model compounds revealed that FabG was inhibited in a noncompetitive manner. FabZ was inhibited competitively, whereas both compounds behaved as tight-binding noncompetitive inhibitors of FabI. In addition, these polyphenols showed in vitro activity against chloroquine-sensitive (NF54) and -resistant (K1) P. falciparum strains in the low to submicromolar range.
|
Inhibition of FabI
|
Plasmodium falciparum
|
200.0
nM
|
|
Journal : J. Med. Chem.
Title : Inhibition of Plasmodium falciparum fatty acid biosynthesis: evaluation of FabG, FabZ, and FabI as drug targets for flavonoids.
Year : 2006
Volume : 49
Issue : 11
First Page : 3345
Last Page : 3353
Authors : Tasdemir D, Lack G, Brun R, Rüedi P, Scapozza L, Perozzo R.
Abstract : After the discovery of a potent natural flavonoid glucoside as a potent inhibitor of FabI, a large flavonoid library was screened against three important enzymes (i.e., FabG, FabZ, and FabI) involved in the fatty acid biosynthesis of P. falciparum. Although flavones with a simple hydroxylation pattern (compounds 4-9) showed moderate inhibitory activity toward the enzymes tested (IC50 10-100 microM), the more complex flavonoids (12-16) exhibited strong activity toward all three enzymes (IC50 0.5-8 microM). Isoflavonoids 26-28 showed moderate (IC50 7-30 microM) but selective activity against FabZ. The most active compounds were C-3 gallic acid esters of catechins (32, 33, 37, 38), which are strong inhibitors of all three enzymes (IC50 0.2-1.1 microM). Kinetic analysis using luteolin (12) and (-)-catechin gallate (37) as model compounds revealed that FabG was inhibited in a noncompetitive manner. FabZ was inhibited competitively, whereas both compounds behaved as tight-binding noncompetitive inhibitors of FabI. In addition, these polyphenols showed in vitro activity against chloroquine-sensitive (NF54) and -resistant (K1) P. falciparum strains in the low to submicromolar range.
|
Inhibition of FabG
|
Plasmodium falciparum
|
300.0
nM
|
|
Journal : J. Med. Chem.
Title : Inhibition of Plasmodium falciparum fatty acid biosynthesis: evaluation of FabG, FabZ, and FabI as drug targets for flavonoids.
Year : 2006
Volume : 49
Issue : 11
First Page : 3345
Last Page : 3353
Authors : Tasdemir D, Lack G, Brun R, Rüedi P, Scapozza L, Perozzo R.
Abstract : After the discovery of a potent natural flavonoid glucoside as a potent inhibitor of FabI, a large flavonoid library was screened against three important enzymes (i.e., FabG, FabZ, and FabI) involved in the fatty acid biosynthesis of P. falciparum. Although flavones with a simple hydroxylation pattern (compounds 4-9) showed moderate inhibitory activity toward the enzymes tested (IC50 10-100 microM), the more complex flavonoids (12-16) exhibited strong activity toward all three enzymes (IC50 0.5-8 microM). Isoflavonoids 26-28 showed moderate (IC50 7-30 microM) but selective activity against FabZ. The most active compounds were C-3 gallic acid esters of catechins (32, 33, 37, 38), which are strong inhibitors of all three enzymes (IC50 0.2-1.1 microM). Kinetic analysis using luteolin (12) and (-)-catechin gallate (37) as model compounds revealed that FabG was inhibited in a noncompetitive manner. FabZ was inhibited competitively, whereas both compounds behaved as tight-binding noncompetitive inhibitors of FabI. In addition, these polyphenols showed in vitro activity against chloroquine-sensitive (NF54) and -resistant (K1) P. falciparum strains in the low to submicromolar range.
|
Inhibition of Plasmodium falciparum ENR
|
Plasmodium falciparum
|
250.0
nM
|
|
Journal : J. Med. Chem.
Title : Green tea catechins potentiate triclosan binding to enoyl-ACP reductase from Plasmodium falciparum (PfENR).
Year : 2007
Volume : 50
Issue : 4
First Page : 765
Last Page : 775
Authors : Sharma SK, Parasuraman P, Kumar G, Surolia N, Surolia A.
Abstract : We have investigated the mechanism of inhibition of enoyl-acyl carrier protein reductase of Plasmodium falciparum (PfENR) by triclosan in the presence of a few important catechins and related plant polyphenols. The examined flavonoids inhibited PfENR reversibly with Ki values in the nanomolar range, EGCG being the best with 79 +/- 2.67 nM. The steady-state kinetics revealed time dependent inhibition of PfENR by triclosan, demonstrating that triclosan exhibited slow tight-binding kinetics with PfENR in the presence of these compounds. Additionally, all of them potentiated the binding of triclosan with PfENR by a two-step mechanism resulting in an overall inhibition constant of triclosan in the low picomolar concentration range. The high affinities of tea catechins and the potentiation of binding of triclosan in their presence are readily explained by molecular modeling studies. The enhancement in the potency of triclosan induced by these compounds holds great promise for the development of effective antimalarial therapy.
|
Inhibition of Plasmodium falciparum ENR using NADH substrate
|
Plasmodium falciparum
|
186.0
nM
|
|
Journal : J. Med. Chem.
Title : Green tea catechins potentiate triclosan binding to enoyl-ACP reductase from Plasmodium falciparum (PfENR).
Year : 2007
Volume : 50
Issue : 4
First Page : 765
Last Page : 775
Authors : Sharma SK, Parasuraman P, Kumar G, Surolia N, Surolia A.
Abstract : We have investigated the mechanism of inhibition of enoyl-acyl carrier protein reductase of Plasmodium falciparum (PfENR) by triclosan in the presence of a few important catechins and related plant polyphenols. The examined flavonoids inhibited PfENR reversibly with Ki values in the nanomolar range, EGCG being the best with 79 +/- 2.67 nM. The steady-state kinetics revealed time dependent inhibition of PfENR by triclosan, demonstrating that triclosan exhibited slow tight-binding kinetics with PfENR in the presence of these compounds. Additionally, all of them potentiated the binding of triclosan with PfENR by a two-step mechanism resulting in an overall inhibition constant of triclosan in the low picomolar concentration range. The high affinities of tea catechins and the potentiation of binding of triclosan in their presence are readily explained by molecular modeling studies. The enhancement in the potency of triclosan induced by these compounds holds great promise for the development of effective antimalarial therapy.
|
Inhibition of Plasmodium falciparum ENR using crotonyl-CoA substrate
|
Plasmodium falciparum
|
79.0
nM
|
|
Journal : J. Med. Chem.
Title : Green tea catechins potentiate triclosan binding to enoyl-ACP reductase from Plasmodium falciparum (PfENR).
Year : 2007
Volume : 50
Issue : 4
First Page : 765
Last Page : 775
Authors : Sharma SK, Parasuraman P, Kumar G, Surolia N, Surolia A.
Abstract : We have investigated the mechanism of inhibition of enoyl-acyl carrier protein reductase of Plasmodium falciparum (PfENR) by triclosan in the presence of a few important catechins and related plant polyphenols. The examined flavonoids inhibited PfENR reversibly with Ki values in the nanomolar range, EGCG being the best with 79 +/- 2.67 nM. The steady-state kinetics revealed time dependent inhibition of PfENR by triclosan, demonstrating that triclosan exhibited slow tight-binding kinetics with PfENR in the presence of these compounds. Additionally, all of them potentiated the binding of triclosan with PfENR by a two-step mechanism resulting in an overall inhibition constant of triclosan in the low picomolar concentration range. The high affinities of tea catechins and the potentiation of binding of triclosan in their presence are readily explained by molecular modeling studies. The enhancement in the potency of triclosan induced by these compounds holds great promise for the development of effective antimalarial therapy.
|
Inhibition of Plasmodium falciparum ENR in presence of triclosan
|
Plasmodium falciparum
|
8.0
nM
|
|
Journal : J. Med. Chem.
Title : Green tea catechins potentiate triclosan binding to enoyl-ACP reductase from Plasmodium falciparum (PfENR).
Year : 2007
Volume : 50
Issue : 4
First Page : 765
Last Page : 775
Authors : Sharma SK, Parasuraman P, Kumar G, Surolia N, Surolia A.
Abstract : We have investigated the mechanism of inhibition of enoyl-acyl carrier protein reductase of Plasmodium falciparum (PfENR) by triclosan in the presence of a few important catechins and related plant polyphenols. The examined flavonoids inhibited PfENR reversibly with Ki values in the nanomolar range, EGCG being the best with 79 +/- 2.67 nM. The steady-state kinetics revealed time dependent inhibition of PfENR by triclosan, demonstrating that triclosan exhibited slow tight-binding kinetics with PfENR in the presence of these compounds. Additionally, all of them potentiated the binding of triclosan with PfENR by a two-step mechanism resulting in an overall inhibition constant of triclosan in the low picomolar concentration range. The high affinities of tea catechins and the potentiation of binding of triclosan in their presence are readily explained by molecular modeling studies. The enhancement in the potency of triclosan induced by these compounds holds great promise for the development of effective antimalarial therapy.
|
Inhibition of chymotrypsin like activity of 20S proteasome
|
Homo sapiens
|
200.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : A para-amino substituent on the D-ring of green tea polyphenol epigallocatechin-3-gallate as a novel proteasome inhibitor and cancer cell apoptosis inducer.
Year : 2007
Volume : 15
Issue : 15
First Page : 5076
Last Page : 5082
Authors : Osanai K, Landis-Piwowar KR, Dou QP, Chan TH.
Abstract : Analogs of (-)-EGCG containing a para-amino group on the D-ring in place of the hydroxyl groups have been synthesized and their proteasome inhibitory activities were studied. We found that, the O-acetylated (-)-EGCG analogs possessing a p-NH(2) or p-NHBoc (Boc; tert-butoxycarbonyl) D-ring (5 and 7) act as novel tumor cellular proteasome inhibitors and apoptosis inducers with potency similar to natural (-)-EGCG and similar to (-)-EGCG peracetate. These data suggest that the acetylated amino-GTP analogs have the potential to be developed into novel anticancer agents.
|
Inhibition of chymotrypsin like activity of 20S proteasome in leukemia Raji B cells at 25 uM after 4 hrs
|
Homo sapiens
|
4.0
%
|
|
Journal : Bioorg. Med. Chem.
Title : A para-amino substituent on the D-ring of green tea polyphenol epigallocatechin-3-gallate as a novel proteasome inhibitor and cancer cell apoptosis inducer.
Year : 2007
Volume : 15
Issue : 15
First Page : 5076
Last Page : 5082
Authors : Osanai K, Landis-Piwowar KR, Dou QP, Chan TH.
Abstract : Analogs of (-)-EGCG containing a para-amino group on the D-ring in place of the hydroxyl groups have been synthesized and their proteasome inhibitory activities were studied. We found that, the O-acetylated (-)-EGCG analogs possessing a p-NH(2) or p-NHBoc (Boc; tert-butoxycarbonyl) D-ring (5 and 7) act as novel tumor cellular proteasome inhibitors and apoptosis inducers with potency similar to natural (-)-EGCG and similar to (-)-EGCG peracetate. These data suggest that the acetylated amino-GTP analogs have the potential to be developed into novel anticancer agents.
|
Inhibition of chymotrypsin like activity of 20S proteasome in leukemia Raji B cells at 25 uM after 24 hrs
|
Homo sapiens
|
10.0
%
|
|
Journal : Bioorg. Med. Chem.
Title : A para-amino substituent on the D-ring of green tea polyphenol epigallocatechin-3-gallate as a novel proteasome inhibitor and cancer cell apoptosis inducer.
Year : 2007
Volume : 15
Issue : 15
First Page : 5076
Last Page : 5082
Authors : Osanai K, Landis-Piwowar KR, Dou QP, Chan TH.
Abstract : Analogs of (-)-EGCG containing a para-amino group on the D-ring in place of the hydroxyl groups have been synthesized and their proteasome inhibitory activities were studied. We found that, the O-acetylated (-)-EGCG analogs possessing a p-NH(2) or p-NHBoc (Boc; tert-butoxycarbonyl) D-ring (5 and 7) act as novel tumor cellular proteasome inhibitors and apoptosis inducers with potency similar to natural (-)-EGCG and similar to (-)-EGCG peracetate. These data suggest that the acetylated amino-GTP analogs have the potential to be developed into novel anticancer agents.
|
Inhibition of yeast G6PD
|
Saccharomyces cerevisiae
|
250.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Catechin gallates are NADP+-competitive inhibitors of glucose-6-phosphate dehydrogenase and other enzymes that employ NADP+ as a coenzyme.
Year : 2008
Volume : 16
Issue : 7
First Page : 3580
Last Page : 3586
Authors : Shin ES, Park J, Shin JM, Cho D, Cho SY, Shin DW, Ham M, Kim JB, Lee TR.
Abstract : Recent studies have shown that glucose-6-phosphate dehydrogenase (G6PD) is an effectual therapeutic target for metabolic disorders, including obesity and diabetes. In this study, we used in silico and conventional screening approaches to identify putative inhibitors of G6PD and found that gallated catechins (EGCG, GCG, ECG, CG), but not ungallated catechins (ECG, GC, EC, C), were NADP(+)-competitive inhibitors of G6PD and other enzymes that employ NADP(+) as a coenzyme, such as IDH and 6PGD.
|
Inhibition of 6PGD
|
None
|
720.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Catechin gallates are NADP+-competitive inhibitors of glucose-6-phosphate dehydrogenase and other enzymes that employ NADP+ as a coenzyme.
Year : 2008
Volume : 16
Issue : 7
First Page : 3580
Last Page : 3586
Authors : Shin ES, Park J, Shin JM, Cho D, Cho SY, Shin DW, Ham M, Kim JB, Lee TR.
Abstract : Recent studies have shown that glucose-6-phosphate dehydrogenase (G6PD) is an effectual therapeutic target for metabolic disorders, including obesity and diabetes. In this study, we used in silico and conventional screening approaches to identify putative inhibitors of G6PD and found that gallated catechins (EGCG, GCG, ECG, CG), but not ungallated catechins (ECG, GC, EC, C), were NADP(+)-competitive inhibitors of G6PD and other enzymes that employ NADP(+) as a coenzyme, such as IDH and 6PGD.
|
Inhibition of beta amyloid 25-35 fibril formation at 10 uM
|
None
|
13.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : New polyphenols active on beta-amyloid aggregation.
Year : 2008
Volume : 18
Issue : 2
First Page : 828
Last Page : 831
Authors : Rivière C, Richard T, Vitrac X, Mérillon JM, Valls J, Monti JP.
Abstract : New polyphenol classes have been tested against amyloid-beta peptide aggregation. We have identified four novel polyphenols which could be efficient fibril inhibitors in Alzheimer's disease: malvidin and its glucoside and curculigosides B and D. We suggest that molecules with the particular C(6)-linkers-C(6) structure could be potent inhibitors. From the results reported for the flavan-3-ol family, their anti-amyloidogenic effects against whole peptides (1-40 and 1-42) could involve several binding sites.
|
Binding affinity to BCL2
|
None
|
234.42
nM
|
|
Journal : Proc. Natl. Acad. Sci. U.S.A.
Title : Small molecule obatoclax (GX15-070) antagonizes MCL-1 and overcomes MCL-1-mediated resistance to apoptosis.
Year : 2007
Volume : 104
Issue : 49
First Page : 19512
Last Page : 19517
Authors : Nguyen M, Marcellus RC, Roulston A, Watson M, Serfass L, Murthy Madiraju SR, Goulet D, Viallet J, Bélec L, Billot X, Acoca S, Purisima E, Wiegmans A, Cluse L, Johnstone RW, Beauparlant P, Shore GC.
Abstract : Elevated expression of members of the BCL-2 pro-survival family of proteins can confer resistance to apoptosis in cancer cells. Small molecule obatoclax (GX15-070), which is predicted to occupy a hydrophobic pocket within the BH3 binding groove of BCL-2, antagonizes these members and induces apoptosis, dependent on BAX and BAK. Reconstitution in yeast confirmed that obatoclax acts on the pathway and overcomes BCL-2-, BCL-XL-, BCL-w-, and MCL-1-mediated resistance to BAX or BAK. The compound potently interfered with the direct interaction between MCL-1 and BAK in intact mitochondrial outer membrane and inhibited the association between MCL-1 and BAK in intact cells. MCL-1 has been shown to confer resistance to the BCL-2/BCL-XL/BCL-w-selective antagonist ABT-737 and to the proteasome inhibitor bortezomib. In both cases, this resistance was overcome by obatoclax. These findings support a rational clinical development opportunity for the compound in cancer indications or treatments where MCL-1 contributes to resistance to cell killing.
|
Antioxidant activity assessed as DPPH free radical scavenging activity after 30 mins
|
None
|
2.7
ug.mL-1
|
|
Journal : J. Nat. Prod.
Title : New diarylheptanoids from the stems of Carpinus cordata.
Year : 2002
Volume : 65
Issue : 9
First Page : 1367
Last Page : 1370
Authors : Lee JS, Kim HJ, Park H, Lee YS.
Abstract : Two new diarylheptanoids, carpinontriols A (1) and B (2), were isolated from the stems of Carpinus cordata, along with the known diarylheptanoid, casuarinondiol (3), and five known compounds, (+)-catechin (4), methyl gallate (5), methyl gallate 3-O-beta-D-glucopyranoside (6), methyl gallate 4-O-beta-D-glucopyranoside (7), and methyl gallate 3-O-beta-D-(6'-O-galloyl)-glucopyranoside (8). The structures of 1 and 2 were elucidated by spectral methods. Among the isolated compounds, compounds 4-6 and 8 showed radical-scavenging activity in the DPPH assay.
|
Antiviral activity against Influenza (A/PR8/34(H1N1))
|
Influenza A virus (A/Puerto Rico/8/1934(H1N1))
|
391.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Enhanced anti-influenza A virus activity of (-)-epigallocatechin-3-O-gallate fatty acid monoester derivatives: effect of alkyl chain length.
Year : 2008
Volume : 18
Issue : 14
First Page : 4249
Last Page : 4252
Authors : Mori S, Miyake S, Kobe T, Nakaya T, Fuller SD, Kato N, Kaihatsu K.
Abstract : A series of fatty acid monoester derivatives of (-)-epigallocatechin-3-O-gallate (EGCG) were prepared by one-pot lipase-catalyzed transesterification. The introduction of long alkyl chains enhanced anti-influenza A/PR8/34 (H1N1) virus activity 24-fold relative to native EGCG.
|
Inhibition of Streptococcus sobrinus glucosyltransferase assessed as blockade of adherent water insoluble glucan synthesis at 100 ug/mL
|
Streptococcus sobrinus
|
26.5
%
|
|
Journal : J. Nat. Prod.
Title : Macrocarpals H, I, and J from the Leaves of Eucalyptus globulus.
Year : 1996
Volume : 59
Issue : 9
First Page : 823
Last Page : 827
Authors : Osawa K, Yasuda H, Morita H, Takeya K, Itokawa H.
Abstract : A 50% EtOH extract of Eucalyptus globulus leaves yielded eight phloroglucinol--sesquiterpene-coupled constituents, including three novel compounds named macrocarpals, H, I, and J. Some of these compounds possessed antibacterial activity against oral pathogenic microorganisms with MIC values ranging from 0.20 micrograms/mL to 6.25 micrograms/mL. Inhibition of glucosyltransferase activity by these compounds was also noted.
|
Inhibition of Streptococcus sobrinus glucosyltransferase assessed as blockade of adherent water insoluble glucan synthesis at 10 ug/mL
|
Streptococcus sobrinus
|
10.5
%
|
|
Journal : J. Nat. Prod.
Title : Macrocarpals H, I, and J from the Leaves of Eucalyptus globulus.
Year : 1996
Volume : 59
Issue : 9
First Page : 823
Last Page : 827
Authors : Osawa K, Yasuda H, Morita H, Takeya K, Itokawa H.
Abstract : A 50% EtOH extract of Eucalyptus globulus leaves yielded eight phloroglucinol--sesquiterpene-coupled constituents, including three novel compounds named macrocarpals, H, I, and J. Some of these compounds possessed antibacterial activity against oral pathogenic microorganisms with MIC values ranging from 0.20 micrograms/mL to 6.25 micrograms/mL. Inhibition of glucosyltransferase activity by these compounds was also noted.
|
Inhibition of Streptococcus sobrinus glucosyltransferase assessed as blockade of adherent water insoluble glucan synthesis at 1 ug/mL
|
Streptococcus sobrinus
|
3.0
%
|
|
Journal : J. Nat. Prod.
Title : Macrocarpals H, I, and J from the Leaves of Eucalyptus globulus.
Year : 1996
Volume : 59
Issue : 9
First Page : 823
Last Page : 827
Authors : Osawa K, Yasuda H, Morita H, Takeya K, Itokawa H.
Abstract : A 50% EtOH extract of Eucalyptus globulus leaves yielded eight phloroglucinol--sesquiterpene-coupled constituents, including three novel compounds named macrocarpals, H, I, and J. Some of these compounds possessed antibacterial activity against oral pathogenic microorganisms with MIC values ranging from 0.20 micrograms/mL to 6.25 micrograms/mL. Inhibition of glucosyltransferase activity by these compounds was also noted.
|
Inhibition of rat squalene epoxidase
|
Rattus norvegicus
|
690.0
nM
|
|
Journal : J. Nat. Prod.
Title : Ellagitannins and hexahydroxydiphenoyl esters as inhibitors of vertebrate squalene epoxidase.
Year : 2001
Volume : 64
Issue : 8
First Page : 1010
Last Page : 1014
Authors : Abe I, Kashiwagi Y, Noguchi H, Tanaka T, Ikeshiro Y, Kashiwada Y.
Abstract : Ellagitannins isolated from various plant sources as well as newly synthesized n-alkyl (C(1)-C(18)) esters of hexahydroxydiphenyl (HHDP) dicarboxylic acid were evaluated as enzyme inhibitors of recombinant rat squalene epoxidase, a rate-limiting enzyme of cholesterol biosynthesis. Among the ellagitannins tested, pedunculagin (IC(50) = 2.0 microM) and eugeniin (IC(50) = 1.6 microM), both containing (S)-HHDP ester group(s), showed remarkable inhibition, which was more potent than those of previously reported substrate analogue inhibitors. Furthermore, ellagic acid (IC(50) = 2.0 microM), a bislactone formed by hydrolytic release of a HHDP group from ellagitannins, was also a good inhibitor of the enzyme. On the other hand, the synthetic HHDP esters with C(6) (IC(50) = 0.93 microM) and C(8) alkyl side chains (IC(50) = 0.83 microM) showed potent enzyme inhibition at the submicromolar concentration range, while esters with shorter chain lengths (C(1)-C(4)) and a C(18) ester exhibited moderate inhibition (IC(50) = 8-47 microM).
|
Antioxidant activity assessed as DPPH radical scavenging activity
|
None
|
5.6
ug.mL-1
|
|
Journal : J. Nat. Prod.
Title : Antioxidant benzoylated flavan-3-ol glycoside from Celastrus orbiculatus.
Year : 2001
Volume : 64
Issue : 1
First Page : 82
Last Page : 84
Authors : Hwang BY, Kim HS, Lee JH, Hong YS, Ro JS, Lee KS, Lee JJ.
Abstract : A new flavan-3-ol glycoside, (-)-epicatechin-5-O-beta-D-glucosyl-3-benzoate (1), and two known compounds, (-)-epicatechin and (-)-epiafzelechin, were isolated from an EtOAc extract of Celastrus orbiculatus aerial parts that exhibited significant antioxidant effect in a 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical assay. The structure of 1 was elucidated by spectroscopic analyses, and compound 1 and its aglycon, (-)-epicatechin-3-benzoate (2), were found to be moderately active as antioxidants in the DPPH assay.
|
Neuroprotection against beta-amyloid peptide 1-42-induced toxicity in human SH-SY5Y cells assessed as lactate dehydrogenase release
|
Homo sapiens
|
39.87
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Neuroprotective activity and evaluation of Hsp90 inhibitors in an immortalized neuronal cell line.
Year : 2009
Volume : 17
Issue : 4
First Page : 1709
Last Page : 1715
Authors : Lu Y, Ansar S, Michaelis ML, Blagg BS.
Abstract : Alzheimer's disease (AD) neuropathology is characterized by loss of synapses and neurons, neuritic plaques consisting of beta-amyloid (Abeta) peptides, and neurofibrillary tangles consisting of intracellular aggregates of hyperphosphorylated tau protein in susceptible brain regions. Abeta oligomers trigger a cascade of pathogenic events including tau hyperphosphorylation and aggregation, inflammatory reactions, and excitotoxicity that contribute to the progression of AD. The molecular chaperone Hsp90 facilitates the folding of newly synthesized and denatured proteins and is believed to play a role in neurodegenerative disorders in which the defining pathology results in misfolded proteins and the accumulation of protein aggregates. Some agents that inhibit Hsp90 protect neurons against Abeta toxicity and tau aggregation, and assays for rapidly screening potential Hsp90 inhibitors are of interest. We used the release of the soluble cytosolic enzyme lactate dehydrogenase (LDH) as an indicator of the loss of cell membrane integrity and cytotoxicity resulting from exposure to Abeta peptides to evaluate the neuroprotective properties of novel novobiocin analogues and established Hsp90 inhibitors. Compounds were assessed for potency in protecting proliferating and differentiated SH-SY5Y neuronal cells against Abeta-induced cell death; the potential toxicity of each agent alone was also determined. The data indicated that several of the compounds decreased Abeta toxicity even at low nanomolar concentrations and, unexpectedly, were more potent in protecting the undifferentiated cells against Abeta. The novobiocin analogues alone were not toxic even up to 10 microM concentrations whereas GDA and the parent compound, novobiocin, were toxic at 1 and 10 microM, respectively. The results suggest that novobiocin analogues may provide novel leads for the development of neuroprotective drugs.
|
Anti-aging activity in human dermal fibroblasts assessed as inhibition rate of MMP1 expression at 10 uM relative to control
|
Homo sapiens
|
46.7
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and in vitro biological activity of retinyl polyhydroxybenzoates, novel hybrid retinoid derivatives.
Year : 2009
Volume : 19
Issue : 2
First Page : 508
Last Page : 512
Authors : Kim S, Kim Y, Kong Y, Kim H, Kang J.
Abstract : A new hybrid derived from retinol was designed to improve the stability and anti-oxidant activity of retinol and also to add whitening properties besides its usual anti-aging properties. A variety of polyhydroxybenzoates of retinol were prepared either by base-catalysis or by direct esterification of retinol and screened for such desirable properties by analyzing the in vitro biological activity of the hybrids. Some of the retinol derivatives enhanced their thermal stability and decreased photosensitivity, and exhibited an activity in collagen synthesis similar to that of retinol. In addition, the retinyl gallate 6 showed higher activities in free radical scavenging and melanogenesis inhibition than retinol. Thus, owing to its excellent stabilities, retinyl gallate 6 may be conveniently used not only as an additive for cosmetics for prevention and improvement of skin aging and whitening but also as medicine for the treatment of skin troubles.
|
Inhibition of TPA-induced EBV-early antigen activation in human Raji cells assessed as EA activation at 1000 molar ratio after 48 hrs relative to TPA
|
Human herpesvirus 4
|
6.4
%
|
|
Journal : J. Nat. Prod.
Title : Dimeric flavonol glycoside and galloylated C-glucosylchromones from Kunzea ambigua.
Year : 2004
Volume : 67
Issue : 3
First Page : 411
Last Page : 415
Authors : Ito H, Kasajima N, Tokuda H, Nishino H, Yoshida T.
Abstract : A novel dimeric flavonol glycoside linked through a methylene group, kunzeagin A (1), and six new chromone C-glucosides, kunzeachromones A-F (2-7), were isolated along with seven known compounds from the leaf extract of Kunzea ambigua. The structures of these compounds were elucidated on the basis of spectroscopic analyses and chemical properties. Kunzeachromones A-F provided additional examples of galloylated C-glucosidic chromones occurring in the Myrtaceae. Kunzeagin A (1) and major constituents of this plant (6-C- and 8-C-glucosylchromones and their monogallates) exhibited potent inhibitory effects on activation of Epstein-Barr virus early antigen induced by 12-O-tetradecanoylphorbol 13-acetate in Raji cells.
|
Inhibition of TPA-induced EBV-early antigen activation in human Raji cells assessed as EA activation at 500 molar ratio after 48 hrs relative to TPA
|
Human herpesvirus 4
|
34.9
%
|
|
Journal : J. Nat. Prod.
Title : Dimeric flavonol glycoside and galloylated C-glucosylchromones from Kunzea ambigua.
Year : 2004
Volume : 67
Issue : 3
First Page : 411
Last Page : 415
Authors : Ito H, Kasajima N, Tokuda H, Nishino H, Yoshida T.
Abstract : A novel dimeric flavonol glycoside linked through a methylene group, kunzeagin A (1), and six new chromone C-glucosides, kunzeachromones A-F (2-7), were isolated along with seven known compounds from the leaf extract of Kunzea ambigua. The structures of these compounds were elucidated on the basis of spectroscopic analyses and chemical properties. Kunzeachromones A-F provided additional examples of galloylated C-glucosidic chromones occurring in the Myrtaceae. Kunzeagin A (1) and major constituents of this plant (6-C- and 8-C-glucosylchromones and their monogallates) exhibited potent inhibitory effects on activation of Epstein-Barr virus early antigen induced by 12-O-tetradecanoylphorbol 13-acetate in Raji cells.
|
Inhibition of TPA-induced EBV-early antigen activation in human Raji cells assessed as EA activation at 100 molar ratio after 48 hrs relative to TPA
|
Human herpesvirus 4
|
68.1
%
|
|
Journal : J. Nat. Prod.
Title : Dimeric flavonol glycoside and galloylated C-glucosylchromones from Kunzea ambigua.
Year : 2004
Volume : 67
Issue : 3
First Page : 411
Last Page : 415
Authors : Ito H, Kasajima N, Tokuda H, Nishino H, Yoshida T.
Abstract : A novel dimeric flavonol glycoside linked through a methylene group, kunzeagin A (1), and six new chromone C-glucosides, kunzeachromones A-F (2-7), were isolated along with seven known compounds from the leaf extract of Kunzea ambigua. The structures of these compounds were elucidated on the basis of spectroscopic analyses and chemical properties. Kunzeachromones A-F provided additional examples of galloylated C-glucosidic chromones occurring in the Myrtaceae. Kunzeagin A (1) and major constituents of this plant (6-C- and 8-C-glucosylchromones and their monogallates) exhibited potent inhibitory effects on activation of Epstein-Barr virus early antigen induced by 12-O-tetradecanoylphorbol 13-acetate in Raji cells.
|
Inhibition of TPA-induced EBV-early antigen activation in human Raji cells assessed as EA activation at 10 molar ratio after 48 hrs relative to TPA
|
Human herpesvirus 4
|
87.7
%
|
|
Journal : J. Nat. Prod.
Title : Dimeric flavonol glycoside and galloylated C-glucosylchromones from Kunzea ambigua.
Year : 2004
Volume : 67
Issue : 3
First Page : 411
Last Page : 415
Authors : Ito H, Kasajima N, Tokuda H, Nishino H, Yoshida T.
Abstract : A novel dimeric flavonol glycoside linked through a methylene group, kunzeagin A (1), and six new chromone C-glucosides, kunzeachromones A-F (2-7), were isolated along with seven known compounds from the leaf extract of Kunzea ambigua. The structures of these compounds were elucidated on the basis of spectroscopic analyses and chemical properties. Kunzeachromones A-F provided additional examples of galloylated C-glucosidic chromones occurring in the Myrtaceae. Kunzeagin A (1) and major constituents of this plant (6-C- and 8-C-glucosylchromones and their monogallates) exhibited potent inhibitory effects on activation of Epstein-Barr virus early antigen induced by 12-O-tetradecanoylphorbol 13-acetate in Raji cells.
|
Inhibition of COX2 at 25 uM
|
None
|
13.0
%
|
|
Journal : J. Nat. Prod.
Title : Expanding the ChemGPS chemical space with natural products.
Year : 2005
Volume : 68
Issue : 7
First Page : 985
Last Page : 991
Authors : Larsson J, Gottfries J, Bohlin L, Backlund A.
Abstract : Recently various attempts have been made to increase the efficacy and precision of chemical libraries used in high-throughput screening (HTS) drug discovery approaches. One such approach is ChemGPS, which provides a defined chemical space for prescreening evaluation of chemical compound properties or virtual dereplication. In the present study, ChemGPS has been applied to a set of natural products shown to exhibit cyclooxygenase-1 and/or -2 (COX-1/2) inhibition. With the purpose of defining chemical properties and linking these to the observed mode of enzyme inhibition, this resulted in two lines of reasoning. On one hand several specific features of these compounds have been identified and discussed. Overall COX inhibition was frequently correlated with the presence of at least one ring in the structure, fragments exhibiting structural rigidity, and a relatively large molecular size. The concept "size" includes several parameters, e.g., molecular volume, weight, and number of bonds. On the other hand, and possibly even more important, was the unexpected finding that the natural products studied to a large extent fell outside the defined ChemGPS chemical space. Therefore, we also propose an expanded space for natural products: ChemGPS-NP.
|
Inhibition of COX1 at 30 ug/mL
|
None
|
51.0
%
|
|
Journal : J. Nat. Prod.
Title : Expanding the ChemGPS chemical space with natural products.
Year : 2005
Volume : 68
Issue : 7
First Page : 985
Last Page : 991
Authors : Larsson J, Gottfries J, Bohlin L, Backlund A.
Abstract : Recently various attempts have been made to increase the efficacy and precision of chemical libraries used in high-throughput screening (HTS) drug discovery approaches. One such approach is ChemGPS, which provides a defined chemical space for prescreening evaluation of chemical compound properties or virtual dereplication. In the present study, ChemGPS has been applied to a set of natural products shown to exhibit cyclooxygenase-1 and/or -2 (COX-1/2) inhibition. With the purpose of defining chemical properties and linking these to the observed mode of enzyme inhibition, this resulted in two lines of reasoning. On one hand several specific features of these compounds have been identified and discussed. Overall COX inhibition was frequently correlated with the presence of at least one ring in the structure, fragments exhibiting structural rigidity, and a relatively large molecular size. The concept "size" includes several parameters, e.g., molecular volume, weight, and number of bonds. On the other hand, and possibly even more important, was the unexpected finding that the natural products studied to a large extent fell outside the defined ChemGPS chemical space. Therefore, we also propose an expanded space for natural products: ChemGPS-NP.
|
Inhibition of human neutrophil elastase at 1 uM
|
Homo sapiens
|
26.6
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Evaluation of human neutrophil elastase inhibitory effect of iridoid glycosides from Hedyotis diffusa.
Year : 2010
Volume : 20
Issue : 2
First Page : 513
Last Page : 515
Authors : Xu GH, Kim YH, Chi SW, Choo SJ, Ryoo IJ, Ahn JS, Yoo ID.
Abstract : Five iridoid glycosides were isolated from the MeOH extract of Hedyotis diffusa, and their structures were elucidated as E-6-O-p-methoxycinnamoyl scandoside methyl ester (1), Z-6-O-p-methoxycinnamoyl scandoside methyl ester (2), E-6-O-p-feruloyl scandoside methyl ester (3), E-6-O-p-coumaroyl scandoside methyl ester (4), and Z-6-O-p-coumaroyl scandoside methyl ester (5) by interpretation of their spectroscopic data. All the isolated compounds were evaluated for human neutrophil elastase inhibitory effect, and compound 1 showed potent activity with an IC(50) value of 18.0muM. The molecular docking simulation suggested a structural model for the inhibition of human neutrophil elastase by compound 1.
|
Inhibition of human neutrophil elastase at 3 uM
|
Homo sapiens
|
41.3
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Evaluation of human neutrophil elastase inhibitory effect of iridoid glycosides from Hedyotis diffusa.
Year : 2010
Volume : 20
Issue : 2
First Page : 513
Last Page : 515
Authors : Xu GH, Kim YH, Chi SW, Choo SJ, Ryoo IJ, Ahn JS, Yoo ID.
Abstract : Five iridoid glycosides were isolated from the MeOH extract of Hedyotis diffusa, and their structures were elucidated as E-6-O-p-methoxycinnamoyl scandoside methyl ester (1), Z-6-O-p-methoxycinnamoyl scandoside methyl ester (2), E-6-O-p-feruloyl scandoside methyl ester (3), E-6-O-p-coumaroyl scandoside methyl ester (4), and Z-6-O-p-coumaroyl scandoside methyl ester (5) by interpretation of their spectroscopic data. All the isolated compounds were evaluated for human neutrophil elastase inhibitory effect, and compound 1 showed potent activity with an IC(50) value of 18.0muM. The molecular docking simulation suggested a structural model for the inhibition of human neutrophil elastase by compound 1.
|
Inhibition of human neutrophil elastase at 10 uM
|
Homo sapiens
|
63.6
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Evaluation of human neutrophil elastase inhibitory effect of iridoid glycosides from Hedyotis diffusa.
Year : 2010
Volume : 20
Issue : 2
First Page : 513
Last Page : 515
Authors : Xu GH, Kim YH, Chi SW, Choo SJ, Ryoo IJ, Ahn JS, Yoo ID.
Abstract : Five iridoid glycosides were isolated from the MeOH extract of Hedyotis diffusa, and their structures were elucidated as E-6-O-p-methoxycinnamoyl scandoside methyl ester (1), Z-6-O-p-methoxycinnamoyl scandoside methyl ester (2), E-6-O-p-feruloyl scandoside methyl ester (3), E-6-O-p-coumaroyl scandoside methyl ester (4), and Z-6-O-p-coumaroyl scandoside methyl ester (5) by interpretation of their spectroscopic data. All the isolated compounds were evaluated for human neutrophil elastase inhibitory effect, and compound 1 showed potent activity with an IC(50) value of 18.0muM. The molecular docking simulation suggested a structural model for the inhibition of human neutrophil elastase by compound 1.
|
Inhibition of human neutrophil elastase at 30 uM
|
Homo sapiens
|
71.4
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Evaluation of human neutrophil elastase inhibitory effect of iridoid glycosides from Hedyotis diffusa.
Year : 2010
Volume : 20
Issue : 2
First Page : 513
Last Page : 515
Authors : Xu GH, Kim YH, Chi SW, Choo SJ, Ryoo IJ, Ahn JS, Yoo ID.
Abstract : Five iridoid glycosides were isolated from the MeOH extract of Hedyotis diffusa, and their structures were elucidated as E-6-O-p-methoxycinnamoyl scandoside methyl ester (1), Z-6-O-p-methoxycinnamoyl scandoside methyl ester (2), E-6-O-p-feruloyl scandoside methyl ester (3), E-6-O-p-coumaroyl scandoside methyl ester (4), and Z-6-O-p-coumaroyl scandoside methyl ester (5) by interpretation of their spectroscopic data. All the isolated compounds were evaluated for human neutrophil elastase inhibitory effect, and compound 1 showed potent activity with an IC(50) value of 18.0muM. The molecular docking simulation suggested a structural model for the inhibition of human neutrophil elastase by compound 1.
|
Inhibition of human neutrophil elastase at 100 uM
|
Homo sapiens
|
78.4
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Evaluation of human neutrophil elastase inhibitory effect of iridoid glycosides from Hedyotis diffusa.
Year : 2010
Volume : 20
Issue : 2
First Page : 513
Last Page : 515
Authors : Xu GH, Kim YH, Chi SW, Choo SJ, Ryoo IJ, Ahn JS, Yoo ID.
Abstract : Five iridoid glycosides were isolated from the MeOH extract of Hedyotis diffusa, and their structures were elucidated as E-6-O-p-methoxycinnamoyl scandoside methyl ester (1), Z-6-O-p-methoxycinnamoyl scandoside methyl ester (2), E-6-O-p-feruloyl scandoside methyl ester (3), E-6-O-p-coumaroyl scandoside methyl ester (4), and Z-6-O-p-coumaroyl scandoside methyl ester (5) by interpretation of their spectroscopic data. All the isolated compounds were evaluated for human neutrophil elastase inhibitory effect, and compound 1 showed potent activity with an IC(50) value of 18.0muM. The molecular docking simulation suggested a structural model for the inhibition of human neutrophil elastase by compound 1.
|
Inhibition of reduced carboxymethylated kappa-casein fibril formation at 50 ug/mL measured every 5 mins after 1000 mins by thioflavin T staining-based binding assay
|
None
|
100.0
%
|
|
Journal : Bioorg. Med. Chem.
Title : Carboxymethylated-kappa-casein: a convenient tool for the identification of polyphenolic inhibitors of amyloid fibril formation.
Year : 2010
Volume : 18
Issue : 1
First Page : 222
Last Page : 228
Authors : Carver JA, Duggan PJ, Ecroyd H, Liu Y, Meyer AG, Tranberg CE.
Abstract : Reduced and carboxymethylated-kappa-casein (RCM-kappa-CN) is a milk-derived amyloidogenic protein that readily undergoes nucleation-dependent aggregation and amyloid fibril formation via a similar pathway to disease-specific amyloidogenic peptides like amyloid beta (Abeta), which is associated with Alzheimer's disease. In this study, a series of flavonoids, many known to be inhibitors of Abeta fibril formation, were screened for their ability to inhibit RCM-kappa-CN fibrilisation, and the results were compared with literature data on Abeta inhibition. Flavonoids that had a high degree of hydroxylation and molecular planarity gave good inhibition of RCM-kappa-CN fibril formation. IC(50) values were between 10- and 200-fold higher with RCM-kappa-CN than literature results for Abeta fibril inhibition, however, with few exceptions, they showed a similar trend in potency. The convenience and reproducibility of the RCM-kappa-CN assay make it an economic alternative first screen for Abeta inhibitory activity, especially for use with large compound libraries.
|
Inhibition of beta amyloid (1 to 42) fibril formation at 50 ug/mL by thioflavin T staining-based binding assay
|
None
|
100.0
%
|
|
Journal : Bioorg. Med. Chem.
Title : Carboxymethylated-kappa-casein: a convenient tool for the identification of polyphenolic inhibitors of amyloid fibril formation.
Year : 2010
Volume : 18
Issue : 1
First Page : 222
Last Page : 228
Authors : Carver JA, Duggan PJ, Ecroyd H, Liu Y, Meyer AG, Tranberg CE.
Abstract : Reduced and carboxymethylated-kappa-casein (RCM-kappa-CN) is a milk-derived amyloidogenic protein that readily undergoes nucleation-dependent aggregation and amyloid fibril formation via a similar pathway to disease-specific amyloidogenic peptides like amyloid beta (Abeta), which is associated with Alzheimer's disease. In this study, a series of flavonoids, many known to be inhibitors of Abeta fibril formation, were screened for their ability to inhibit RCM-kappa-CN fibrilisation, and the results were compared with literature data on Abeta inhibition. Flavonoids that had a high degree of hydroxylation and molecular planarity gave good inhibition of RCM-kappa-CN fibril formation. IC(50) values were between 10- and 200-fold higher with RCM-kappa-CN than literature results for Abeta fibril inhibition, however, with few exceptions, they showed a similar trend in potency. The convenience and reproducibility of the RCM-kappa-CN assay make it an economic alternative first screen for Abeta inhibitory activity, especially for use with large compound libraries.
|
Inhibition of beta amyloid (1 to 40) fibril formation
|
None
|
180.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Carboxymethylated-kappa-casein: a convenient tool for the identification of polyphenolic inhibitors of amyloid fibril formation.
Year : 2010
Volume : 18
Issue : 1
First Page : 222
Last Page : 228
Authors : Carver JA, Duggan PJ, Ecroyd H, Liu Y, Meyer AG, Tranberg CE.
Abstract : Reduced and carboxymethylated-kappa-casein (RCM-kappa-CN) is a milk-derived amyloidogenic protein that readily undergoes nucleation-dependent aggregation and amyloid fibril formation via a similar pathway to disease-specific amyloidogenic peptides like amyloid beta (Abeta), which is associated with Alzheimer's disease. In this study, a series of flavonoids, many known to be inhibitors of Abeta fibril formation, were screened for their ability to inhibit RCM-kappa-CN fibrilisation, and the results were compared with literature data on Abeta inhibition. Flavonoids that had a high degree of hydroxylation and molecular planarity gave good inhibition of RCM-kappa-CN fibril formation. IC(50) values were between 10- and 200-fold higher with RCM-kappa-CN than literature results for Abeta fibril inhibition, however, with few exceptions, they showed a similar trend in potency. The convenience and reproducibility of the RCM-kappa-CN assay make it an economic alternative first screen for Abeta inhibitory activity, especially for use with large compound libraries.
|
Inhibition of chymotrypsin like activity of proteasome
|
None
|
86.0
nM
|
|
Inhibition of chymotrypsin like activity of proteasome
|
None
|
170.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Proteasome inhibition in human breast cancer cells with high catechol-O-methyltransferase activity by green tea polyphenol EGCG analogs.
Year : 2010
Volume : 18
Issue : 3
First Page : 1252
Last Page : 1258
Authors : Huo C, Yang H, Cui QC, Dou QP, Chan TH.
Abstract : A pro-drug 8 of a synthetic analog 7 is more active in its antiproliferative activity against human breast cancer MDA-MB-231 cells possessing high catechol-O-methyltransferase (COMT) activity than the pro-drugs of EGCG and the analog 5. The higher activity of 8 is attributed to it not being a substrate of COMT.
|
Inhibition of chymotrypsin like activity of 20S proteasome in human MDA-MB-231 cells lysates with high catechol-O-methyltransferase activity assessed as cleavage of Suc-LLVY-AMC substrate at 10 uM after 2 hrs by fluorogenic assay
|
Homo sapiens
|
22.0
%
|
|
Journal : Bioorg. Med. Chem.
Title : Proteasome inhibition in human breast cancer cells with high catechol-O-methyltransferase activity by green tea polyphenol EGCG analogs.
Year : 2010
Volume : 18
Issue : 3
First Page : 1252
Last Page : 1258
Authors : Huo C, Yang H, Cui QC, Dou QP, Chan TH.
Abstract : A pro-drug 8 of a synthetic analog 7 is more active in its antiproliferative activity against human breast cancer MDA-MB-231 cells possessing high catechol-O-methyltransferase (COMT) activity than the pro-drugs of EGCG and the analog 5. The higher activity of 8 is attributed to it not being a substrate of COMT.
|
Inhibition of osteoclastogenesis in RANKL-stimulated mouse osteoclast at 10 uM
|
Mus musculus
|
17.0
%
|
|
Journal : J. Med. Chem.
Title : Emerging targets in osteoporosis disease modification.
Year : 2010
Volume : 53
Issue : 11
First Page : 4332
Last Page : 4353
Authors : Allen JG, Fotsch C, Babij P.
|
Inhibition of osteoclastogenesis in RANKL-stimulated mouse osteoclast at 20 uM
|
Mus musculus
|
32.0
%
|
|
Journal : J. Med. Chem.
Title : Emerging targets in osteoporosis disease modification.
Year : 2010
Volume : 53
Issue : 11
First Page : 4332
Last Page : 4353
Authors : Allen JG, Fotsch C, Babij P.
|
Inhibition of Plasmodium falciparum FabZ by spectrophotometric analysis
|
Plasmodium falciparum
|
0.03
ug.mL-1
|
|
Journal : Bioorg. Med. Chem.
Title : 2-Hexadecynoic acid inhibits plasmodial FAS-II enzymes and arrests erythrocytic and liver stage Plasmodium infections.
Year : 2010
Volume : 18
Issue : 21
First Page : 7475
Last Page : 7485
Authors : Tasdemir D, Sanabria D, Lauinger IL, Tarun A, Herman R, Perozzo R, Zloh M, Kappe SH, Brun R, Carballeira NM.
Abstract : Acetylenic fatty acids are known to display several biological activities, but their antimalarial activity has remained unexplored. In this study, we synthesized the 2-, 5-, 6-, and 9-hexadecynoic acids (HDAs) and evaluated their in vitro activity against erythrocytic (blood) stages of Plasmodium falciparum and liver stages of Plasmodium yoelii infections. Since the type II fatty acid biosynthesis pathway (PfFAS-II) has recently been shown to be indispensable for liver stage malaria parasites, the inhibitory potential of the HDAs against multiple P. falciparum FAS-II (PfFAS-II) elongation enzymes was also evaluated. The highest antiplasmodial activity against blood stages of P. falciparum was displayed by 5-HDA (IC(50) value 6.6 μg/ml), whereas the 2-HDA was the only acid arresting the growth of liver stage P. yoelii infection, in both flow cytometric assay (IC(50) value 2-HDA 15.3 μg/ml, control drug atovaquone 2.5 ng/ml) and immunofluorescence analysis (IC(50) 2-HDA 4.88 μg/ml, control drug atovaquone 0.37 ng/ml). 2-HDA showed the best inhibitory activity against the PfFAS-II enzymes PfFabI and PfFabZ with IC(50) values of 0.38 and 0.58 μg/ml (IC(50) control drugs 14 and 30 ng/ml), respectively. Enzyme kinetics and molecular modeling studies revealed valuable insights into the binding mechanism of 2-HDA on the target enzymes. All HDAs showed in vitro activity against Trypanosoma brucei rhodesiense (IC(50) values 3.7-31.7 μg/ml), Trypanosoma cruzi (only 2-HDA, IC(50) 20.2 μg/ml), and Leishmania donovani (IC(50) values 4.1-13.4 μg/ml) with generally low or no significant toxicity on mammalian cells. This is the first study to indicate therapeutic potential of HDAs against various parasitic protozoa. It also points out that the malarial liver stage growth inhibitory effect of the 2-HDA may be promoted via PfFAS-II enzymes. The lack of cytotoxicity, lipophilic nature, and calculated pharmacokinetic properties suggests that 2-HDA could be a useful compound to study the interaction of fatty acids with these key P. falciparum enzymes.
|
Inhibition of Plasmodium falciparum FabG by spectrophotometric analysis
|
Plasmodium falciparum
|
0.32
ug.mL-1
|
|
Journal : Bioorg. Med. Chem.
Title : 2-Hexadecynoic acid inhibits plasmodial FAS-II enzymes and arrests erythrocytic and liver stage Plasmodium infections.
Year : 2010
Volume : 18
Issue : 21
First Page : 7475
Last Page : 7485
Authors : Tasdemir D, Sanabria D, Lauinger IL, Tarun A, Herman R, Perozzo R, Zloh M, Kappe SH, Brun R, Carballeira NM.
Abstract : Acetylenic fatty acids are known to display several biological activities, but their antimalarial activity has remained unexplored. In this study, we synthesized the 2-, 5-, 6-, and 9-hexadecynoic acids (HDAs) and evaluated their in vitro activity against erythrocytic (blood) stages of Plasmodium falciparum and liver stages of Plasmodium yoelii infections. Since the type II fatty acid biosynthesis pathway (PfFAS-II) has recently been shown to be indispensable for liver stage malaria parasites, the inhibitory potential of the HDAs against multiple P. falciparum FAS-II (PfFAS-II) elongation enzymes was also evaluated. The highest antiplasmodial activity against blood stages of P. falciparum was displayed by 5-HDA (IC(50) value 6.6 μg/ml), whereas the 2-HDA was the only acid arresting the growth of liver stage P. yoelii infection, in both flow cytometric assay (IC(50) value 2-HDA 15.3 μg/ml, control drug atovaquone 2.5 ng/ml) and immunofluorescence analysis (IC(50) 2-HDA 4.88 μg/ml, control drug atovaquone 0.37 ng/ml). 2-HDA showed the best inhibitory activity against the PfFAS-II enzymes PfFabI and PfFabZ with IC(50) values of 0.38 and 0.58 μg/ml (IC(50) control drugs 14 and 30 ng/ml), respectively. Enzyme kinetics and molecular modeling studies revealed valuable insights into the binding mechanism of 2-HDA on the target enzymes. All HDAs showed in vitro activity against Trypanosoma brucei rhodesiense (IC(50) values 3.7-31.7 μg/ml), Trypanosoma cruzi (only 2-HDA, IC(50) 20.2 μg/ml), and Leishmania donovani (IC(50) values 4.1-13.4 μg/ml) with generally low or no significant toxicity on mammalian cells. This is the first study to indicate therapeutic potential of HDAs against various parasitic protozoa. It also points out that the malarial liver stage growth inhibitory effect of the 2-HDA may be promoted via PfFAS-II enzymes. The lack of cytotoxicity, lipophilic nature, and calculated pharmacokinetic properties suggests that 2-HDA could be a useful compound to study the interaction of fatty acids with these key P. falciparum enzymes.
|
PUBCHEM_BIOASSAY: Fluorescent Polarization Homogeneous Dose Response HTS to Identify Inhibitors of Mex-5 Binding to TCR-2. (Class of assay: confirmatory) [Related pubchem assays: 1833 (Project Summary), 1832 (Primary HTS)]
|
Caenorhabditis elegans
|
727.0
nM
|
|
Title : PubChem BioAssay data set
|
Cytotoxicity against African green monkey Vero cells assessed as viability at 100 uM after 24 hrs
|
Chlorocebus sabaeus
|
80.0
%
|
|
Journal : Antimicrob. Agents Chemother.
Title : Epigallocatechin gallate inactivates clinical isolates of herpes simplex virus.
Year : 2008
Volume : 52
Issue : 3
First Page : 962
Last Page : 970
Authors : Isaacs CE, Wen GY, Xu W, Jia JH, Rohan L, Corbo C, Di Maggio V, Jenkins EC, Hillier S.
Abstract : In the absence of a fully effective herpes simplex virus (HSV) vaccine, topical microbicides represent an important strategy for preventing HSV transmission. (-)-Epigallocatechin gallate (EGCG) (molecular weight, 458.4) is the primary catechin in green tea. The present study shows that EGCG has greater anti-HSV activity than other green tea catechins and inactivates multiple clinical isolates of HSV type 1 (HSV-1) and HSV-2. EGCG reduced HSV-2 titers by >or=1,000-fold in 10 to 20 min and reduced HSV-1 titers by the same amount in 30 to 40 min. The anti-HSV activity of EGCG is due to a direct effect on the virion, and incubating Vero and CV1 cells with EGCG for 48 h prior to infection with HSV-1 and HSV-2, respectively, does not reduce HSV production. Electron microscopic (EM) studies showed that purified virions exposed to EGCG were damaged, and EM immunogold labeling of the envelope glycoproteins gB and gD was significantly reduced following EGCG treatment while capsid protein labeling was unchanged. When purified HSV-1 envelope glycoproteins gB and gD were incubated with EGCG and then examined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, lower-molecular-weight gB and gD bands decreased and new higher-molecular-weight bands appeared, indicating the EGCG-dependent production of macromolecular complexes. gB and gD are essential for HSV infectivity, and these results suggest that EGCG could inactivate HSV virions by binding to gB, gD, or another envelope glycoprotein. EGCG is stable in the pH range found in the vagina and appears to be a promising candidate for use in a microbicide to reduce HSV transmission.
|
Cytotoxicity against African green monkey CV1 cells assessed as viability at 100 uM after 24 hrs
|
Chlorocebus aethiops
|
97.0
%
|
|
Journal : Antimicrob. Agents Chemother.
Title : Epigallocatechin gallate inactivates clinical isolates of herpes simplex virus.
Year : 2008
Volume : 52
Issue : 3
First Page : 962
Last Page : 970
Authors : Isaacs CE, Wen GY, Xu W, Jia JH, Rohan L, Corbo C, Di Maggio V, Jenkins EC, Hillier S.
Abstract : In the absence of a fully effective herpes simplex virus (HSV) vaccine, topical microbicides represent an important strategy for preventing HSV transmission. (-)-Epigallocatechin gallate (EGCG) (molecular weight, 458.4) is the primary catechin in green tea. The present study shows that EGCG has greater anti-HSV activity than other green tea catechins and inactivates multiple clinical isolates of HSV type 1 (HSV-1) and HSV-2. EGCG reduced HSV-2 titers by >or=1,000-fold in 10 to 20 min and reduced HSV-1 titers by the same amount in 30 to 40 min. The anti-HSV activity of EGCG is due to a direct effect on the virion, and incubating Vero and CV1 cells with EGCG for 48 h prior to infection with HSV-1 and HSV-2, respectively, does not reduce HSV production. Electron microscopic (EM) studies showed that purified virions exposed to EGCG were damaged, and EM immunogold labeling of the envelope glycoproteins gB and gD was significantly reduced following EGCG treatment while capsid protein labeling was unchanged. When purified HSV-1 envelope glycoproteins gB and gD were incubated with EGCG and then examined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, lower-molecular-weight gB and gD bands decreased and new higher-molecular-weight bands appeared, indicating the EGCG-dependent production of macromolecular complexes. gB and gD are essential for HSV infectivity, and these results suggest that EGCG could inactivate HSV virions by binding to gB, gD, or another envelope glycoprotein. EGCG is stable in the pH range found in the vagina and appears to be a promising candidate for use in a microbicide to reduce HSV transmission.
|
Anticancer activity against human PC3 cells xenografted in sc dosed SCID mouse assessed as inhibition of tumor growth at 80 mg/kg, ip qd for 14 days
|
Homo sapiens
|
32.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis and structure-activity relationship of 3-O-acylated (-)-epigallocatechins as 5α-reductase inhibitors.
Year : 2010
Volume : 45
Issue : 12
First Page : 6068
Last Page : 6076
Authors : Lin SF, Lin YH, Lin M, Kao YF, Wang RW, Teng LW, Chuang SH, Chang JM, Yuan TT, Fu KC, Huang KP, Lee YS, Chiang CC, Yang SC, Lai CL, Liao CB, Chen P, Lin YS, Lai KT, Huang HJ, Yang JY, Liu CW, Wei WY, Chen CK, Hiipakka RA, Liao S, Huang JJ.
Abstract : A series of 3-O-acylated (-)-epigallocatechins were synthesized and their inhibition of steroid 5α-reductase was studied. They were prepared from the reaction of EGCG with tert-butyldimethylsilyl chloride followed by reductive cleavage of the ester bond. The resultant (-)-epigallocatechins penta-O-tert-butyldimethylsilyl ether was esterified with different fatty acids then desilylated to provide the corresponding products. The activity of 3-O-acylated (-)-epigallocatechins increased with the increasing carbon numbers of the fatty acid moiety, reaching maximum for 16 carbon atoms (compound 4h) with an IC50 of 0.53 μM, which was ∼12-fold more potent than EGCG (IC50=6.29 μM). Introduction of monounsaturated fatty acid provided the most potent compound 6 (IC50=0.48 μM), which showed moderate anti-tumor activity in vivo.
|
Antiproliferative activity against rat HSC-T6 cells at 100 uM after 48 hrs by MTT assay
|
Rattus norvegicus
|
33.4
%
|
|
Journal : J. Nat. Prod.
Title : Antiproliferative triterpenes from the leaves and twigs of Juglans sinensis on HSC-T6 cells.
Year : 2011
Volume : 74
Issue : 4
First Page : 751
Last Page : 756
Authors : Yang H, Jeong EJ, Kim J, Sung SH, Kim YC.
Abstract : Bioassay-guided fractionation of an 80% MeOH extract of leaves and twigs of Juglan sinensis has resulted in the isolation of four new triterpenes (1-4) and 17 known triterpenes (5-21). The new compounds were determined to be 1-oxo-3β,23-dihydroxyolean-12-en-28-oic acid 28-O-β-D-glucopyranoside (1), 1-oxo-3β-hydroxyolean-18-ene (2), 3β,23-dihydroxyurs-12-en-28-oic acid 28-O-β-D-glucopyranoside (3), and 3β,22α-dihydroxyurs-12-en-28-oic acid 28-O-β-D-glucopyranoside (4) by spectroscopic analysis. Compounds 2, 13, 15, and 21 showed antiproliferative activities (14.2, 14.8, 15.6, and 11.0% at 100 μM, respectively) in HSC-T6 cells. Flow cytometry assays revealed that these compounds inhibited HSC-T6 proliferation by inducing apoptosis.
|
Antiproliferative activity against rat HSC-T6 cells at 10 uM after 48 hrs by MTT assay
|
Rattus norvegicus
|
83.8
%
|
|
Journal : J. Nat. Prod.
Title : Antiproliferative triterpenes from the leaves and twigs of Juglans sinensis on HSC-T6 cells.
Year : 2011
Volume : 74
Issue : 4
First Page : 751
Last Page : 756
Authors : Yang H, Jeong EJ, Kim J, Sung SH, Kim YC.
Abstract : Bioassay-guided fractionation of an 80% MeOH extract of leaves and twigs of Juglan sinensis has resulted in the isolation of four new triterpenes (1-4) and 17 known triterpenes (5-21). The new compounds were determined to be 1-oxo-3β,23-dihydroxyolean-12-en-28-oic acid 28-O-β-D-glucopyranoside (1), 1-oxo-3β-hydroxyolean-18-ene (2), 3β,23-dihydroxyurs-12-en-28-oic acid 28-O-β-D-glucopyranoside (3), and 3β,22α-dihydroxyurs-12-en-28-oic acid 28-O-β-D-glucopyranoside (4) by spectroscopic analysis. Compounds 2, 13, 15, and 21 showed antiproliferative activities (14.2, 14.8, 15.6, and 11.0% at 100 μM, respectively) in HSC-T6 cells. Flow cytometry assays revealed that these compounds inhibited HSC-T6 proliferation by inducing apoptosis.
|
Antiproliferative activity against rat HSC-T6 cells at 50 uM after 48 hrs by MTT assay
|
Rattus norvegicus
|
41.7
%
|
|
Journal : J. Nat. Prod.
Title : Antiproliferative triterpenes from the leaves and twigs of Juglans sinensis on HSC-T6 cells.
Year : 2011
Volume : 74
Issue : 4
First Page : 751
Last Page : 756
Authors : Yang H, Jeong EJ, Kim J, Sung SH, Kim YC.
Abstract : Bioassay-guided fractionation of an 80% MeOH extract of leaves and twigs of Juglan sinensis has resulted in the isolation of four new triterpenes (1-4) and 17 known triterpenes (5-21). The new compounds were determined to be 1-oxo-3β,23-dihydroxyolean-12-en-28-oic acid 28-O-β-D-glucopyranoside (1), 1-oxo-3β-hydroxyolean-18-ene (2), 3β,23-dihydroxyurs-12-en-28-oic acid 28-O-β-D-glucopyranoside (3), and 3β,22α-dihydroxyurs-12-en-28-oic acid 28-O-β-D-glucopyranoside (4) by spectroscopic analysis. Compounds 2, 13, 15, and 21 showed antiproliferative activities (14.2, 14.8, 15.6, and 11.0% at 100 μM, respectively) in HSC-T6 cells. Flow cytometry assays revealed that these compounds inhibited HSC-T6 proliferation by inducing apoptosis.
|
Inhibition of Influenza A/Udorn/72/H3N2 full length GST-tagged NS1A/FAM-double strand RNA-interaction at 50 uM after 1 hr by fluorescence polarization assay
|
Influenza A virus (A/udorn/1972(H3N2))
|
89.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and evaluation of quinoxaline derivatives as potential influenza NS1A protein inhibitors.
Year : 2011
Volume : 21
Issue : 10
First Page : 3007
Last Page : 3011
Authors : You L, Cho EJ, Leavitt J, Ma LC, Montelione GT, Anslyn EV, Krug RM, Ellington A, Robertus JD.
Abstract : A library of quinoxaline derivatives were prepared to target non-structural protein 1 of influenza A (NS1A) as a means to develop anti-influenza drug leads. An in vitro fluorescence polarization assay demonstrated that these compounds disrupted the dsRNA-NS1A interaction to varying extents. Changes of substituent at positions 2, 3 and 6 on the quinoxaline ring led to variance in responses. The most active compounds (35 and 44) had IC(50) values in the range of low micromolar concentration without exhibiting significant dsRNA intercalation. Compound 44 was able to inhibit influenza A/Udorn/72 virus growth.
|
Inhibition of GST-tagged human DYRK1A using dephosphorylated MBP as substrate at 10 uM after 10 mins by Kinase-Glo plus luminescent kinase assay
|
Homo sapiens
|
47.6
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of potent small molecule inhibitors of DYRK1A by structure-based virtual screening and bioassay.
Year : 2012
Volume : 22
Issue : 1
First Page : 168
Last Page : 171
Authors : Wang D, Wang F, Tan Y, Dong L, Chen L, Zhu W, Wang H.
Abstract : In this study, six novel dual-specificity tyrosine phosphorylation regulated kinase 1A (DYRK1A) inhibitors with IC(50) values ranging from 1.51 to 88.13 μM were successfully identified through virtual screening and in vitro plus cell based bioassay. Compound 5 with IC(50) value of 1.51 μM is the most potent hit against DYRK1A in vitro, while compound 3 exhibited the most potent activity in cultured cells. The inhibition mechanism was explored by molecular docking approach. This study may provide a start point for further mechanism based study as well as discovery of drug candidate against Down syndrome (DS).
|
Antiinflammatory activity in mouse RAW264.7 cells assessed as inhibition of LPS-induced MMP9 expression at 25 uM by Western blotting relative to control
|
Mus musculus
|
70.0
%
|
|
Journal : J. Nat. Prod.
Title : Phenolic substances from Phagnalon rupestre protect against 2,4,6-trinitrochlorobenzene-induced contact hypersensitivity.
Year : 2011
Volume : 74
Issue : 5
First Page : 1079
Last Page : 1084
Authors : Giner E, El Alami M, Máñez S, Recio MC, Ríos JL, Giner RM.
Abstract : 2-isoprenylhydroquinone-1-glucoside (1), 3,5-dicaffeoylquinic acid (2), and 3,5-dicaffeoylquinic acid methyl ester (3), isolated from Phagnalon rupestre, improved the contact hypersensitivity response to 2,4,6-trinitrochlorobenzene in mice. These phenolics reduced ear swelling and IL-1β content by 50% 24 h after challenge; in addition, 2 inhibited tumor necrosis factor-α by 53%. All three compounds also reduced interleukin-2 content by 50% 72 h after challenge. Both 2 and 3 inhibited metalloproteinase-9 levels in the skin lesions by 66% and 41%, respectively, and lowered cyclooxygenase-2 expression by 44% and 49%, respectively, at 24 h. Moreover, 2 was effective against atopic dermatitis induced by repeated application of 2,4,6-trinitrochlorobenzene; it attenuated edema by over 40% from day 7 and inhibited inflammatory cell infiltration by 44% at day 22. In addition, 1-3 reduced metalloproteinase-9 expression in a dose-dependent manner in macrophages RAW 264.7 stimulated with lipopolysaccharide. Thus, compounds 2 and 3 were found to exhibit a greater activity against contact hypersensitivity than 1.
|
Antiinflammatory activity in mouse RAW264.7 cells assessed as inhibition of LPS-induced MMP9 expression at 50 uM by Western blotting relative to control
|
Mus musculus
|
75.0
%
|
|
Journal : J. Nat. Prod.
Title : Phenolic substances from Phagnalon rupestre protect against 2,4,6-trinitrochlorobenzene-induced contact hypersensitivity.
Year : 2011
Volume : 74
Issue : 5
First Page : 1079
Last Page : 1084
Authors : Giner E, El Alami M, Máñez S, Recio MC, Ríos JL, Giner RM.
Abstract : 2-isoprenylhydroquinone-1-glucoside (1), 3,5-dicaffeoylquinic acid (2), and 3,5-dicaffeoylquinic acid methyl ester (3), isolated from Phagnalon rupestre, improved the contact hypersensitivity response to 2,4,6-trinitrochlorobenzene in mice. These phenolics reduced ear swelling and IL-1β content by 50% 24 h after challenge; in addition, 2 inhibited tumor necrosis factor-α by 53%. All three compounds also reduced interleukin-2 content by 50% 72 h after challenge. Both 2 and 3 inhibited metalloproteinase-9 levels in the skin lesions by 66% and 41%, respectively, and lowered cyclooxygenase-2 expression by 44% and 49%, respectively, at 24 h. Moreover, 2 was effective against atopic dermatitis induced by repeated application of 2,4,6-trinitrochlorobenzene; it attenuated edema by over 40% from day 7 and inhibited inflammatory cell infiltration by 44% at day 22. In addition, 1-3 reduced metalloproteinase-9 expression in a dose-dependent manner in macrophages RAW 264.7 stimulated with lipopolysaccharide. Thus, compounds 2 and 3 were found to exhibit a greater activity against contact hypersensitivity than 1.
|
Antiinflammatory activity in mouse RAW264.7 cells assessed as inhibition of LPS-induced MMP9 expression at 100 uM by Western blotting relative to control
|
Mus musculus
|
90.0
%
|
|
Journal : J. Nat. Prod.
Title : Phenolic substances from Phagnalon rupestre protect against 2,4,6-trinitrochlorobenzene-induced contact hypersensitivity.
Year : 2011
Volume : 74
Issue : 5
First Page : 1079
Last Page : 1084
Authors : Giner E, El Alami M, Máñez S, Recio MC, Ríos JL, Giner RM.
Abstract : 2-isoprenylhydroquinone-1-glucoside (1), 3,5-dicaffeoylquinic acid (2), and 3,5-dicaffeoylquinic acid methyl ester (3), isolated from Phagnalon rupestre, improved the contact hypersensitivity response to 2,4,6-trinitrochlorobenzene in mice. These phenolics reduced ear swelling and IL-1β content by 50% 24 h after challenge; in addition, 2 inhibited tumor necrosis factor-α by 53%. All three compounds also reduced interleukin-2 content by 50% 72 h after challenge. Both 2 and 3 inhibited metalloproteinase-9 levels in the skin lesions by 66% and 41%, respectively, and lowered cyclooxygenase-2 expression by 44% and 49%, respectively, at 24 h. Moreover, 2 was effective against atopic dermatitis induced by repeated application of 2,4,6-trinitrochlorobenzene; it attenuated edema by over 40% from day 7 and inhibited inflammatory cell infiltration by 44% at day 22. In addition, 1-3 reduced metalloproteinase-9 expression in a dose-dependent manner in macrophages RAW 264.7 stimulated with lipopolysaccharide. Thus, compounds 2 and 3 were found to exhibit a greater activity against contact hypersensitivity than 1.
|
Inhibition of recombinant human BACE1 expressed in CHO cells co-transfected with human APP with Swedish mutation assessed as amyloid beta1-40 secretion at 10 uM by alphaLISA technique
|
Homo sapiens
|
5.78
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : The green tea polyphenol (2)-epigallocatechin-3-gallate (EGCG) is not a β-secretase inhibitor.
Year : 2012
Volume : 22
Issue : 3
First Page : 1408
Last Page : 1414
Authors : Cheng XR, Zhou JW, Zhou Y, Cheng JP, Yang RF, Zhou WX, Zhang YX, Yun LH.
Abstract : (2)-Epigallocatechin-3-gallate (EGCG) is a major polyphenolic component of green tea. A number of studies have demonstrated EGCG has the possibility for delaying the onset or retarding the progression of Alzheimer's disease (AD) and indicated EGCG possess inhibition of β-secretase activity. We utilized homogeneous time-resolved fluorescence assay with a substrate Eu-CEVNLDAEFK-Qsy7 to screen β-secretase inhibitor in a cell-free system and AlphaLISA assay in cell system. The results first showed that EGCG had significant inhibition of β-secretase activity with IC(50) value of 7.57 × 10(-7)M in screening assay, but then we found EGCG had significant fluorescence-quenching effect in confirming assay, this indicates EGCG has the false positive β-secretase inhibitory activity. Furthermore, the followed AlphaLISA assay based on cell showed EGCG did not reduce the β-amyloid 1-40 secretion in HuAPPswe/HuBACE1 Chinese hamster ovary cell without affecting cell viability. Therefore our findings indicate EGCG do not inhibit β-secretase cleavage activity. Overall this study illustrates that EGCG is not a β-secretase inhibitor based on the compelling data. This provides further support that the choice of complementary assay format or technology is a critical factor in molecular screening and drug development for improving the hit-finding capability and efficiency.
|
Inhibition of recombinant human BACE1 using Eu-CEVNLDAEFK-Qsy7 as substrate by HTRF assay
|
Homo sapiens
|
757.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : The green tea polyphenol (2)-epigallocatechin-3-gallate (EGCG) is not a β-secretase inhibitor.
Year : 2012
Volume : 22
Issue : 3
First Page : 1408
Last Page : 1414
Authors : Cheng XR, Zhou JW, Zhou Y, Cheng JP, Yang RF, Zhou WX, Zhang YX, Yun LH.
Abstract : (2)-Epigallocatechin-3-gallate (EGCG) is a major polyphenolic component of green tea. A number of studies have demonstrated EGCG has the possibility for delaying the onset or retarding the progression of Alzheimer's disease (AD) and indicated EGCG possess inhibition of β-secretase activity. We utilized homogeneous time-resolved fluorescence assay with a substrate Eu-CEVNLDAEFK-Qsy7 to screen β-secretase inhibitor in a cell-free system and AlphaLISA assay in cell system. The results first showed that EGCG had significant inhibition of β-secretase activity with IC(50) value of 7.57 × 10(-7)M in screening assay, but then we found EGCG had significant fluorescence-quenching effect in confirming assay, this indicates EGCG has the false positive β-secretase inhibitory activity. Furthermore, the followed AlphaLISA assay based on cell showed EGCG did not reduce the β-amyloid 1-40 secretion in HuAPPswe/HuBACE1 Chinese hamster ovary cell without affecting cell viability. Therefore our findings indicate EGCG do not inhibit β-secretase cleavage activity. Overall this study illustrates that EGCG is not a β-secretase inhibitor based on the compelling data. This provides further support that the choice of complementary assay format or technology is a critical factor in molecular screening and drug development for improving the hit-finding capability and efficiency.
|
Inhibition of recombinant human BACE1 expressed in CHO cells co-transfected with human APP with Swedish mutation assessed as amyloid beta1-40 secretion at 1 nM by alphaLISA technique
|
Homo sapiens
|
-18.24
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : The green tea polyphenol (2)-epigallocatechin-3-gallate (EGCG) is not a β-secretase inhibitor.
Year : 2012
Volume : 22
Issue : 3
First Page : 1408
Last Page : 1414
Authors : Cheng XR, Zhou JW, Zhou Y, Cheng JP, Yang RF, Zhou WX, Zhang YX, Yun LH.
Abstract : (2)-Epigallocatechin-3-gallate (EGCG) is a major polyphenolic component of green tea. A number of studies have demonstrated EGCG has the possibility for delaying the onset or retarding the progression of Alzheimer's disease (AD) and indicated EGCG possess inhibition of β-secretase activity. We utilized homogeneous time-resolved fluorescence assay with a substrate Eu-CEVNLDAEFK-Qsy7 to screen β-secretase inhibitor in a cell-free system and AlphaLISA assay in cell system. The results first showed that EGCG had significant inhibition of β-secretase activity with IC(50) value of 7.57 × 10(-7)M in screening assay, but then we found EGCG had significant fluorescence-quenching effect in confirming assay, this indicates EGCG has the false positive β-secretase inhibitory activity. Furthermore, the followed AlphaLISA assay based on cell showed EGCG did not reduce the β-amyloid 1-40 secretion in HuAPPswe/HuBACE1 Chinese hamster ovary cell without affecting cell viability. Therefore our findings indicate EGCG do not inhibit β-secretase cleavage activity. Overall this study illustrates that EGCG is not a β-secretase inhibitor based on the compelling data. This provides further support that the choice of complementary assay format or technology is a critical factor in molecular screening and drug development for improving the hit-finding capability and efficiency.
|
Inhibition of recombinant human BACE1 expressed in CHO cells co-transfected with human APP with Swedish mutation assessed as amyloid beta1-40 secretion at 0.01 uM by alphaLISA technique
|
Homo sapiens
|
-12.61
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : The green tea polyphenol (2)-epigallocatechin-3-gallate (EGCG) is not a β-secretase inhibitor.
Year : 2012
Volume : 22
Issue : 3
First Page : 1408
Last Page : 1414
Authors : Cheng XR, Zhou JW, Zhou Y, Cheng JP, Yang RF, Zhou WX, Zhang YX, Yun LH.
Abstract : (2)-Epigallocatechin-3-gallate (EGCG) is a major polyphenolic component of green tea. A number of studies have demonstrated EGCG has the possibility for delaying the onset or retarding the progression of Alzheimer's disease (AD) and indicated EGCG possess inhibition of β-secretase activity. We utilized homogeneous time-resolved fluorescence assay with a substrate Eu-CEVNLDAEFK-Qsy7 to screen β-secretase inhibitor in a cell-free system and AlphaLISA assay in cell system. The results first showed that EGCG had significant inhibition of β-secretase activity with IC(50) value of 7.57 × 10(-7)M in screening assay, but then we found EGCG had significant fluorescence-quenching effect in confirming assay, this indicates EGCG has the false positive β-secretase inhibitory activity. Furthermore, the followed AlphaLISA assay based on cell showed EGCG did not reduce the β-amyloid 1-40 secretion in HuAPPswe/HuBACE1 Chinese hamster ovary cell without affecting cell viability. Therefore our findings indicate EGCG do not inhibit β-secretase cleavage activity. Overall this study illustrates that EGCG is not a β-secretase inhibitor based on the compelling data. This provides further support that the choice of complementary assay format or technology is a critical factor in molecular screening and drug development for improving the hit-finding capability and efficiency.
|
Inhibition of recombinant human BACE1 expressed in CHO cells co-transfected with human APP with Swedish mutation assessed as amyloid beta1-40 secretion at 0.1 uM by alphaLISA technique
|
Homo sapiens
|
-0.72
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : The green tea polyphenol (2)-epigallocatechin-3-gallate (EGCG) is not a β-secretase inhibitor.
Year : 2012
Volume : 22
Issue : 3
First Page : 1408
Last Page : 1414
Authors : Cheng XR, Zhou JW, Zhou Y, Cheng JP, Yang RF, Zhou WX, Zhang YX, Yun LH.
Abstract : (2)-Epigallocatechin-3-gallate (EGCG) is a major polyphenolic component of green tea. A number of studies have demonstrated EGCG has the possibility for delaying the onset or retarding the progression of Alzheimer's disease (AD) and indicated EGCG possess inhibition of β-secretase activity. We utilized homogeneous time-resolved fluorescence assay with a substrate Eu-CEVNLDAEFK-Qsy7 to screen β-secretase inhibitor in a cell-free system and AlphaLISA assay in cell system. The results first showed that EGCG had significant inhibition of β-secretase activity with IC(50) value of 7.57 × 10(-7)M in screening assay, but then we found EGCG had significant fluorescence-quenching effect in confirming assay, this indicates EGCG has the false positive β-secretase inhibitory activity. Furthermore, the followed AlphaLISA assay based on cell showed EGCG did not reduce the β-amyloid 1-40 secretion in HuAPPswe/HuBACE1 Chinese hamster ovary cell without affecting cell viability. Therefore our findings indicate EGCG do not inhibit β-secretase cleavage activity. Overall this study illustrates that EGCG is not a β-secretase inhibitor based on the compelling data. This provides further support that the choice of complementary assay format or technology is a critical factor in molecular screening and drug development for improving the hit-finding capability and efficiency.
|
Inhibition of recombinant human BACE1 expressed in CHO cells co-transfected with human APP with Swedish mutation assessed as amyloid beta1-40 secretion at 1 uM by alphaLISA technique
|
Homo sapiens
|
-11.78
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : The green tea polyphenol (2)-epigallocatechin-3-gallate (EGCG) is not a β-secretase inhibitor.
Year : 2012
Volume : 22
Issue : 3
First Page : 1408
Last Page : 1414
Authors : Cheng XR, Zhou JW, Zhou Y, Cheng JP, Yang RF, Zhou WX, Zhang YX, Yun LH.
Abstract : (2)-Epigallocatechin-3-gallate (EGCG) is a major polyphenolic component of green tea. A number of studies have demonstrated EGCG has the possibility for delaying the onset or retarding the progression of Alzheimer's disease (AD) and indicated EGCG possess inhibition of β-secretase activity. We utilized homogeneous time-resolved fluorescence assay with a substrate Eu-CEVNLDAEFK-Qsy7 to screen β-secretase inhibitor in a cell-free system and AlphaLISA assay in cell system. The results first showed that EGCG had significant inhibition of β-secretase activity with IC(50) value of 7.57 × 10(-7)M in screening assay, but then we found EGCG had significant fluorescence-quenching effect in confirming assay, this indicates EGCG has the false positive β-secretase inhibitory activity. Furthermore, the followed AlphaLISA assay based on cell showed EGCG did not reduce the β-amyloid 1-40 secretion in HuAPPswe/HuBACE1 Chinese hamster ovary cell without affecting cell viability. Therefore our findings indicate EGCG do not inhibit β-secretase cleavage activity. Overall this study illustrates that EGCG is not a β-secretase inhibitor based on the compelling data. This provides further support that the choice of complementary assay format or technology is a critical factor in molecular screening and drug development for improving the hit-finding capability and efficiency.
|
Inhibition of recombinant human BACE1 using substrate conjugated with reporter EDANS and DABCYL at 0.03 mg/mL
|
Homo sapiens
|
38.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : The green tea polyphenol (2)-epigallocatechin-3-gallate (EGCG) is not a β-secretase inhibitor.
Year : 2012
Volume : 22
Issue : 3
First Page : 1408
Last Page : 1414
Authors : Cheng XR, Zhou JW, Zhou Y, Cheng JP, Yang RF, Zhou WX, Zhang YX, Yun LH.
Abstract : (2)-Epigallocatechin-3-gallate (EGCG) is a major polyphenolic component of green tea. A number of studies have demonstrated EGCG has the possibility for delaying the onset or retarding the progression of Alzheimer's disease (AD) and indicated EGCG possess inhibition of β-secretase activity. We utilized homogeneous time-resolved fluorescence assay with a substrate Eu-CEVNLDAEFK-Qsy7 to screen β-secretase inhibitor in a cell-free system and AlphaLISA assay in cell system. The results first showed that EGCG had significant inhibition of β-secretase activity with IC(50) value of 7.57 × 10(-7)M in screening assay, but then we found EGCG had significant fluorescence-quenching effect in confirming assay, this indicates EGCG has the false positive β-secretase inhibitory activity. Furthermore, the followed AlphaLISA assay based on cell showed EGCG did not reduce the β-amyloid 1-40 secretion in HuAPPswe/HuBACE1 Chinese hamster ovary cell without affecting cell viability. Therefore our findings indicate EGCG do not inhibit β-secretase cleavage activity. Overall this study illustrates that EGCG is not a β-secretase inhibitor based on the compelling data. This provides further support that the choice of complementary assay format or technology is a critical factor in molecular screening and drug development for improving the hit-finding capability and efficiency.
|
Antialzheimer's disease activity in mouse cortex assessed as inhibition of beta-secretase mediated amyloid beta1-42 production at 1.5 mg/kg
|
Mus musculus
|
18.64
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : The green tea polyphenol (2)-epigallocatechin-3-gallate (EGCG) is not a β-secretase inhibitor.
Year : 2012
Volume : 22
Issue : 3
First Page : 1408
Last Page : 1414
Authors : Cheng XR, Zhou JW, Zhou Y, Cheng JP, Yang RF, Zhou WX, Zhang YX, Yun LH.
Abstract : (2)-Epigallocatechin-3-gallate (EGCG) is a major polyphenolic component of green tea. A number of studies have demonstrated EGCG has the possibility for delaying the onset or retarding the progression of Alzheimer's disease (AD) and indicated EGCG possess inhibition of β-secretase activity. We utilized homogeneous time-resolved fluorescence assay with a substrate Eu-CEVNLDAEFK-Qsy7 to screen β-secretase inhibitor in a cell-free system and AlphaLISA assay in cell system. The results first showed that EGCG had significant inhibition of β-secretase activity with IC(50) value of 7.57 × 10(-7)M in screening assay, but then we found EGCG had significant fluorescence-quenching effect in confirming assay, this indicates EGCG has the false positive β-secretase inhibitory activity. Furthermore, the followed AlphaLISA assay based on cell showed EGCG did not reduce the β-amyloid 1-40 secretion in HuAPPswe/HuBACE1 Chinese hamster ovary cell without affecting cell viability. Therefore our findings indicate EGCG do not inhibit β-secretase cleavage activity. Overall this study illustrates that EGCG is not a β-secretase inhibitor based on the compelling data. This provides further support that the choice of complementary assay format or technology is a critical factor in molecular screening and drug development for improving the hit-finding capability and efficiency.
|
Antialzheimer's disease activity in mouse cortex assessed as inhibition of beta-secretase mediated amyloid beta1-42 production at 3 mg/kg
|
Mus musculus
|
51.17
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : The green tea polyphenol (2)-epigallocatechin-3-gallate (EGCG) is not a β-secretase inhibitor.
Year : 2012
Volume : 22
Issue : 3
First Page : 1408
Last Page : 1414
Authors : Cheng XR, Zhou JW, Zhou Y, Cheng JP, Yang RF, Zhou WX, Zhang YX, Yun LH.
Abstract : (2)-Epigallocatechin-3-gallate (EGCG) is a major polyphenolic component of green tea. A number of studies have demonstrated EGCG has the possibility for delaying the onset or retarding the progression of Alzheimer's disease (AD) and indicated EGCG possess inhibition of β-secretase activity. We utilized homogeneous time-resolved fluorescence assay with a substrate Eu-CEVNLDAEFK-Qsy7 to screen β-secretase inhibitor in a cell-free system and AlphaLISA assay in cell system. The results first showed that EGCG had significant inhibition of β-secretase activity with IC(50) value of 7.57 × 10(-7)M in screening assay, but then we found EGCG had significant fluorescence-quenching effect in confirming assay, this indicates EGCG has the false positive β-secretase inhibitory activity. Furthermore, the followed AlphaLISA assay based on cell showed EGCG did not reduce the β-amyloid 1-40 secretion in HuAPPswe/HuBACE1 Chinese hamster ovary cell without affecting cell viability. Therefore our findings indicate EGCG do not inhibit β-secretase cleavage activity. Overall this study illustrates that EGCG is not a β-secretase inhibitor based on the compelling data. This provides further support that the choice of complementary assay format or technology is a critical factor in molecular screening and drug development for improving the hit-finding capability and efficiency.
|
Antialzheimer's disease activity in mouse hippocampus assessed as inhibition of beta-secretase mediated amyloid beta1-42 production at 1.5 mg/kg
|
Mus musculus
|
25.48
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : The green tea polyphenol (2)-epigallocatechin-3-gallate (EGCG) is not a β-secretase inhibitor.
Year : 2012
Volume : 22
Issue : 3
First Page : 1408
Last Page : 1414
Authors : Cheng XR, Zhou JW, Zhou Y, Cheng JP, Yang RF, Zhou WX, Zhang YX, Yun LH.
Abstract : (2)-Epigallocatechin-3-gallate (EGCG) is a major polyphenolic component of green tea. A number of studies have demonstrated EGCG has the possibility for delaying the onset or retarding the progression of Alzheimer's disease (AD) and indicated EGCG possess inhibition of β-secretase activity. We utilized homogeneous time-resolved fluorescence assay with a substrate Eu-CEVNLDAEFK-Qsy7 to screen β-secretase inhibitor in a cell-free system and AlphaLISA assay in cell system. The results first showed that EGCG had significant inhibition of β-secretase activity with IC(50) value of 7.57 × 10(-7)M in screening assay, but then we found EGCG had significant fluorescence-quenching effect in confirming assay, this indicates EGCG has the false positive β-secretase inhibitory activity. Furthermore, the followed AlphaLISA assay based on cell showed EGCG did not reduce the β-amyloid 1-40 secretion in HuAPPswe/HuBACE1 Chinese hamster ovary cell without affecting cell viability. Therefore our findings indicate EGCG do not inhibit β-secretase cleavage activity. Overall this study illustrates that EGCG is not a β-secretase inhibitor based on the compelling data. This provides further support that the choice of complementary assay format or technology is a critical factor in molecular screening and drug development for improving the hit-finding capability and efficiency.
|
Antialzheimer's disease activity in mouse hippocampus assessed as inhibition of beta-secretase mediated amyloid beta1-42 production at 3 mg/kg
|
Mus musculus
|
39.79
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : The green tea polyphenol (2)-epigallocatechin-3-gallate (EGCG) is not a β-secretase inhibitor.
Year : 2012
Volume : 22
Issue : 3
First Page : 1408
Last Page : 1414
Authors : Cheng XR, Zhou JW, Zhou Y, Cheng JP, Yang RF, Zhou WX, Zhang YX, Yun LH.
Abstract : (2)-Epigallocatechin-3-gallate (EGCG) is a major polyphenolic component of green tea. A number of studies have demonstrated EGCG has the possibility for delaying the onset or retarding the progression of Alzheimer's disease (AD) and indicated EGCG possess inhibition of β-secretase activity. We utilized homogeneous time-resolved fluorescence assay with a substrate Eu-CEVNLDAEFK-Qsy7 to screen β-secretase inhibitor in a cell-free system and AlphaLISA assay in cell system. The results first showed that EGCG had significant inhibition of β-secretase activity with IC(50) value of 7.57 × 10(-7)M in screening assay, but then we found EGCG had significant fluorescence-quenching effect in confirming assay, this indicates EGCG has the false positive β-secretase inhibitory activity. Furthermore, the followed AlphaLISA assay based on cell showed EGCG did not reduce the β-amyloid 1-40 secretion in HuAPPswe/HuBACE1 Chinese hamster ovary cell without affecting cell viability. Therefore our findings indicate EGCG do not inhibit β-secretase cleavage activity. Overall this study illustrates that EGCG is not a β-secretase inhibitor based on the compelling data. This provides further support that the choice of complementary assay format or technology is a critical factor in molecular screening and drug development for improving the hit-finding capability and efficiency.
|
Inhibition of mammosphere formation in human MDA-MB-231 cells at 10 uM after 7 days by inverted phase-contrast microscopy
|
Homo sapiens
|
20.1
%
|
|
Journal : Bioorg. Med. Chem.
Title : Novel epigallocatechin gallate (EGCG) analogs activate AMP-activated protein kinase pathway and target cancer stem cells.
Year : 2012
Volume : 20
Issue : 9
First Page : 3031
Last Page : 3037
Authors : Chen D, Pamu S, Cui Q, Chan TH, Dou QP.
Abstract : AMP-activated protein kinase (AMPK) is a critical monitor of cellular energy status and also controls processes related to tumor development, including cell cycle progression, protein synthesis, cell growth and survival. Therefore AMPK as an anti-cancer target has received intensive attention recently. It has been reported that the anti-diabetic drug metformin and some natural compounds, such as quercetin, genistein, capsaicin and green tea polyphenol epigallocatechin gallate (EGCG), can activate AMPK and inhibit cancer cell growth. Indeed, natural products have been the most productive source of leads for the development of anti-cancer drugs but perceived disadvantages, such as low bioavailability and week potency, have limited their development and use in the clinic. In this study we demonstrated that synthetic EGCG analogs 4 and 6 were more potent AMPK activators than metformin and EGCG. Activation of AMPK by these EGCG analogs resulted in inhibition of cell proliferation, up-regulation of the cyclin-dependent kinase inhibitor p21, down-regulation of mTOR pathway, and suppression of stem cell population in human breast cancer cells. Our findings suggest that novel potent and specific AMPK activators can be discovered from natural and synthetic sources that have potential to be used for anti-cancer therapy in the clinic.
|
Inhibition of mammosphere formation in human MDA-MB-231 cells at 20 uM after 7 days by inverted phase-contrast microscopy
|
Homo sapiens
|
51.3
%
|
|
Journal : Bioorg. Med. Chem.
Title : Novel epigallocatechin gallate (EGCG) analogs activate AMP-activated protein kinase pathway and target cancer stem cells.
Year : 2012
Volume : 20
Issue : 9
First Page : 3031
Last Page : 3037
Authors : Chen D, Pamu S, Cui Q, Chan TH, Dou QP.
Abstract : AMP-activated protein kinase (AMPK) is a critical monitor of cellular energy status and also controls processes related to tumor development, including cell cycle progression, protein synthesis, cell growth and survival. Therefore AMPK as an anti-cancer target has received intensive attention recently. It has been reported that the anti-diabetic drug metformin and some natural compounds, such as quercetin, genistein, capsaicin and green tea polyphenol epigallocatechin gallate (EGCG), can activate AMPK and inhibit cancer cell growth. Indeed, natural products have been the most productive source of leads for the development of anti-cancer drugs but perceived disadvantages, such as low bioavailability and week potency, have limited their development and use in the clinic. In this study we demonstrated that synthetic EGCG analogs 4 and 6 were more potent AMPK activators than metformin and EGCG. Activation of AMPK by these EGCG analogs resulted in inhibition of cell proliferation, up-regulation of the cyclin-dependent kinase inhibitor p21, down-regulation of mTOR pathway, and suppression of stem cell population in human breast cancer cells. Our findings suggest that novel potent and specific AMPK activators can be discovered from natural and synthetic sources that have potential to be used for anti-cancer therapy in the clinic.
|
Competitive inhibition of Spiroplasma sp. MQ1 SssI methyltransferase using pUC18 as substrate measured for 10 mins by Dixon plot analysis
|
Spiroplasma monobiae
|
28.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : New cytosine derivatives as inhibitors of DNA methylation.
Year : 2012
Volume : 55
First Page : 243
Last Page : 254
Authors : Plitta B, Adamska E, Giel-Pietraszuk M, Fedoruk-Wyszomirska A, Naskręt-Barciszewska M, Markiewicz WT, Barciszewski J.
Abstract : DNA cytosine methylation catalyzed by DNA methyltransferase 1 (DNMT1) is an epigenetic method of gene expression regulation and development. Changes in methylation pattern lead to carcinogenesis. Inhibition of DNMT1 activity could be a good strategy of safe and efficient epigenetic therapy. In this work, we present a novel group of cytosine analogs as inhibitors of DNA methylation. We show new methods of synthesis and their effect on in vitro reaction of DNA methylation. Almost all of analyzed compounds inhibit DNA methyltransferase activity in the competitive manner. K(i) values for the most potent compound 4-N-furfuryl-5,6-dihydroazacytosines is 0.7 μM. These compounds cause also a decrease of 5-methylcytosine (m(5)C) level in DNA of mammalian HeLa and HEK293 cells.
|
Inhibition of DNMT1 in human HeLa cell nuclear extract assessed as methylated substrate level at 10 uM by ELISA
|
Homo sapiens
|
42.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : New cytosine derivatives as inhibitors of DNA methylation.
Year : 2012
Volume : 55
First Page : 243
Last Page : 254
Authors : Plitta B, Adamska E, Giel-Pietraszuk M, Fedoruk-Wyszomirska A, Naskręt-Barciszewska M, Markiewicz WT, Barciszewski J.
Abstract : DNA cytosine methylation catalyzed by DNA methyltransferase 1 (DNMT1) is an epigenetic method of gene expression regulation and development. Changes in methylation pattern lead to carcinogenesis. Inhibition of DNMT1 activity could be a good strategy of safe and efficient epigenetic therapy. In this work, we present a novel group of cytosine analogs as inhibitors of DNA methylation. We show new methods of synthesis and their effect on in vitro reaction of DNA methylation. Almost all of analyzed compounds inhibit DNA methyltransferase activity in the competitive manner. K(i) values for the most potent compound 4-N-furfuryl-5,6-dihydroazacytosines is 0.7 μM. These compounds cause also a decrease of 5-methylcytosine (m(5)C) level in DNA of mammalian HeLa and HEK293 cells.
|
Inhibition of HER2 phosphorylation in human SK-BR-3 cells after 6 hrs by Western blot analysis
|
Homo sapiens
|
18.0
%
|
|
Journal : J. Med. Chem.
Title : New synthetic inhibitors of fatty acid synthase with anticancer activity.
Year : 2012
Volume : 55
Issue : 11
First Page : 5013
Last Page : 5023
Authors : Turrado C, Puig T, García-Cárceles J, Artola M, Benhamú B, Ortega-Gutiérrez S, Relat J, Oliveras G, Blancafort A, Haro D, Marrero PF, Colomer R, López-Rodríguez ML.
Abstract : Fatty acid synthase (FASN) is a lipogenic enzyme that is highly expressed in different human cancers. Here we report the development of a new series of polyphenolic compounds 5-30 that have been evaluated for their cytotoxic capacity in SK-Br3 cells, a human breast cancer cell line with high FASN expression. The compounds with an IC(50) < 50 μM have been tested for their ability to inhibit FASN activity. Among them, derivative 30 blocks the 90% of FASN activity at low concentration (4 μM), is highly cytotoxic in a broad panel of tumor cells, induces apoptosis, and blocks the activation of HER2, AKT, and ERK pathways. Remarkably, 30 does not activate carnitine palmitoyltransferase-1 (CPT-1) nor induces in mice weight loss, which are the main drawbacks of other previously described FASN inhibitors. Thus, FASN inhibitor 30 may aid the validation of this enzyme as a therapeutic target for the treatment of cancer.
|
Antioxidant activity assessed as superoxide dismutase-like activity by SOD-WST assay
|
None
|
26.1
ug.mL-1
|
|
Journal : J. Nat. Prod.
Title : Diarylheptanoid sulfates and related compounds from Myrica rubra bark.
Year : 2012
Volume : 75
Issue : 10
First Page : 1798
Last Page : 1802
Authors : Yoshimura M, Yamakami S, Amakura Y, Yoshida T.
Abstract : Three new diarylheptanoids, myricanol 11-sulfate (1), juglanin B 11-sulfate (2), and myricanone 5-O-(6'-O-galloyl)glucoside (3), were isolated from the bark of Myrica rubra. Compounds 1 and 2 were characterized as diarylheptanoid sulfates on the basis of spectroscopic analyses. The antioxidative activities of the fractionated extracts and isolated compounds were estimated by the oxygen radical absorbance capacity (ORAC) and superoxide dismutase (SOD)-like activity assays. The major isolate, myricitrin (4), displayed a high ORAC value and moderate SOD-like activity (13,198 μmol TE (Trolox equivalent)/g and IC₅₀ 127.5 μg/mL, respectively), which might explain the potent antioxidative activity of this material.
|
Inhibition of electric eel AChE at 2 mg/ml by Ellman's method
|
Electrophorus electricus
|
-14.31
%
|
|
Journal : Bioorg. Med. Chem.
Title : Exploration of natural compounds as sources of new bifunctional scaffolds targeting cholinesterases and beta amyloid aggregation: the case of chelerythrine.
Year : 2012
Volume : 20
Issue : 22
First Page : 6669
Last Page : 6679
Authors : Brunhofer G, Fallarero A, Karlsson D, Batista-Gonzalez A, Shinde P, Gopi Mohan C, Vuorela P.
Abstract : The presented project started by screening a library consisting of natural and natural based compounds for their acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activity. Active compounds were chemically clustered into groups and further tested on the human cholinesterases isoforms. The aim of the presented study was to identify compounds that could be used as leads to target two key mechanisms associated with the AD's pathogenesis simultaneously: cholinergic depletion and beta amyloid (Aβ) aggregation. Berberin, palmatine and chelerythrine, chemically clustered in the so-called isoquinoline group, showed promising cholinesterase inhibitory activity and were therefore further investigated. Moreover, the compounds demonstrated moderate to good inhibition of Aβ aggregation as well as the ability to disaggregate already preformed Aβ aggregates in an experimental set-up using HFIP as promotor of Aβ aggregates. Analysis of the kinetic mechanism of the AChE inhibition revealed chelerythrine as a mixed inhibitor. Using molecular docking studies, it was further proven that chelerythrine binds on both the catalytic site and the peripheral anionic site (PAS) of the AChE. In view of this, we went on to investigate its effect on inhibiting Aβ aggregation stimulated by AChE. Chelerythrine showed inhibition of fibril formation in the same range as propidium iodide. This approach enabled for the first time to identify a cholinesterase inhibitor of natural origin-chelerythrine-acting on AChE and BChE with a dual ability to inhibit Aβ aggregation as well as to disaggregate preformed Aβ aggregates. This compound could be an excellent starting point paving the way to develop more successful anti-AD drugs.
|
Inhibition of horse BChE at 2 mg/ml by Ellman's method
|
Equus caballus
|
-4.27
%
|
|
Journal : Bioorg. Med. Chem.
Title : Exploration of natural compounds as sources of new bifunctional scaffolds targeting cholinesterases and beta amyloid aggregation: the case of chelerythrine.
Year : 2012
Volume : 20
Issue : 22
First Page : 6669
Last Page : 6679
Authors : Brunhofer G, Fallarero A, Karlsson D, Batista-Gonzalez A, Shinde P, Gopi Mohan C, Vuorela P.
Abstract : The presented project started by screening a library consisting of natural and natural based compounds for their acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activity. Active compounds were chemically clustered into groups and further tested on the human cholinesterases isoforms. The aim of the presented study was to identify compounds that could be used as leads to target two key mechanisms associated with the AD's pathogenesis simultaneously: cholinergic depletion and beta amyloid (Aβ) aggregation. Berberin, palmatine and chelerythrine, chemically clustered in the so-called isoquinoline group, showed promising cholinesterase inhibitory activity and were therefore further investigated. Moreover, the compounds demonstrated moderate to good inhibition of Aβ aggregation as well as the ability to disaggregate already preformed Aβ aggregates in an experimental set-up using HFIP as promotor of Aβ aggregates. Analysis of the kinetic mechanism of the AChE inhibition revealed chelerythrine as a mixed inhibitor. Using molecular docking studies, it was further proven that chelerythrine binds on both the catalytic site and the peripheral anionic site (PAS) of the AChE. In view of this, we went on to investigate its effect on inhibiting Aβ aggregation stimulated by AChE. Chelerythrine showed inhibition of fibril formation in the same range as propidium iodide. This approach enabled for the first time to identify a cholinesterase inhibitor of natural origin-chelerythrine-acting on AChE and BChE with a dual ability to inhibit Aβ aggregation as well as to disaggregate preformed Aβ aggregates. This compound could be an excellent starting point paving the way to develop more successful anti-AD drugs.
|
Inhibition of tetrahymena telomerase using 3'-ACT TCG TAG AGC AGA TTG-5' as substrate incubated for 10 mins prior to extension reaction by telomeric repeat amplification protocol
|
Tetrahymena
|
370.0
nM
|
|
Journal : J. Med. Chem.
Title : A new strategy for detection and development of tractable telomerase inhibitors.
Year : 2012
Volume : 55
Issue : 8
First Page : 3678
Last Page : 3686
Authors : Cohn EP, Wu KL, Pettus TR, Reich NO.
Abstract : Despite intense academic and industrial efforts and innumerable in vitro and cell studies, no small-molecule telomerase inhibitors have emerged as drugs. Insufficient understanding of enzyme structure and mechanisms of interdiction coupled with the substantial complexities presented by its dimeric composition have stalled all progress toward small-molecule therapeutics. Here we challenge the assumption that human telomerase provides the best platform for inhibitor development by probing a monomeric Tetrahymena telomerase with six tool compounds. We find BIBR-1532 (2) and MST-312 (5) inhibit only human telomerase, whereas β-R (1), THyF (3), TMPyP4 (6), and EGCG (4) inhibit both enzymes. Our study demonstrates that some small-molecule scaffolds can be easily surveyed with in vitro studies using Tetrahymena telomerase, a finding that could lead to more tractable inhibitors with a greater potential for development given the more precise insights that can be gleaned from this more easily expressed and assayed monomeric enzyme.
|
Displacement of NLWAAQRYGRELRRMSD-K(FITC)-FVD from Bcl-2 (unknown origin) by fluorescence polarization assay
|
Homo sapiens
|
335.0
nM
|
|
Journal : Med Chem Res
Title : Molecular docking study on anticancer activity of plant-derived natural products
Year : 2010
Volume : 19
Issue : 8
First Page : 817
Last Page : 835
Authors : Phosrithong N, Ungwitayatorn J
|
Cytotoxicity against ER-negative Homo sapiens (human) MDA-MB-468 cells assessed as inhibition of cell viability at 5 to 80 ug/ml after 24 to 72 hr by MTT assay
|
Homo sapiens
|
3.0
%
|
|
Journal : Med Chem Res
Title : Pharmacological profile of green tea and its polyphenols: a review
Year : 2012
Volume : 21
Issue : 11
First Page : 3347
Last Page : 3360
Authors : Bansal S, Syan N, Mathur P, Choudhary S
|
Antioxidant activity in Homo sapiens (human) epidermal microsomal fractions assessed as inhibition of UV-induced lipid peroxidation measured at 6 to 48 hr
|
Homo sapiens
|
41.0
%
|
|
Journal : Med Chem Res
Title : Pharmacological profile of green tea and its polyphenols: a review
Year : 2012
Volume : 21
Issue : 11
First Page : 3347
Last Page : 3360
Authors : Bansal S, Syan N, Mathur P, Choudhary S
|
Antioxidant activity in Homo sapiens (human) dermis cytosolic form assessed as inhibition of UV-induced nitric oxide production administered before UV induction at 48 hr by Griess assay
|
Homo sapiens
|
30.0
%
|
|
Journal : Med Chem Res
Title : Pharmacological profile of green tea and its polyphenols: a review
Year : 2012
Volume : 21
Issue : 11
First Page : 3347
Last Page : 3360
Authors : Bansal S, Syan N, Mathur P, Choudhary S
|
Antioxidant activity in Homo sapiens (human) epidermis cytosolic form assessed as inhibition of UV-induced nitric oxide production administered before UV induction at 48 hr by Griess assay
|
Homo sapiens
|
30.0
%
|
|
Journal : Med Chem Res
Title : Pharmacological profile of green tea and its polyphenols: a review
Year : 2012
Volume : 21
Issue : 11
First Page : 3347
Last Page : 3360
Authors : Bansal S, Syan N, Mathur P, Choudhary S
|
Antioxidant activity in Homo sapiens (human) dermis assessed as inhibition of UV-induced hydrogen peroxide production administered before UV induction at 48 hr by DHR assay
|
Homo sapiens
|
30.0
%
|
|
Journal : Med Chem Res
Title : Pharmacological profile of green tea and its polyphenols: a review
Year : 2012
Volume : 21
Issue : 11
First Page : 3347
Last Page : 3360
Authors : Bansal S, Syan N, Mathur P, Choudhary S
|
Antioxidant activity in Homo sapiens (human) epidermis assessed as inhibition of UV-induced hydrogen peroxide production administered before UV induction at 48 hr by DHR assay
|
Homo sapiens
|
30.0
%
|
|
Journal : Med Chem Res
Title : Pharmacological profile of green tea and its polyphenols: a review
Year : 2012
Volume : 21
Issue : 11
First Page : 3347
Last Page : 3360
Authors : Bansal S, Syan N, Mathur P, Choudhary S
|
Inhibition of Plasmodium falciparum FabZ using crotonoyl-CoA as substrate preincubated for 10 mins prior to substrate addition
|
Plasmodium falciparum
|
700.0
nM
|
|
Journal : J. Nat. Prod.
Title : Potential of lichen secondary metabolites against Plasmodium liver stage parasites with FAS-II as the potential target.
Year : 2013
Volume : 76
Issue : 6
First Page : 1064
Last Page : 1070
Authors : Lauinger IL, Vivas L, Perozzo R, Stairiker C, Tarun A, Zloh M, Zhang X, Xu H, Tonge PJ, Franzblau SG, Pham DH, Esguerra CV, Crawford AD, Maes L, Tasdemir D.
Abstract : Chemicals targeting the liver stage (LS) of the malaria parasite are useful for causal prophylaxis of malaria. In this study, four lichen metabolites, evernic acid (1), vulpic acid (2), psoromic acid (3), and (+)-usnic acid (4), were evaluated against LS parasites of Plasmodium berghei. Inhibition of P. falciparum blood stage (BS) parasites was also assessed to determine stage specificity. Compound 4 displayed the highest LS activity and stage specificity (LS IC50 value 2.3 μM, BS IC50 value 47.3 μM). The compounds 1-3 inhibited one or more enzymes (PfFabI, PfFabG, and PfFabZ) from the plasmodial fatty acid biosynthesis (FAS-II) pathway, a potential drug target for LS activity. To determine species specificity and to clarify the mechanism of reported antibacterial effects, 1-4 were also evaluated against FabI homologues and whole cells of various pathogens (S. aureus, E. coli, M. tuberculosis). Molecular modeling studies suggest that lichen acids act indirectly via binding to allosteric sites on the protein surface of the FAS-II enzymes. Potential toxicity of compounds was assessed in human hepatocyte and cancer cells (in vitro) as well as in a zebrafish model (in vivo). This study indicates the therapeutic and prophylactic potential of lichen metabolites as antibacterial and antiplasmodial agents.
|
Inhibition of Clostridium histolyticum collagenase using N-[3-(2-Furyl)acryloyl]-Leu-Gly-Pro-Ala as substrate at 100 ug/ml after 15 mins by spectrophotometric analysis relative to control
|
Clostridium histolyticum
|
41.16
%
|
|
Journal : Bioorg. Med. Chem.
Title : (+)-Usnic acid enamines with remarkable cicatrizing properties.
Year : 2013
Volume : 21
Issue : 7
First Page : 1834
Last Page : 1843
Authors : Bruno M, Trucchi B, Burlando B, Ranzato E, Martinotti S, Akkol EK, Süntar I, Keleş H, Verotta L.
Abstract : Wound healing is a significant concern in many pathologies (post-surgeries, burns, scars) and the search for new chemical entities is advisable. The lichen compound (+)-usnic acid (1) has found application in dermatological and cosmetic preparations, due to its bacteriostatic and antioxidant activities. The compound has also been shown to stimulate the wound closure of keratinocyte monolayers at subtoxic doses. Here we describe the design and synthesis of usnic acid enamines (compounds 2-11), obtained through nucleophilic attack of amino acids or decarboxyamino acids at the acyl carbonyl of the enolized 1,3 diketone. The wound repair properties of these derivatives were evaluated using in vitro and in vivo assays. Compounds 8 and 9 combine low cytotoxicity with high wound healing performance, suggesting their possible use in wound healing-promoting or antiage skin preparations.
|
Inhibition of human neutrophil elastase assessed as N-methoxysuccinyl-Ala-Ala-Pro-Val p-nitroanilide conversion to p-nitroaniline at 100 ug/ml after 1 hr by spectrophotometric analysis relative to control
|
Homo sapiens
|
88.17
%
|
|
Journal : Bioorg. Med. Chem.
Title : (+)-Usnic acid enamines with remarkable cicatrizing properties.
Year : 2013
Volume : 21
Issue : 7
First Page : 1834
Last Page : 1843
Authors : Bruno M, Trucchi B, Burlando B, Ranzato E, Martinotti S, Akkol EK, Süntar I, Keleş H, Verotta L.
Abstract : Wound healing is a significant concern in many pathologies (post-surgeries, burns, scars) and the search for new chemical entities is advisable. The lichen compound (+)-usnic acid (1) has found application in dermatological and cosmetic preparations, due to its bacteriostatic and antioxidant activities. The compound has also been shown to stimulate the wound closure of keratinocyte monolayers at subtoxic doses. Here we describe the design and synthesis of usnic acid enamines (compounds 2-11), obtained through nucleophilic attack of amino acids or decarboxyamino acids at the acyl carbonyl of the enolized 1,3 diketone. The wound repair properties of these derivatives were evaluated using in vitro and in vivo assays. Compounds 8 and 9 combine low cytotoxicity with high wound healing performance, suggesting their possible use in wound healing-promoting or antiage skin preparations.
|
Inhibition of recombinant Plasmodium falciparum FabZ using crotonoyl-CoA as substrate after 10 mins
|
Plasmodium falciparum
|
30.0
nM
|
|
Journal : J. Med. Chem.
Title : Design, synthesis, and biological and crystallographic evaluation of novel inhibitors of Plasmodium falciparum enoyl-ACP-reductase (PfFabI).
Year : 2013
Volume : 56
Issue : 19
First Page : 7516
Last Page : 7526
Authors : Belluti F, Perozzo R, Lauciello L, Colizzi F, Kostrewa D, Bisi A, Gobbi S, Rampa A, Bolognesi ML, Recanatini M, Brun R, Scapozza L, Cavalli A.
Abstract : Malaria, a disease of worldwide significance, is responsible for over one million deaths annually. The liver-stage of Plasmodium's life cycle is the first, obligatory, but clinically silent step in malaria infection. The P. falciparum type II fatty acid biosynthesis pathway (PfFAS-II) has been found to be essential for complete liver-stage development and has been regarded as a potential antimalarial target for the development of drugs for malaria prophylaxis and liver-stage eradication. In this paper, new coumarin-based triclosan analogues are reported and their biological profile is explored in terms of inhibitory potency against enzymes of the PfFAS-II pathway. Among the tested compounds, 7 and 8 showed the highest inhibitory potency against Pf enoyl-ACP-reductase (PfFabI), followed by 15 and 3. Finally, we determined the crystal structures of compounds 7 and 11 in complex with PfFabI to identify their mode of binding and to confirm outcomes of docking simulations.
|
Inhibition of recombinant Plasmodium falciparum 3D7 FabG using acetoacetyl-CoA as substrate after 10 mins in presence of NADPH
|
Plasmodium falciparum 3D7
|
320.0
nM
|
|
Journal : J. Med. Chem.
Title : Design, synthesis, and biological and crystallographic evaluation of novel inhibitors of Plasmodium falciparum enoyl-ACP-reductase (PfFabI).
Year : 2013
Volume : 56
Issue : 19
First Page : 7516
Last Page : 7526
Authors : Belluti F, Perozzo R, Lauciello L, Colizzi F, Kostrewa D, Bisi A, Gobbi S, Rampa A, Bolognesi ML, Recanatini M, Brun R, Scapozza L, Cavalli A.
Abstract : Malaria, a disease of worldwide significance, is responsible for over one million deaths annually. The liver-stage of Plasmodium's life cycle is the first, obligatory, but clinically silent step in malaria infection. The P. falciparum type II fatty acid biosynthesis pathway (PfFAS-II) has been found to be essential for complete liver-stage development and has been regarded as a potential antimalarial target for the development of drugs for malaria prophylaxis and liver-stage eradication. In this paper, new coumarin-based triclosan analogues are reported and their biological profile is explored in terms of inhibitory potency against enzymes of the PfFAS-II pathway. Among the tested compounds, 7 and 8 showed the highest inhibitory potency against Pf enoyl-ACP-reductase (PfFabI), followed by 15 and 3. Finally, we determined the crystal structures of compounds 7 and 11 in complex with PfFabI to identify their mode of binding and to confirm outcomes of docking simulations.
|
Inhibition of sodium fluorescein uptake in OATP1B1-transfected CHO cells at an equimolar substrate-inhibitor concentration of 10 uM
|
Cricetulus griseus
|
49.04
%
|
|
Journal : Mol. Pharmacol.
Title : Structure-based identification of OATP1B1/3 inhibitors.
Year : 2013
Volume : 83
Issue : 6
First Page : 1257
Last Page : 1267
Authors : De Bruyn T, van Westen GJ, Ijzerman AP, Stieger B, de Witte P, Augustijns PF, Annaert PP.
Abstract : Several recent studies show that inhibition of the hepatic transport proteins organic anion-transporting polypeptide 1B1 (OATP1B1) and 1B3 (OATP1B3) can result in clinically relevant drug-drug interactions (DDI). To avoid late-stage development drug failures due to OATP1B-mediated DDI, predictive in vitro and in silico methods should be implemented at an early stage of the drug candidate evaluation process. In the present study, we first developed a high-throughput in vitro transporter inhibition assay for the OATP1B subfamily. A total of 2000 compounds were tested as potential modulators of the uptake of the OATP1B substrate sodium fluorescein, in OATP1B1- or 1B3-transfected Chinese hamster ovary cells. At an equimolar substrate-inhibitor concentration of 10 µM, 212 and 139 molecules were identified as OATP1B1 and OATP1B3 inhibitors, respectively (minimum 50% inhibition). For 69 compounds, previously not identified as OATP1B inhibitors, concentration-dependent inhibition was also determined, yielding Ki values ranging from 0.06 to 6.5 µM. Based on these in vitro data, we subsequently developed a proteochemometrics-based in silico model, which predicted OATP1B inhibitors in the test group (20% of the dataset) with high specificity (86%) and sensitivity (78%). Moreover, several physicochemical compound properties and substructures related to OATP1B1/1B3 inhibition or inactivity were identified. Finally, model performance was prospectively verified with a set of 54 compounds not included in the original dataset. This validation indicated that 80 and 74% of the compounds were correctly classified for OATP1B1 and OATP1B3 inhibition, respectively.
|
Inhibition of sodium fluorescein uptake in OATP1B3-transfected CHO cells at an equimolar substrate-inhibitor concentration of 10 uM
|
Cricetulus griseus
|
45.88
%
|
|
Journal : Mol. Pharmacol.
Title : Structure-based identification of OATP1B1/3 inhibitors.
Year : 2013
Volume : 83
Issue : 6
First Page : 1257
Last Page : 1267
Authors : De Bruyn T, van Westen GJ, Ijzerman AP, Stieger B, de Witte P, Augustijns PF, Annaert PP.
Abstract : Several recent studies show that inhibition of the hepatic transport proteins organic anion-transporting polypeptide 1B1 (OATP1B1) and 1B3 (OATP1B3) can result in clinically relevant drug-drug interactions (DDI). To avoid late-stage development drug failures due to OATP1B-mediated DDI, predictive in vitro and in silico methods should be implemented at an early stage of the drug candidate evaluation process. In the present study, we first developed a high-throughput in vitro transporter inhibition assay for the OATP1B subfamily. A total of 2000 compounds were tested as potential modulators of the uptake of the OATP1B substrate sodium fluorescein, in OATP1B1- or 1B3-transfected Chinese hamster ovary cells. At an equimolar substrate-inhibitor concentration of 10 µM, 212 and 139 molecules were identified as OATP1B1 and OATP1B3 inhibitors, respectively (minimum 50% inhibition). For 69 compounds, previously not identified as OATP1B inhibitors, concentration-dependent inhibition was also determined, yielding Ki values ranging from 0.06 to 6.5 µM. Based on these in vitro data, we subsequently developed a proteochemometrics-based in silico model, which predicted OATP1B inhibitors in the test group (20% of the dataset) with high specificity (86%) and sensitivity (78%). Moreover, several physicochemical compound properties and substructures related to OATP1B1/1B3 inhibition or inactivity were identified. Finally, model performance was prospectively verified with a set of 54 compounds not included in the original dataset. This validation indicated that 80 and 74% of the compounds were correctly classified for OATP1B1 and OATP1B3 inhibition, respectively.
|
Inhibition of human GST-fused DYRK1A expressed in Escherichia coli using KISGRLSPIMTEQ as substrate
|
Homo sapiens
|
330.0
nM
|
|
Journal : J. Med. Chem.
Title : Development of DANDYs, new 3,5-diaryl-7-azaindoles demonstrating potent DYRK1A kinase inhibitory activity.
Year : 2013
Volume : 56
Issue : 23
First Page : 9569
Last Page : 9585
Authors : Gourdain S, Dairou J, Denhez C, Bui LC, Rodrigues-Lima F, Janel N, Delabar JM, Cariou K, Dodd RH.
Abstract : A series of 3,5-diaryl-1H-pyrrolo[2,3-b]pyridines were synthesized and evaluated for inhibition of DYRKIA kinase in vitro. Derivatives having hydroxy groups on the aryl moieties (2c, 2j-l) demonstrated high inhibitory potencies with Kis in the low nanomolar range. Their methoxy analogues were up to 100 times less active. Docking studies at the ATP binding site suggested that these compounds bind tightly to this site via a network of multiple H-bonds with the peptide backbone. None of the active compounds were cytotoxic to KB cells at 10(-6) M. Kinase profiling revealed that compound 2j showed 2-fold selectivity for DYRK1A with respect to DYRK2 and DYRK3.
|
Inhibition of 67LR co-localization in lipid rafts containing cholera toxin labeled GM1 gangliosides in human A431 cells after 30 mins by immunofluorescence-based confocal microscopic analysis (Rvb = 75%)
|
Homo sapiens
|
47.0
%
|
|
Journal : J. Nat. Prod.
Title : Epigallocatechin 3-O-gallate induces 67 kDa laminin receptor-mediated cell death accompanied by downregulation of ErbB proteins and altered lipid raft clustering in mammary and epidermoid carcinoma cells.
Year : 2014
Volume : 77
Issue : 2
First Page : 250
Last Page : 257
Authors : Mocanu MM, Ganea C, Georgescu L, Váradi T, Shrestha D, Baran I, Katona E, Nagy P, Szöllősi J.
Abstract : Since the administration of synthetic medicines is associated with drug resistance and undesired side effects, utilization of natural compounds could be an alternative and complementary modality to inhibit or prevent the development of tumors. Epigallocatechin 3-O-gallate (EGCG, 1), the major flavan component of green tea, and genistein (2), a soy isoflavonoid, are known to have chemopreventive and chemotherapeutic effects against cancer. This study demonstrated that both flavonoids inhibit cell proliferation, an effect enhanced under serum-free conditions. Compound 1, but not 2, induced downregulation of ErbB1 and ErbB2 in mammary and epidermoid carcinoma cells, and its inhibitory effect on cell viability was mediated by the 67 kDa laminin receptor (67LR). While 1 was superior in inducing cell death, 2 was more efficient in arresting the tumor cells in the G2/M phase. Furthermore, number and brightness analysis revealed that 1 decreased the homoclustering of a lipid raft marker, glycosylphosphatidylinositol-anchored GFP, and it also reduced the co-localization between lipid rafts and 67LR. The main conclusion made is that the primary target of 1 may be the lipid raft component of the plasma membrane followed by secondary changes in the expression of ErbB proteins. Compound 2, on the other hand, must have other unidentified targets.
|
Binding affinity to STAT1 (unknown origin) by surface plasmon resonance assay
|
Homo sapiens
|
700.0
nM
|
|
Journal : J. Nat. Prod.
Title : Direct interaction of garcinol and related polyisoprenylated benzophenones of Garcinia cambogia fruits with the transcription factor STAT-1 as a likely mechanism of their inhibitory effect on cytokine signaling pathways.
Year : 2014
Volume : 77
Issue : 3
First Page : 543
Last Page : 549
Authors : Masullo M, Menegazzi M, Di Micco S, Beffy P, Bifulco G, Dal Bosco M, Novelli M, Pizza C, Masiello P, Piacente S.
Abstract : Garcinol (1), a polyisoprenylated benzophenone occurring in Garcinia species, has been reported to exert anti-inflammatory activity in LPS-stimulated macrophages, through inhibition of NF-κB and/or JAK/STAT-1 activation. In order to provide deeper insight into its effects on the cytokine signaling pathway and to clarify the underlying molecular mechanisms, 1 was isolated from the fruits of Garcinia cambogia along with two other polyisoprenylated benzophenones, guttiferones K (2) and guttiferone M (3), differing from each other in their isoprenyl moieties and their positions on the benzophenone core. The affinities of 1-3 for the STAT-1 protein have been evaluated by surface plasmon resonance and molecular docking studies and resulted in KD values in the micromolar range. Consistent with the observed high affinity toward the STAT-1 protein, garcinol and guttiferones K and M were able to modulate cytokine signaling in different cultured cell lines, mainly by inhibiting STAT-1 nuclear transfer and DNA binding, as assessed by an electrophorectic mobility shift assay.
|
Binding affinity to rat brain cell membrane
|
Rattus norvegicus
|
25.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Cell membrane mediated (-)-epicatechin effects on upstream endothelial cell signaling: evidence for a surface receptor.
Year : 2014
Volume : 24
Issue : 12
First Page : 2749
Last Page : 2752
Authors : Moreno-Ulloa A, Romero-Perez D, Villarreal F, Ceballos G, Ramirez-Sanchez I.
Abstract : The consumption of cacao-derived products, particularly in the form of dark chocolate is known to provide beneficial cardiovascular effects in normal individuals and in those with vascular dysfunction (reduced nitric oxide [NO] bioavailability and/or synthesis). Upstream mechanisms by which flavonoids exert these effects are poorly understood and may involve the participation of cell membrane receptors. We previously demonstrated that the flavanol (-)-epicatechin (EPI) stimulates NO production via Ca(+2)-independent eNOS activation/phosphorylation. We wished to investigate the plausible participation of a cell surface receptor using a novel cell-membrane impermeable EPI-Dextran conjugate (EPI-Dx). Under Ca(2+)-free conditions, human coronary artery endothelial cells (HCAEC) were treated for 10min with EPI or EPI-Dx at equimolar concentrations (100nM). Results demonstrate that both EPI and EPI-Dx induced the phosphorylation/activation of PI3K, PDK-1, AKT and eNOS. Interestingly, EPI-Dx effects were significantly higher in magnitude than those of EPI alone. The capacity of EPI-Dx to stimulate cell responses supports the existence of an EPI cell membrane receptor mediating eNOS activation.
|
Antimalarial activity against chloroquine-sensitive/mefloquine-resistant Plasmodium falciparum D6 by malaria SYBR green 1-based fluorescence (MSF) assay
|
Plasmodium falciparum D6
|
73.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : The synthesis, antimalarial activity and CoMFA analysis of novel aminoalkylated quercetin analogs.
Year : 2015
Volume : 25
Issue : 2
First Page : 327
Last Page : 332
Authors : Helgren TR, Sciotti RJ, Lee P, Duffy S, Avery VM, Igbinoba O, Akoto M, Hagen TJ.
Abstract : A series of novel aminoalkylated quercetin analogs, prepared via the Mannich reaction of various primary and secondary amines with formaldehyde, were tested for antimalarial activity. The compounds were screened against three drug resistant malarial strains (D6, C235 and W2) and were found to exhibit sub-micromolar activity across all three strains (0.065-13.0μM). The structure-activity relationship determined from the antimalarial activity data suggests the inclusion of phenethyl amine sidechains on the quercetin scaffolding is necessary for potent activity. Additionally, the most active compounds ((5) and (6)) were tested for both early and late stage anti-gametocytocidal activity. Finally, the antimalarial activity data were utilized to construct comparative molecular field analysis (CoMFA) models to be used for further compound refinement.
|
Antimalarial activity against chloroquine /mefloquine/pyrimethamine-resistant Plasmodium falciparum C235 by malaria SYBR green 1-based fluorescence (MSF) assay
|
Plasmodium falciparum
|
610.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : The synthesis, antimalarial activity and CoMFA analysis of novel aminoalkylated quercetin analogs.
Year : 2015
Volume : 25
Issue : 2
First Page : 327
Last Page : 332
Authors : Helgren TR, Sciotti RJ, Lee P, Duffy S, Avery VM, Igbinoba O, Akoto M, Hagen TJ.
Abstract : A series of novel aminoalkylated quercetin analogs, prepared via the Mannich reaction of various primary and secondary amines with formaldehyde, were tested for antimalarial activity. The compounds were screened against three drug resistant malarial strains (D6, C235 and W2) and were found to exhibit sub-micromolar activity across all three strains (0.065-13.0μM). The structure-activity relationship determined from the antimalarial activity data suggests the inclusion of phenethyl amine sidechains on the quercetin scaffolding is necessary for potent activity. Additionally, the most active compounds ((5) and (6)) were tested for both early and late stage anti-gametocytocidal activity. Finally, the antimalarial activity data were utilized to construct comparative molecular field analysis (CoMFA) models to be used for further compound refinement.
|
Inhibition of human type O erythrocyte ICAM1-mediated Plasmodium falciparum infection with at 50 uM
|
Homo sapiens
|
85.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : The synthesis, antimalarial activity and CoMFA analysis of novel aminoalkylated quercetin analogs.
Year : 2015
Volume : 25
Issue : 2
First Page : 327
Last Page : 332
Authors : Helgren TR, Sciotti RJ, Lee P, Duffy S, Avery VM, Igbinoba O, Akoto M, Hagen TJ.
Abstract : A series of novel aminoalkylated quercetin analogs, prepared via the Mannich reaction of various primary and secondary amines with formaldehyde, were tested for antimalarial activity. The compounds were screened against three drug resistant malarial strains (D6, C235 and W2) and were found to exhibit sub-micromolar activity across all three strains (0.065-13.0μM). The structure-activity relationship determined from the antimalarial activity data suggests the inclusion of phenethyl amine sidechains on the quercetin scaffolding is necessary for potent activity. Additionally, the most active compounds ((5) and (6)) were tested for both early and late stage anti-gametocytocidal activity. Finally, the antimalarial activity data were utilized to construct comparative molecular field analysis (CoMFA) models to be used for further compound refinement.
|
Inhibition of Plasmodium falciparum FabZ
|
Plasmodium falciparum
|
0.03
ug.mL-1
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 2-Octadecynoic acid as a dual life stage inhibitor of Plasmodium infections and plasmodial FAS-II enzymes.
Year : 2014
Volume : 24
Issue : 17
First Page : 4151
Last Page : 4157
Authors : Carballeira NM, Bwalya AG, Itoe MA, Andricopulo AD, Cordero-Maldonado ML, Kaiser M, Mota MM, Crawford AD, Guido RV, Tasdemir D.
Abstract : The malaria parasite Plasmodium goes through two life stages in the human host, a non-symptomatic liver stage (LS) followed by a blood stage with all clinical manifestation of the disease. In this study, we investigated a series of 2-alkynoic fatty acids (2-AFAs) with chain lengths between 14 and 18 carbon atoms for dual in vitro activity against both life stages. 2-Octadecynoic acid (2-ODA) was identified as the best inhibitor of Plasmodium berghei parasites with ten times higher potency (IC50=0.34 μg/ml) than the control drug. In target determination studies, the same compound inhibited three Plasmodium falciparum FAS-II (PfFAS-II) elongation enzymes PfFabI, PfFabZ, and PfFabG with the lowest IC50 values (0.28-0.80 μg/ml, respectively). Molecular modeling studies provided insights into the molecular aspects underlying the inhibitory activity of this series of 2-AFAs and a likely explanation for the considerably different inhibition potentials. Blood stages of P. falciparum followed a similar trend where 2-ODA emerged as the most active compound, with 20 times less potency. The general toxicity and hepatotoxicity of 2-AFAs were evaluated by in vitro and in vivo methods in mammalian cell lines and zebrafish models, respectively. This study identifies 2-ODA as the most promising antiparasitic 2-AFA, particularly towards P. berghei parasites.
|
Inhibition of Plasmodium falciparum FabG
|
Plasmodium falciparum
|
0.2
ug.mL-1
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 2-Octadecynoic acid as a dual life stage inhibitor of Plasmodium infections and plasmodial FAS-II enzymes.
Year : 2014
Volume : 24
Issue : 17
First Page : 4151
Last Page : 4157
Authors : Carballeira NM, Bwalya AG, Itoe MA, Andricopulo AD, Cordero-Maldonado ML, Kaiser M, Mota MM, Crawford AD, Guido RV, Tasdemir D.
Abstract : The malaria parasite Plasmodium goes through two life stages in the human host, a non-symptomatic liver stage (LS) followed by a blood stage with all clinical manifestation of the disease. In this study, we investigated a series of 2-alkynoic fatty acids (2-AFAs) with chain lengths between 14 and 18 carbon atoms for dual in vitro activity against both life stages. 2-Octadecynoic acid (2-ODA) was identified as the best inhibitor of Plasmodium berghei parasites with ten times higher potency (IC50=0.34 μg/ml) than the control drug. In target determination studies, the same compound inhibited three Plasmodium falciparum FAS-II (PfFAS-II) elongation enzymes PfFabI, PfFabZ, and PfFabG with the lowest IC50 values (0.28-0.80 μg/ml, respectively). Molecular modeling studies provided insights into the molecular aspects underlying the inhibitory activity of this series of 2-AFAs and a likely explanation for the considerably different inhibition potentials. Blood stages of P. falciparum followed a similar trend where 2-ODA emerged as the most active compound, with 20 times less potency. The general toxicity and hepatotoxicity of 2-AFAs were evaluated by in vitro and in vivo methods in mammalian cell lines and zebrafish models, respectively. This study identifies 2-ODA as the most promising antiparasitic 2-AFA, particularly towards P. berghei parasites.
|
Reduction in amyloid beta levels in Tg2576 mouse
|
Mus musculus
|
50.0
%
|
|
Journal : Bioorg. Med. Chem.
Title : β-sheet interfering molecules acting against β-amyloid aggregation and fibrillogenesis.
Year : 2015
Volume : 23
Issue : 8
First Page : 1671
Last Page : 1683
Authors : Francioso A, Punzi P, Boffi A, Lori C, Martire S, Giordano C, D'Erme M, Mosca L.
Abstract : β-Sheet aggregates and amyloid fibrils rising from conformational changes of proteins are observed in several pathological human conditions. These structures are organized in β-strands that can reciprocally interact by hydrophobic and π-π interactions. The amyloid aggregates can give rise to pathological conditions through complex biochemical mechanisms whose physico-chemical nature has been understood in recent times. This review focuses on the various classes of natural and synthetic small molecules able to act against β-amyloid fibrillogenesis and toxicity that may represent new pharmacological tools in Alzheimer's diseases. Some peptides, named 'β-sheet breaker peptides', are able to hamper amyloid aggregation and fibrillogenesis by interfering with and destabilizing the non native β-sheet structures. Other natural compounds, like polyphenols or indolic molecules such as melatonin, can interfere with β-amyloid peptide pathogenicity by inhibiting aggregation and counteracting oxidative stress that is a key hallmark in Alzheimer's disease.
|
Reduction in amyloid beta plaques in Tg2576 mouse
|
Mus musculus
|
50.0
%
|
|
Journal : Bioorg. Med. Chem.
Title : β-sheet interfering molecules acting against β-amyloid aggregation and fibrillogenesis.
Year : 2015
Volume : 23
Issue : 8
First Page : 1671
Last Page : 1683
Authors : Francioso A, Punzi P, Boffi A, Lori C, Martire S, Giordano C, D'Erme M, Mosca L.
Abstract : β-Sheet aggregates and amyloid fibrils rising from conformational changes of proteins are observed in several pathological human conditions. These structures are organized in β-strands that can reciprocally interact by hydrophobic and π-π interactions. The amyloid aggregates can give rise to pathological conditions through complex biochemical mechanisms whose physico-chemical nature has been understood in recent times. This review focuses on the various classes of natural and synthetic small molecules able to act against β-amyloid fibrillogenesis and toxicity that may represent new pharmacological tools in Alzheimer's diseases. Some peptides, named 'β-sheet breaker peptides', are able to hamper amyloid aggregation and fibrillogenesis by interfering with and destabilizing the non native β-sheet structures. Other natural compounds, like polyphenols or indolic molecules such as melatonin, can interfere with β-amyloid peptide pathogenicity by inhibiting aggregation and counteracting oxidative stress that is a key hallmark in Alzheimer's disease.
|
Inhibition of His6-tagged human recombinant DNMT1 expressed in insect Sf9 cells assessed as reduction in DNA methyltransferase activity using 5'-biotinylated 45-bp unmethylated or hemimethylated oligonucleotide substrates and [3H]-AdoMet by liquid scintillation counting method
|
Homo sapiens
|
500.0
nM
|
|
Journal : J. Med. Chem.
Title : Targeting DNA methylation with small molecules: what's next?
Year : 2015
Volume : 58
Issue : 6
First Page : 2569
Last Page : 2583
Authors : Erdmann A, Halby L, Fahy J, Arimondo PB.
Abstract : DNA methylation is a mammalian epigenetic mark that is involved in defining where and when genes are expressed, both in normal cells and in the context of diseases. Like other epigenetic marks, it is reversible and can be modulated by chemical agents. Because it plays an important role in cancer by silencing certain genes, such as tumor suppressor genes, and by reactivating other regions, such as repeated elements, it is a promising therapeutic target. Two compounds are already approved to treat hematological cancers. Many efforts have been carried out to discover new molecules that are able to efficiently inhibit DNA methylation in cancer cells. We will briefly overview the foremost of these efforts by focusing on what we have learned to this point on non-nucleoside inhibitors and on what we consider to be the features of an ideal inhibitor.
|
Inhibition of amyloid beta (1 to 42) (unknown origin) aggregation at 100 uM incubated at 37 degC for 16 hrs by thioflavin T fluorescence assay
|
Homo sapiens
|
95.1
%
|
|
Journal : J. Nat. Prod.
Title : Nodulisporiviridins A-H, Bioactive Viridins from Nodulisporium sp.
Year : 2015
Volume : 78
Issue : 6
First Page : 1221
Last Page : 1230
Authors : Zhao Q, Chen GD, Feng XL, Yu Y, He RR, Li XX, Huang Y, Zhou WX, Guo LD, Zheng YZ, Yao XS, Gao H.
Abstract : Eight new viridins, nodulisporiviridins A-H (1-8), were isolated from the extract of an endolichenic fungal strain Nodulisporium sp. (No. 65-17-2-1) that was fermented with potato-dextrose broth. The structures were determined using spectroscopic and X-ray crystallographic analysis. Nodulisporiviridins A-D (1-4) are unique viridins with an opened ring A. The Aβ42 aggregation inhibitory activities of 1-8 were evaluated using a thioflavin T (ThT) assay with epigallocatechin gallate (EGCG) as the positive control (EGCG IC50 of 0.5 μM). Nodulisporiviridin G (7) displayed potent inhibitory activity with an IC50 value of 1.2 μM, and the preliminary trend of activity of these viridins as Aβ42 aggregation inhibitors was proposed. The short-term memory assay on an Aβ transgenic drosophila model of Alzheimer's disease showed that all eight compounds improved the short-term memory capacity, with potencies close to that of the positive control (memantine).
|
Inhibition of amyloid beta (1 to 42) (unknown origin) aggregation incubated at 37 degC for 16 hrs by thioflavin T fluorescence assay
|
Homo sapiens
|
500.0
nM
|
|
Journal : J. Nat. Prod.
Title : Nodulisporiviridins A-H, Bioactive Viridins from Nodulisporium sp.
Year : 2015
Volume : 78
Issue : 6
First Page : 1221
Last Page : 1230
Authors : Zhao Q, Chen GD, Feng XL, Yu Y, He RR, Li XX, Huang Y, Zhou WX, Guo LD, Zheng YZ, Yao XS, Gao H.
Abstract : Eight new viridins, nodulisporiviridins A-H (1-8), were isolated from the extract of an endolichenic fungal strain Nodulisporium sp. (No. 65-17-2-1) that was fermented with potato-dextrose broth. The structures were determined using spectroscopic and X-ray crystallographic analysis. Nodulisporiviridins A-D (1-4) are unique viridins with an opened ring A. The Aβ42 aggregation inhibitory activities of 1-8 were evaluated using a thioflavin T (ThT) assay with epigallocatechin gallate (EGCG) as the positive control (EGCG IC50 of 0.5 μM). Nodulisporiviridin G (7) displayed potent inhibitory activity with an IC50 value of 1.2 μM, and the preliminary trend of activity of these viridins as Aβ42 aggregation inhibitors was proposed. The short-term memory assay on an Aβ transgenic drosophila model of Alzheimer's disease showed that all eight compounds improved the short-term memory capacity, with potencies close to that of the positive control (memantine).
|
Modulation of P-gp (unknown origin) transfected in human MDA435/LCC6MDR cells assessed as reversible of paclitaxel resistance measured as IC50 for paclitaxel at 1 uM after 5 days by CellTiter 96 Aqueous assay
|
Homo sapiens
|
124.1
nM
|
|
Journal : J. Med. Chem.
Title : Potent and Nontoxic Chemosensitizer of P-Glycoprotein-Mediated Multidrug Resistance in Cancer: Synthesis and Evaluation of Methylated Epigallocatechin, Gallocatechin, and Dihydromyricetin Derivatives.
Year : 2015
Volume : 58
Issue : 11
First Page : 4529
Last Page : 4549
Authors : Wong IL, Wang BC, Yuan J, Duan LX, Liu Z, Liu T, Li XM, Hu X, Zhang XY, Jiang T, Wan SB, Chow LM.
Abstract : We are interested in developing novel natural product-derived P-gp inhibitors to reverse cancer drug resistance. Here, we have synthesized 55 novel derivatives of methylated epigallocatechin (EGC), gallocatechin (GC), and dihydromyricetin (DHM). Three EGC derivatives (23, 35, and 36) and three GC derivatives (50, 51, and 53) are significantly better than epigallocatechin gallate (EGCG) with a relative fold (RF) ranging from 31.4 to 53.6. The effective concentration (EC50) of 23 and 51 ranges from 102 to 195 nM. Compounds 23 and 51 are noncytotoxic to fibroblasts with IC50 > 100 μM. Compound 23 is specific for P-gp without modulating activity toward MRP1 or BCRP. Compounds 23 and 51 are non-P-gp substrates. Important pharmacophores for P-gp modulation were identified. In summary, methylated EGC and GC derivatives represent a new class of potent, specific, noncytotoxic, and nonsubstrate P-gp modulators.
|
Modulation of P-gp (unknown origin) transfected in human MDA435/LCC6MDR cells assessed as reversible of paclitaxel resistance measured as IC50 for paclitaxel at 10 uM after 5 days by CellTiter 96 Aqueous assay
|
Homo sapiens
|
122.6
nM
|
|
Journal : J. Med. Chem.
Title : Potent and Nontoxic Chemosensitizer of P-Glycoprotein-Mediated Multidrug Resistance in Cancer: Synthesis and Evaluation of Methylated Epigallocatechin, Gallocatechin, and Dihydromyricetin Derivatives.
Year : 2015
Volume : 58
Issue : 11
First Page : 4529
Last Page : 4549
Authors : Wong IL, Wang BC, Yuan J, Duan LX, Liu Z, Liu T, Li XM, Hu X, Zhang XY, Jiang T, Wan SB, Chow LM.
Abstract : We are interested in developing novel natural product-derived P-gp inhibitors to reverse cancer drug resistance. Here, we have synthesized 55 novel derivatives of methylated epigallocatechin (EGC), gallocatechin (GC), and dihydromyricetin (DHM). Three EGC derivatives (23, 35, and 36) and three GC derivatives (50, 51, and 53) are significantly better than epigallocatechin gallate (EGCG) with a relative fold (RF) ranging from 31.4 to 53.6. The effective concentration (EC50) of 23 and 51 ranges from 102 to 195 nM. Compounds 23 and 51 are noncytotoxic to fibroblasts with IC50 > 100 μM. Compound 23 is specific for P-gp without modulating activity toward MRP1 or BCRP. Compounds 23 and 51 are non-P-gp substrates. Important pharmacophores for P-gp modulation were identified. In summary, methylated EGC and GC derivatives represent a new class of potent, specific, noncytotoxic, and nonsubstrate P-gp modulators.
|
Inhibition of rat Dyrk1A using Woodtide as substrate after 40 mins by P81 membrane assay in presence of [33P]-g-ATP
|
Rattus norvegicus
|
330.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Meridianin derivatives as potent Dyrk1A inhibitors and neuroprotective agents.
Year : 2015
Volume : 25
Issue : 15
First Page : 2948
Last Page : 2952
Authors : Yadav RR, Sharma S, Joshi P, Wani A, Vishwakarma RA, Kumar A, Bharate SB.
Abstract : Meridianins are a group of marine-derived indole alkaloids which are reported to possess kinase inhibitory activities. In the present Letter, we report synthesis of N1-substituted and C-ring modified meridianin derivatives and their evaluation as Dyrk1A inhibitors and neuroprotective agents. Among the library of 52 compounds screened, morpholinoyl linked derivative 26b and 2-nitro-4-trifluoromethyl phenyl sulfonyl derivative 29v displayed potent inhibition of Dyrk1A with IC50 values of 0.5 and 0.53 μM, respectively. The derivative 26b also inhibited Dyrk2 and Dyrk3 with IC50 values of 1.4 and 2.2 μM, respectively showing 2.2 and 4.4 fold selectivity for Dyrk1A with respect to Dyrk2 and Dyrk3. The compound 26b was not cytotoxic to human neuroblastoma SH-SY5Y cells (IC50>100 μM) and it displayed significant neuroprotection against glutamate-induced neurotoxicity in these cells at 10 μM. Molecular modelling studies of compound 26b led to identification of key interactions in the binding site of Dyrk1A and the possible reasons for observed Dyrk1A selectivity over Dyrk2.
|
Inhibition of wild type His-tagged translin/trax E126A mutant (unknown origin) coexpressed in Escherichia coli BL21 cells using RNase Alert as substrate at 30 uM incubated for 10 mins prior to substrate addition monitored over 60 mins by fluorescence assay
|
Homo sapiens
|
88.0
%
|
|
Journal : Bioorg Med Chem Lett
Title : A druggable target for rescuing microRNA defects.
Year : 2016
Volume : 26
Issue : 20
First Page : 4942
Last Page : 4946
Authors : Asada K, Canestrari E, Paroo Z.
Abstract : Despite immense promise, development of microRNA (miRNA) therapeutics remains limited by pharmacodynamic challenges that have hindered progress of related oligonucleotide-based technologies. Recent discovery of enzymes that mediate miRNA metabolism represent potential pharmacological targets for directing miRNA function, circumventing barriers associated with oligonucleotides. We previously identified the Translin/Trax (TN/TX) ribonuclease complex as a pre-miRNA degrading enzyme that competes with pre-miRNA processing by Dicer. Here, we establish a high-throughput TN/TX assay and screened 2320 drug and natural product compounds for inhibitors of TN/TX. Secondary analyses demonstrate small molecule mediated inhibition of pre-miRNA degradation by TN/TX and enhanced miRNA processing by Dicer. This application of traditional enzyme-inhibitor pharmacology to the miRNA pathway establishes a druggable target for rescuing global miRNA defects, providing an important complement to current approaches towards miRNA therapeutics. More broadly, demonstrating feasibility of pharmacological targeting of the 'ribonucleome' is particularly important given emerging classes of regulatory RNA and growing understanding of their importance in health and disease.
|
Antiviral activity against HBV infected in human HuS-E/2 cells assessed as inhibition of viral mRNA level at 50 uM treated for 20 hrs measured after 7 days by RT-PCR method relative to control
|
Hepatitis B virus
|
80.0
%
|
|
Journal : J Med Chem
Title : Past, Current, and Future Developments of Therapeutic Agents for Treatment of Chronic Hepatitis B Virus Infection.
Year : 2017
Volume : 60
Issue : 15
First Page : 6461
Last Page : 6479
Authors : Pei Y, Wang C, Yan SF, Liu G.
Abstract : For decades, treatment of hepatitis B virus (HBV) infection has been relying on interferon (IFN)-based therapies and nucleoside/nucleotide analogues (NAs) that selectively target the viral polymerase reverse transcriptase (RT) domain and thereby disrupt HBV viral DNA synthesis. We have summarized here the key steps in the HBV viral life cycle, which could potentially be targeted by novel anti-HBV therapeutics. A wide range of next-generation direct antiviral agents (DAAs) with distinct mechanisms of actions are discussed, including entry inhibitors, transcription inhibitors, nucleoside/nucleotide analogues, inhibitors of viral ribonuclease H (RNase H), modulators of viral capsid assembly, inhibitors of HBV surface antigen (HBsAg) secretion, RNA interference (RNAi) gene silencers, antisense oligonucleotides (ASOs), and natural products. Compounds that exert their antiviral activities mainly through host factors and immunomodulation, such as host targeting agents (HTAs), programmed cell death protein 1 (PD-1)/programmed death ligand 1 (PD-L1) inhibitors, and Toll-like receptor (TLR) agonists, are also discussed. In this Perspective, we hope to provide an overview, albeit by no means being comprehensive, for the recent development of novel therapeutic agents for the treatment of chronic HBV infection, which not only are able to sustainably suppress viral DNA but also aim to achieve functional cure warranted by HBsAg loss and ultimately lead to virus eradication and cure of hepatitis B.
|
Binding affinity to recombinant human transthyretin expressed in Escherichia coli BL21 by STD-NMR spectroscopic method
|
Homo sapiens
|
400.0
nM
|
|
Journal : J Med Chem
Title : Insights on the Interaction between Transthyretin and Aβ in Solution. A Saturation Transfer Difference (STD) NMR Analysis of the Role of Iododiflunisal.
Year : 2017
Volume : 60
Issue : 13
First Page : 5749
Last Page : 5758
Authors : Gimeno A, Santos LM, Alemi M, Rivas J, Blasi D, Cotrina EY, Llop J, Valencia G, Cardoso I, Quintana J, Arsequell G, Jiménez-Barbero J.
Abstract : Several strategies against Alzheimer disease (AD) are directed to target Aβ-peptides. The ability of transthyretin (TTR) to bind Aβ-peptides and the positive effect exerted by some TTR stabilizers for modulating the TTR-Aβ interaction have been previously studied. Herein, key structural features of the interaction between TTR and the Aβ(12-28) peptide (3), the essential recognition element of Aβ, have been unravelled by STD-NMR spectroscopy methods in solution. Molecular aspects related to the role of the TTR stabilizer iododiflunisal (IDIF, 5) on the TTR-Aβ complex have been also examined. The NMR results, assisted by molecular modeling protocols, have provided a structural model for the TTR-Aβ interaction, as well as for the ternary complex formed in the presence of IDIF. This basic structural information could be relevant for providing light on the mechanisms involved in the ameliorating effects of AD symptoms observed in AD/TTR± animal models after IDIF treatment and eventually for designing new molecules toward AD therapeutic drugs.
|
Inhibition of recombinant human ACE at 100 uM using Mca-R-P-PG-F-S-A-F-K(Dnp)-OH as substrate measured every 2 mins for 8 mins by fluorescence assay
|
Homo sapiens
|
82.02
%
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery of a potent angiotensin converting enzyme inhibitor via virtual screening.
Year : 2017
Volume : 27
Issue : 16
First Page : 3688
Last Page : 3692
Authors : Ke Z, Su Z, Zhang X, Cao Z, Ding Y, Cao L, Ding G, Wang Z, Liu H, Xiao W.
Abstract : Prompted by the prominent role of angiotensin converting enzyme (ACE) in hypertension, heart failures, myocardial infarction and diabetic nephropathy, we have attempted to discover novel ACE inhibitors through ligand-based virtual screening. Molecular docking method and rigorously validated model was utilized to search a natural compounds database. Finally, 36 compounds were randomly selected and subjected to in vitro ACE kinase inhibitory assay using fluorescence assays method. The results showed that three compounds (Licochalcone A, Echinatin and EGCG) have strong potential to be developed as a new class of ACE inhibitors. Further chemical modification via fragment modifications guided by structure and ligand-based computational methodologies can lead to discover better agents as potential clinical candidates.
|
Antiviral activity against Chikungunya virus infected in HEK293T cells assessed as reduction in infectious virus particle production by luciferase reporter gene assay
|
Chikungunya virus
|
6.54
ug.mL-1
|
|
Journal : Bioorg Med Chem
Title : The medicinal chemistry of Chikungunya virus.
Year : 2017
Volume : 25
Issue : 16
First Page : 4219
Last Page : 4244
Authors : da Silva-Júnior EF, Leoncini GO, Rodrigues ÉES, Aquino TM, Araújo-Júnior JX.
Abstract : Arthropod-borne viruses (arboviruses) are an important threat to human and animal health globally. Among these, zoonotic diseases account for billions of cases of human illness and millions of deaths every year, representing an increasing public health problem. Chikungunya virus belongs to the genus Alphavirus of the family Togariridae, and is transmitted mainly by the bite of female mosquitoes of the Aedes aegypti and/or A. albopictus species. The focus of this review will be on the medicinal chemistry of Chikungunya virus, including synthetic and natural products, as well as rationally designed compounds.
|
Inhibition of HFIP-pretreated amyloid beta (1 to 42) (unknown origin) self-induced aggregation at 20 uM incubated for 24 hrs under dark condition by thioflavin-T based fluorometric assay relative to control
|
Homo sapiens
|
86.1
%
|
|
Journal : Bioorg Med Chem Lett
Title : Flavonoids and their derivatives with β-amyloid aggregation inhibitory activity from the leaves and twigs of Pithecellobium clypearia Benth.
Year : 2017
Volume : 27
Issue : 21
First Page : 4823
Last Page : 4827
Authors : Wang YX, Ren Q, Yan ZY, Wang W, Zhao L, Bai M, Wang XB, Huang XX, Song SJ.
Abstract : To explore potential compounds with marked effect on Alzheimer's disease (AD) in Pithecellobium clypearia Benth., nineteen compounds (1-19) were obtained, including two new flavonoid derivatives, named pithecellobiumol A (1) and pithecellobiumol B (2) and 17 flavonoids (3-19). Their structures were elucidated based on 1D and 2D-NMR spectra as well as HR-ESI-MS data. The absolute configurations of new compounds were assigned by comparing their experimental specific rotation or ECD curves with the calculated data. The inhibitory activity on Aβ aggregation was screened by ThT assay, and compounds 7 (70.7%), 9 (86.5%), 10 (88.4%), 15 (86.1%) and 16 (87.7%) showed outstanding inhibition rate at 20μM compared to the positive control, curcumin (65.64%). In addition, docking study was performed to initially examine possible molecular mechanisms. Considering the important role of oxidative stress in AD, all the isolated compounds were tested for their H2O2-induced damage in human neuronblastoma SH-SY5Y cells. Among them, compound 16 (91.0%) was the most potent candidate in the treatment of AD.
|
Displacement of [3H]resveratrol from Sprague-Dawley rat brain plasma membranes after 1 hr by beta counting method
|
Rattus norvegicus
|
25.0
nM
|
|
Journal : J Med Chem
Title : Polyphenolic Phytochemicals in Cancer Prevention and Therapy: Bioavailability versus Bioefficacy.
Year : 2017
Volume : 60
Issue : 23
First Page : 9413
Last Page : 9436
Authors : Estrela JM, Mena S, Obrador E, Benlloch M, Castellano G, Salvador R, Dellinger RW.
Abstract : Natural polyphenols are organic chemicals which contain phenol units in their structures. They show antitumor properties. However, a key problem is their short half-life and low bioavailability under in vivo conditions. Still, definitively demonstrating the human benefits of isolated polyphenolic compounds (alone or in combination) using modern scientific methodology has proved challenging. The most common discrepancy between experimental and clinical observations is the use of nonphysiologically relevant concentrations of polyphenols in mechanistic studies. Thus, it remains highly controversial how applicable underlying mechanisms are with bioavailable concentrations and biological half-life. The present Perspective analyses proposed antitumor mechanisms, in vivo reported antitumor effects, and possible mechanisms that may explain discrepancies between bioavailability and bioefficacy. Polyphenol metabolism and possible toxic side effects are also considered. Our main conclusion emphasizes that these natural molecules (and their chemical derivatives) indeed can be very useful, not only as cancer chemopreventive agents but also in oncotherapy.
|
Inhibition of enolase (unknown origin) at 0.625 uM using 2-PG relative to control
|
Homo sapiens
|
63.0
%
|
|
Journal : Bioorg Med Chem
Title : Xanthone derivatives as phosphoglycerate mutase 1 inhibitors: Design, synthesis, and biological evaluation.
Year : 2018
Volume : 26
Issue : 8
First Page : 1961
Last Page : 1970
Authors : Wang P, Jiang L, Cao Y, Zhang X, Chen B, Zhang S, Huang K, Ye D, Zhou L.
Abstract : Phosphoglycerate mutase 1 (PGAM1) is a glycolytic enzyme that dynamically converts 3-phosphoglycerate (3PG) to 2-phosphoglycerate (2PG), which was upregulated to coordinate glycolysis, pentose phosphate pathway (PPP) and serine biosynthesis to promote cancer cell proliferation and tumor growth in a variety of cancers. However, only a few inhibitors of PGAM1 have been reported with poor molecular or cellular efficacy. In this paper, a series of xanthone derivatives were discovered as novel PGAM1 inhibitors through scaffold hopping and sulfonamide reversal strategy based on the lead compound PGMI-004A. Most xanthone derivatives showed higher potency against PGAM1 than PGMI-004A and exhibited moderate anti-proliferation activity on different cancer cell lines.
|
Inhibition of LDH (unknown origin) at 0.625 uM using 2-PG relative to control
|
Homo sapiens
|
63.0
%
|
|
Journal : Bioorg Med Chem
Title : Xanthone derivatives as phosphoglycerate mutase 1 inhibitors: Design, synthesis, and biological evaluation.
Year : 2018
Volume : 26
Issue : 8
First Page : 1961
Last Page : 1970
Authors : Wang P, Jiang L, Cao Y, Zhang X, Chen B, Zhang S, Huang K, Ye D, Zhou L.
Abstract : Phosphoglycerate mutase 1 (PGAM1) is a glycolytic enzyme that dynamically converts 3-phosphoglycerate (3PG) to 2-phosphoglycerate (2PG), which was upregulated to coordinate glycolysis, pentose phosphate pathway (PPP) and serine biosynthesis to promote cancer cell proliferation and tumor growth in a variety of cancers. However, only a few inhibitors of PGAM1 have been reported with poor molecular or cellular efficacy. In this paper, a series of xanthone derivatives were discovered as novel PGAM1 inhibitors through scaffold hopping and sulfonamide reversal strategy based on the lead compound PGMI-004A. Most xanthone derivatives showed higher potency against PGAM1 than PGMI-004A and exhibited moderate anti-proliferation activity on different cancer cell lines.
|
Inhibition of pyruvate kinase (unknown origin) at 0.625 uM using 2-PG relative to control
|
Homo sapiens
|
63.0
%
|
|
Journal : Bioorg Med Chem
Title : Xanthone derivatives as phosphoglycerate mutase 1 inhibitors: Design, synthesis, and biological evaluation.
Year : 2018
Volume : 26
Issue : 8
First Page : 1961
Last Page : 1970
Authors : Wang P, Jiang L, Cao Y, Zhang X, Chen B, Zhang S, Huang K, Ye D, Zhou L.
Abstract : Phosphoglycerate mutase 1 (PGAM1) is a glycolytic enzyme that dynamically converts 3-phosphoglycerate (3PG) to 2-phosphoglycerate (2PG), which was upregulated to coordinate glycolysis, pentose phosphate pathway (PPP) and serine biosynthesis to promote cancer cell proliferation and tumor growth in a variety of cancers. However, only a few inhibitors of PGAM1 have been reported with poor molecular or cellular efficacy. In this paper, a series of xanthone derivatives were discovered as novel PGAM1 inhibitors through scaffold hopping and sulfonamide reversal strategy based on the lead compound PGMI-004A. Most xanthone derivatives showed higher potency against PGAM1 than PGMI-004A and exhibited moderate anti-proliferation activity on different cancer cell lines.
|
Inhibition of recombinant human His-tagged PGAM1 expressed in Escherichia coli BL21 competent cells by kinase-glo assay
|
Homo sapiens
|
490.0
nM
|
|
Journal : Bioorg Med Chem
Title : Xanthone derivatives as phosphoglycerate mutase 1 inhibitors: Design, synthesis, and biological evaluation.
Year : 2018
Volume : 26
Issue : 8
First Page : 1961
Last Page : 1970
Authors : Wang P, Jiang L, Cao Y, Zhang X, Chen B, Zhang S, Huang K, Ye D, Zhou L.
Abstract : Phosphoglycerate mutase 1 (PGAM1) is a glycolytic enzyme that dynamically converts 3-phosphoglycerate (3PG) to 2-phosphoglycerate (2PG), which was upregulated to coordinate glycolysis, pentose phosphate pathway (PPP) and serine biosynthesis to promote cancer cell proliferation and tumor growth in a variety of cancers. However, only a few inhibitors of PGAM1 have been reported with poor molecular or cellular efficacy. In this paper, a series of xanthone derivatives were discovered as novel PGAM1 inhibitors through scaffold hopping and sulfonamide reversal strategy based on the lead compound PGMI-004A. Most xanthone derivatives showed higher potency against PGAM1 than PGMI-004A and exhibited moderate anti-proliferation activity on different cancer cell lines.
|
Inhibition of human recombinant GST-tagged DYRK1A expressed in Escherichia coli using KKISGRLSPIMTEQ as substrate after 40 mins in presence of [gamma33P-ATP]
|
Homo sapiens
|
330.0
nM
|
|
Journal : J Med Chem
Title : Dual-Specificity Tyrosine Phosphorylation-Regulated Kinase 1A (DYRK1A) Inhibitors as Potential Therapeutics.
Year : 2018
Volume : 61
Issue : 22
First Page : 9791
Last Page : 9810
Authors : Jarhad DB, Mashelkar KK, Kim HR, Noh M, Jeong LS.
Abstract : Dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) is a member of an evolutionarily conserved family of protein kinases that belongs to the CMGC group of kinases. DYRK1A, encoded by a gene located in the human chromosome 21q22.2 region, has attracted attention due to its association with both neuropathological phenotypes and cancer susceptibility in patients with Down syndrome (DS). Inhibition of DYRK1A attenuates cognitive dysfunctions in animal models for both DS and Alzheimer's disease (AD). Furthermore, DYRK1A has been studied as a potential cancer therapeutic target because of its role in the regulation of cell cycle progression by affecting both tumor suppressors and oncogenes. Consequently, selective synthetic inhibitors have been developed to determine the role of DYRK1A in various human diseases. Our perspective includes a comprehensive review of potent and selective DYRK1A inhibitors and their forthcoming therapeutic applications.
|
Antibacterial activity against Staphylococcus aureus MRSA ATCC 43300 (CO-ADD:GP_020); MIC in CAMBH media, using NBS plates, by OD(600)
|
Staphylococcus aureus subsp. aureus
|
13.39
%
|
|
|
Antibacterial activity against Escherichia coli ATCC 25922 (CO-ADD:GN_001); MIC in CAMBH media using NBS plates, by OD(600)
|
Escherichia coli
|
5.85
%
|
|
|
Antibacterial activity against Klebsiella pneumoniae MDR ATCC 70063 (CO-ADD:GN_003); MIC in CAMBH media using NBS plates, by OD(600)
|
Klebsiella pneumoniae
|
17.83
%
|
|
|
Antibacterial activity against Pseudomonas aeruginosa ATCC 27853 (CO-ADD:GN_042); MIC in CAMBH media using NBS plates, by OD(600)
|
Pseudomonas aeruginosa
|
27.87
%
|
|
|
Antibacterial activity against Acinetobacter baumannii ATCC 19606 (CO-ADD:GN_034); MIC in CAMBH media using NBS plates, by OD600
|
Acinetobacter baumannii
|
29.27
%
|
|
|
Antifungal activity against Candida albicans ATCC 90028 (CO-ADD:FG_001); MIC in YNB media using NBS plates, by OD630
|
Candida albicans
|
3.47
%
|
|
|
Antifungal activity against Cryptococcus neoformans H99 ATCC 208821 (CO-ADD:FG_002); MIC in YNB media using NBS plates, by Resazurin OD(600-570)
|
Cryptococcus neoformans
|
-2.04
%
|
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of Caco-2 cells at 10 uM after 48 hours by high content imaging
|
Homo sapiens
|
6.28
%
|
|
Title : Identification of inhibitors of SARS-CoV-2 in-vitro cellular toxicity in human (Caco-2) cells using a large scale drug repurposing collection
Year : 2020
Authors : Bernhard Ellinger, Denisa Bojkova, Andrea Zaliani, Jindrich Cinatl, Carsten Claussen, Sandra Westhaus, Jeanette Reinshagen, Maria Kuzikov, Markus Wolf, Gerd Geisslinger, Philip Gribbon, Sandra Ciesek
Abstract : To identify possible candidates for progression towards clinical studies against SARS-CoV-2, we screened a well-defined collection of 5632 compounds including 3488 compounds which have undergone clinical investigations (marketed drugs, phases 1 -3, and withdrawn) across 600 indications. Compounds were screened for their inhibition of viral induced cytotoxicity using the human epithelial colorectal adenocarcinoma cell line Caco-2 and a SARS-CoV-2 isolate. The primary screen of 5632 compounds gave 271 hits. A total of 64 compounds with IC50 <20 µM were identified, including 19 compounds with IC50 < 1 µM. Of this confirmed hit population, 90% have not yet been previously reported as active against SARS-CoV-2 in-vitro cell assays. Some 37 of the actives are launched drugs, 19 are in phases 1-3 and 10 pre-clinical. Several inhibitors were associated with modulation of host pathways including kinase signaling P53 activation, ubiquitin pathways and PDE activity modulation, with long chain acyl transferases were effective viral inhibitors.
|
Inhibition of HFIP-pretreated amyloid beta (1 to 42 residues) (unknown origin) self aggregation at 25 uM after 7 days by ThT-based fluorometric method relative to control
|
Homo sapiens
|
52.9
%
|
|
Journal : Eur J Med Chem
Title : On the role of synthesized hydroxylated chalcones as dual functional amyloid-β aggregation and ferroptosis inhibitors for potential treatment of Alzheimer's disease.
Year : 2019
Volume : 166
First Page : 11
Last Page : 21
Authors : Cong L, Dong X, Wang Y, Deng Y, Li B, Dai R.
Abstract : In addition to amyloid cascade hypothesis, ferroptosis - a recently identified cell death pathway associated with the accumulation of lipid hydroperoxides - was hypothesized as one of the main forms of cell death in Alzheimer's disease. Herein, a series of hydroxylated chalcones were designed and synthesized as dual-functional inhibitors to inhibit amyloid-β peptide (Aβ) aggregation as well as ferroptosis simultaneously. Thioflavin-T assay indicated trihydroxy chalcones inhibited Aβ aggregation better. In human neuroblastoma SH-SY5Y cells, cytoprotective chalcones 14a-c with three hydroxyl substituents exhibited a significant neuroprotection against Aβ1-42 aggregation induced toxicity. In addition, chalcones 14a-c were found to be good inhibitors of ferroptosis induced by either pharmacological inhibition of the hydroperoxide-detoxifying enzyme Gpx4 using (1S, 3R)-RSL4 or cystine/glutamate antiporter system Xc- inhibition by erastin through lipid peroxidation inhibition mechanism. Trihydroxy chalcone 14a was also able to completely subvert lipid peroxidation induced by Aβ1-42 aggregation in SH-SY5Y cells indicating that they can reduce the neurotoxicity involved with oxidative stress. Compound 14a-c showed good ADMET properties and blood-brain barrier penetration in silico simulation software. From these data, a picture emerges wherein trihydroxy chalcones are potential candidates for the treatment of Alzheimer's disease by simultaneously inhibition of Aβ1-42 aggregation and ferroptosis.
|
Inhibition of Streptococcus mutans F-ATPase activity relative to control
|
Streptococcus mutans
|
50.0
%
|
|
Journal : MedChemComm
Title : Targeting <i>S. mutans</i> biofilms: a perspective on preventing dental caries.
Year : 2019
Volume : 10
Issue : 7
First Page : 1057
Last Page : 1067
Authors : Scharnow AM, Solinski AE, Wuest WM.
Abstract : The prevalence of biofilm diseases, and dental caries in particular, have encouraged extensive research on <i>S. mutans</i> biofilms, including methods of preventing its formation. Numerous small molecules with specific anti-biofilm activity against this pathogen have been isolated and synthesized. Generally, these molecules can be characterized into three categories: sucrose-dependent anti-adhesion, sucrose-independent anti-adhesion and cellular signaling interference. This review aims to provide an overview of the current small molecule strategies used for targeting <i>S. mutans</i> biofilms, and a perspective of the future for the field.
|
Inhibition of Escherichia coli GroEL expressed in Escherichia coli DH5alpha/Escherichia coli GroES expressed in Escherichia coli BL21 (DE3) assessed as reduction in GroEL/GroES-mediated denatured rhodanese refolding by measuring rhodanese enzyme activity after 45 mins by Fe(SCN)3 dye based spectrometric analysis
|
Escherichia coli
|
580.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : HSP60/10 chaperonin systems are inhibited by a variety of approved drugs, natural products, and known bioactive molecules.
Year : 2019
Volume : 29
Issue : 9
First Page : 1106
Last Page : 1112
Authors : Stevens M, Abdeen S, Salim N, Ray AM, Washburn A, Chitre S, Sivinski J, Park Y, Hoang QQ, Chapman E, Johnson SM.
Abstract : All living organisms contain a unique class of molecular chaperones called 60 kDa heat shock proteins (HSP60 - also known as GroEL in bacteria). While some organisms contain more than one HSP60 or GroEL isoform, at least one isoform has always proven to be essential. Because of this, we have been investigating targeting HSP60 and GroEL chaperonin systems as an antibiotic strategy. Our initial studies focused on applying this antibiotic strategy for treating African sleeping sickness (caused by Trypanosoma brucei parasites) and drug-resistant bacterial infections (in particular Methicillin-resistant Staphylococcus aureus - MRSA). Intriguingly, during our studies we found that three known antibiotics - suramin, closantel, and rafoxanide - were potent inhibitors of bacterial GroEL and human HSP60 chaperonin systems. These findings prompted us to explore what other approved drugs, natural products, and known bioactive molecules might also inhibit HSP60 and GroEL chaperonin systems. Initial high-throughput screening of 3680 approved drugs, natural products, and known bioactives identified 161 hit inhibitors of the Escherichia coli GroEL chaperonin system (4.3% hit rate). From a purchased subset of 60 hits, 29 compounds (48%) re-confirmed as selective GroEL inhibitors in our assays, all of which were nearly equipotent against human HSP60. These findings illuminate the notion that targeting chaperonin systems might be a more common occurrence than we previously appreciated. Future studies are needed to determine if the in vivo modes of action of these approved drugs, natural products, and known bioactive molecules are related to GroEL and HSP60 inhibition.
|
Inhibition of Escherichia coli GroEL expressed in Escherichia coliDH5alpha/Escherichia coli GroES expressed in Escherichia coli BL21 (DE3) assessed as reduction in GroEL/GroES-mediated denatured soluble pig heart MDH refolding by measuring MDH enzyme activity using sodium mesoxalate as substrate after 20 to 40 mins by malachite green dye based spectrometric analysis
|
Escherichia coli
|
360.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : HSP60/10 chaperonin systems are inhibited by a variety of approved drugs, natural products, and known bioactive molecules.
Year : 2019
Volume : 29
Issue : 9
First Page : 1106
Last Page : 1112
Authors : Stevens M, Abdeen S, Salim N, Ray AM, Washburn A, Chitre S, Sivinski J, Park Y, Hoang QQ, Chapman E, Johnson SM.
Abstract : All living organisms contain a unique class of molecular chaperones called 60 kDa heat shock proteins (HSP60 - also known as GroEL in bacteria). While some organisms contain more than one HSP60 or GroEL isoform, at least one isoform has always proven to be essential. Because of this, we have been investigating targeting HSP60 and GroEL chaperonin systems as an antibiotic strategy. Our initial studies focused on applying this antibiotic strategy for treating African sleeping sickness (caused by Trypanosoma brucei parasites) and drug-resistant bacterial infections (in particular Methicillin-resistant Staphylococcus aureus - MRSA). Intriguingly, during our studies we found that three known antibiotics - suramin, closantel, and rafoxanide - were potent inhibitors of bacterial GroEL and human HSP60 chaperonin systems. These findings prompted us to explore what other approved drugs, natural products, and known bioactive molecules might also inhibit HSP60 and GroEL chaperonin systems. Initial high-throughput screening of 3680 approved drugs, natural products, and known bioactives identified 161 hit inhibitors of the Escherichia coli GroEL chaperonin system (4.3% hit rate). From a purchased subset of 60 hits, 29 compounds (48%) re-confirmed as selective GroEL inhibitors in our assays, all of which were nearly equipotent against human HSP60. These findings illuminate the notion that targeting chaperonin systems might be a more common occurrence than we previously appreciated. Future studies are needed to determine if the in vivo modes of action of these approved drugs, natural products, and known bioactive molecules are related to GroEL and HSP60 inhibition.
|
Inhibition of Escherichia coli GroEL expressed in Escherichia coliDH5alpha/Escherichia coli GroES expressed in Escherichia coli BL21 (DE3) assessed as reduction in GroEL/GroES-mediated denatured soluble pig heart MDH refolding by measuring MDH enzyme activity using sodium mesoxalate as substrate after 20 to 40 mins by malachite green dye based spectrometric analysis relative to untreated control
|
Escherichia coli
|
90.0
%
|
|
Journal : Bioorg Med Chem Lett
Title : HSP60/10 chaperonin systems are inhibited by a variety of approved drugs, natural products, and known bioactive molecules.
Year : 2019
Volume : 29
Issue : 9
First Page : 1106
Last Page : 1112
Authors : Stevens M, Abdeen S, Salim N, Ray AM, Washburn A, Chitre S, Sivinski J, Park Y, Hoang QQ, Chapman E, Johnson SM.
Abstract : All living organisms contain a unique class of molecular chaperones called 60 kDa heat shock proteins (HSP60 - also known as GroEL in bacteria). While some organisms contain more than one HSP60 or GroEL isoform, at least one isoform has always proven to be essential. Because of this, we have been investigating targeting HSP60 and GroEL chaperonin systems as an antibiotic strategy. Our initial studies focused on applying this antibiotic strategy for treating African sleeping sickness (caused by Trypanosoma brucei parasites) and drug-resistant bacterial infections (in particular Methicillin-resistant Staphylococcus aureus - MRSA). Intriguingly, during our studies we found that three known antibiotics - suramin, closantel, and rafoxanide - were potent inhibitors of bacterial GroEL and human HSP60 chaperonin systems. These findings prompted us to explore what other approved drugs, natural products, and known bioactive molecules might also inhibit HSP60 and GroEL chaperonin systems. Initial high-throughput screening of 3680 approved drugs, natural products, and known bioactives identified 161 hit inhibitors of the Escherichia coli GroEL chaperonin system (4.3% hit rate). From a purchased subset of 60 hits, 29 compounds (48%) re-confirmed as selective GroEL inhibitors in our assays, all of which were nearly equipotent against human HSP60. These findings illuminate the notion that targeting chaperonin systems might be a more common occurrence than we previously appreciated. Future studies are needed to determine if the in vivo modes of action of these approved drugs, natural products, and known bioactive molecules are related to GroEL and HSP60 inhibition.
|
Inhibition of Escherichia coli GroEL expressed in Escherichia coli DH5alpha/Escherichia coli GroES expressed in Escherichia coli BL21 (DE3) assessed as reduction in GroEL/GroES-mediated denatured rhodanese refolding by measuring rhodanese enzyme activity after 45 mins by Fe(SCN)3 dye based spectrometric analysis relative to untreated control
|
Escherichia coli
|
98.0
%
|
|
Journal : Bioorg Med Chem Lett
Title : HSP60/10 chaperonin systems are inhibited by a variety of approved drugs, natural products, and known bioactive molecules.
Year : 2019
Volume : 29
Issue : 9
First Page : 1106
Last Page : 1112
Authors : Stevens M, Abdeen S, Salim N, Ray AM, Washburn A, Chitre S, Sivinski J, Park Y, Hoang QQ, Chapman E, Johnson SM.
Abstract : All living organisms contain a unique class of molecular chaperones called 60 kDa heat shock proteins (HSP60 - also known as GroEL in bacteria). While some organisms contain more than one HSP60 or GroEL isoform, at least one isoform has always proven to be essential. Because of this, we have been investigating targeting HSP60 and GroEL chaperonin systems as an antibiotic strategy. Our initial studies focused on applying this antibiotic strategy for treating African sleeping sickness (caused by Trypanosoma brucei parasites) and drug-resistant bacterial infections (in particular Methicillin-resistant Staphylococcus aureus - MRSA). Intriguingly, during our studies we found that three known antibiotics - suramin, closantel, and rafoxanide - were potent inhibitors of bacterial GroEL and human HSP60 chaperonin systems. These findings prompted us to explore what other approved drugs, natural products, and known bioactive molecules might also inhibit HSP60 and GroEL chaperonin systems. Initial high-throughput screening of 3680 approved drugs, natural products, and known bioactives identified 161 hit inhibitors of the Escherichia coli GroEL chaperonin system (4.3% hit rate). From a purchased subset of 60 hits, 29 compounds (48%) re-confirmed as selective GroEL inhibitors in our assays, all of which were nearly equipotent against human HSP60. These findings illuminate the notion that targeting chaperonin systems might be a more common occurrence than we previously appreciated. Future studies are needed to determine if the in vivo modes of action of these approved drugs, natural products, and known bioactive molecules are related to GroEL and HSP60 inhibition.
|
Inhibition of HAT (unknown origin) relative to control
|
Homo sapiens
|
50.0
%
|
|
Journal : Eur J Med Chem
Title : Histone acetyltransferase inhibitors: An overview in synthesis, structure-activity relationship and molecular mechanism.
Year : 2019
Volume : 178
First Page : 259
Last Page : 286
Authors : Huang M, Huang J, Zheng Y, Sun Q.
Abstract : Acetylation, a key component in post-translational modification regulated by HATs and HDACs, is relevant to many crucial cellular contexts in organisms. Based on crucial pharmacophore patterns and the structure of targeted proteins, HAT inhibitors are designed and modified for higher affinity and better bioactivity. However, there are still some challenges, such as cell permeability, selectivity, toxicity and synthetic availability, which limit the improvement of HAT inhibitors. So far, only few HAT inhibitors have been approved for commercialization, indicating the urgent need for more successful and effective structure-based drug design and synthetic strategies. Here, we summarized three classes of HAT inhibitors based on their sources and structural scaffolds, emphasizing on their synthetic methods and structure-activity relationships and molecular mechanisms, hoping to facilitate the development and further application of HAT inhibitors.
|
Antileishmanial activity against Leishmania infantum MHOM/MA/67/ITMAP263 promastigotes infected in BALB/c mouse peritoneal macrophages assessed as decrease in parasitic infection index at 48 uM incubated for 72 hrs by light microscopy relative to control
|
Leishmania infantum
|
97.7
%
|
|
Journal : J Nat Prod
Title : (-)-Epigallocatechin 3-O-Gallate as a New Approach for the Treatment of Visceral Leishmaniasis.
Year : 2019
Volume : 82
Issue : 9
First Page : 2664
Last Page : 2667
Authors : Inacio JDF, Fonseca MS, Almeida-Amaral EE.
Abstract : In addition to generating side effects and resistance, treatment for visceral leishmaniasis remains mostly ineffective and expensive, and it has a long duration. Thus, natural products are an important alternative for treatment of the disease. In this study, we demonstrate the in vitro and in vivo activity of (-)-epigallocatechin 3-O-gallate (1) against Leishmania infantum. Compound 1 reduced the infection index with an EC50 value of 2.6 μM. Oral administration of 1 on L. infantum-infected BALB/c mice was capable to reduce the liver-parasite load with a ED50 and ED90 value of 12.4 and 21.5 mg/kg/day, respectively. Together, the results demonstrated 1 as a new compound for the treatment of visceral leishmaniasis.
|
Antileishmanial activity against stationary phase of Leishmania infantum MHOM/MA/67/ITMAP263 infected in BALB/c mouse assessed as decrease in parasitic load in liver at 12.5 mg/kg/day administered orally via gavage as bid for 5 days on 7th day post infection and measured on day 30 by limiting dilution assay relative to control
|
Leishmania infantum
|
47.5
%
|
|
Journal : J Nat Prod
Title : (-)-Epigallocatechin 3-O-Gallate as a New Approach for the Treatment of Visceral Leishmaniasis.
Year : 2019
Volume : 82
Issue : 9
First Page : 2664
Last Page : 2667
Authors : Inacio JDF, Fonseca MS, Almeida-Amaral EE.
Abstract : In addition to generating side effects and resistance, treatment for visceral leishmaniasis remains mostly ineffective and expensive, and it has a long duration. Thus, natural products are an important alternative for treatment of the disease. In this study, we demonstrate the in vitro and in vivo activity of (-)-epigallocatechin 3-O-gallate (1) against Leishmania infantum. Compound 1 reduced the infection index with an EC50 value of 2.6 μM. Oral administration of 1 on L. infantum-infected BALB/c mice was capable to reduce the liver-parasite load with a ED50 and ED90 value of 12.4 and 21.5 mg/kg/day, respectively. Together, the results demonstrated 1 as a new compound for the treatment of visceral leishmaniasis.
|
Antileishmanial activity against stationary phase of Leishmania infantum MHOM/MA/67/ITMAP263 infected in BALB/c mouse assessed as decrease in parasitic load in liver at 25 mg/kg/day administered orally via gavage as bid for 5 days on 7th day post infection and measured on day 30 by limiting dilution assay relative to control
|
Leishmania infantum
|
93.6
%
|
|
Journal : J Nat Prod
Title : (-)-Epigallocatechin 3-O-Gallate as a New Approach for the Treatment of Visceral Leishmaniasis.
Year : 2019
Volume : 82
Issue : 9
First Page : 2664
Last Page : 2667
Authors : Inacio JDF, Fonseca MS, Almeida-Amaral EE.
Abstract : In addition to generating side effects and resistance, treatment for visceral leishmaniasis remains mostly ineffective and expensive, and it has a long duration. Thus, natural products are an important alternative for treatment of the disease. In this study, we demonstrate the in vitro and in vivo activity of (-)-epigallocatechin 3-O-gallate (1) against Leishmania infantum. Compound 1 reduced the infection index with an EC50 value of 2.6 μM. Oral administration of 1 on L. infantum-infected BALB/c mice was capable to reduce the liver-parasite load with a ED50 and ED90 value of 12.4 and 21.5 mg/kg/day, respectively. Together, the results demonstrated 1 as a new compound for the treatment of visceral leishmaniasis.
|
Antileishmanial activity against stationary phase of Leishmania infantum MHOM/MA/67/ITMAP263 promastigotes infected in BALB/c mouse assessed as decrease in parasitic load in liver at 50 mg/kg/day administered orally via gavage as bid for 5 days on 7th day post infection and measured on day 30 by limiting dilution assay relative to control
|
Leishmania infantum
|
98.7
%
|
|
Journal : J Nat Prod
Title : (-)-Epigallocatechin 3-O-Gallate as a New Approach for the Treatment of Visceral Leishmaniasis.
Year : 2019
Volume : 82
Issue : 9
First Page : 2664
Last Page : 2667
Authors : Inacio JDF, Fonseca MS, Almeida-Amaral EE.
Abstract : In addition to generating side effects and resistance, treatment for visceral leishmaniasis remains mostly ineffective and expensive, and it has a long duration. Thus, natural products are an important alternative for treatment of the disease. In this study, we demonstrate the in vitro and in vivo activity of (-)-epigallocatechin 3-O-gallate (1) against Leishmania infantum. Compound 1 reduced the infection index with an EC50 value of 2.6 μM. Oral administration of 1 on L. infantum-infected BALB/c mice was capable to reduce the liver-parasite load with a ED50 and ED90 value of 12.4 and 21.5 mg/kg/day, respectively. Together, the results demonstrated 1 as a new compound for the treatment of visceral leishmaniasis.
|
Inhibition of chymotrypsin-like activity of purified human 20S proteasome assessed as decrease in AMC hydrolysis using Suc-Leu-Leu-Val-Tyr-AMC as substrate incubated for 30 mins by fluorometric analysis
|
Homo sapiens
|
86.0
nM
|
|
Journal : Eur J Med Chem
Title : Another look at phenolic compounds in cancer therapy the effect of polyphenols on ubiquitin-proteasome system.
Year : 2019
Volume : 167
First Page : 291
Last Page : 311
Authors : Golonko A, Pienkowski T, Swislocka R, Lazny R, Roszko M, Lewandowski W.
Abstract : Inhibitors of the ubiquitin-proteasome system (UPS) have been the object of research interests for many years because of their potential as anti-cancer agents. Research in this field is aimed at improving the specificity and safety of known proteasome inhibitors. Unfortunately, in vitro conditions do not reflect the processes taking place in the human body. Recent reports indicate that the components of human plasma affect the course of many signaling pathways, proteasome activity and the effectiveness of synthetic cytostatic drugs. Therefore, it is believed that the key issue is to determine the effects of components of the human diet, including effects of chemically active polyphenols on the ubiquitin-proteasome system activity in both physiological and pathological (cancerous) states. The following article summarizes the current knowledge on the direct and indirect synergistic and antagonistic effects between polyphenolic compounds present in the human diet and the efficiency of protein degradation via the UPS.
|
Inhibition of RAD52 (unknown origin) assessed as reduction in RAD52-ssDNA interaction using Cy3-dT30-Cy5 ssDNA by FRET assay
|
Homo sapiens
|
277.0
nM
|
|
Title : HTS Assay for Identifying Small Molecule Inhibitors of RAD52 and Uses of Identified Small Molecule Inhibitors for Treatment and Prevention of BRCA-Deficient Malignancies
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
99.33
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
99.51
%
|
|
Title : Identification of inhibitors of SARS-Cov2 M-Pro enzymatic activity using a small molecule repurposing screen
Year : 2020
Authors : Maria Kuzikov, Elisa Costanzi, Jeanette Reinshagen, Francesca Esposito, Laura Vangeel, Markus Wolf, Bernhard Ellinger, Carsten Claussen, Gerd Geisslinger, Angela Corona, Daniela Iaconis, Carmine Talarico, Candida Manelfi, Rolando Cannalire, Giulia Rossetti, Jonas Gossen, Simone Albani, Francesco Musiani, Katja Herzog, Yang Ye, Barbara Giabbai, Nicola Demitri, Dirk Jochmans, Steven De Jonghe, Jasper Rymenants, Vincenzo Summa, Enzo Tramontano, Andrea R. Beccari, Pieter Leyssen, Paola Storici, Johan Neyts, Philip Gribbon, and Andrea Zaliani
Abstract : Compound repurposing is an important strategy being pursued in the identification of effective treatment against the SARS-CoV-2 infection and COVID-19 disease. In this regard, SARS-CoV-2 main protease (M-Pro), also termed 3CL-Pro, is an attractive drug target as it plays a central role in viral replication by processing the viral polyprotein into 11 non-structural proteins. We report the results of a screening campaign involving ca 8.7 K compounds containing marketed drugs, clinical and preclinical candidates, and chemicals regarded as safe in humans. We confirmed previously reported inhibitors of 3CL-Pro, but we have also identified 68 compounds with IC50 lower than 1 uM and 127 compounds with IC50 lower than 5 uM. Profiling showed 67% of confirmed hits were selective (> 5 fold) against other Cys- and Ser- proteases (Chymotrypsin and Cathepsin-L) and MERS 3CL-Pro. Selected compounds were also analysed in their binding characteristics.
|
SARS-CoV-2 3CL-Pro protease inhibition IC50 determined by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
720.0
nM
|
|
Title : Identification of inhibitors of SARS-Cov2 M-Pro enzymatic activity using a small molecule repurposing screen
Year : 2020
Authors : Maria Kuzikov, Elisa Costanzi, Jeanette Reinshagen, Francesca Esposito, Laura Vangeel, Markus Wolf, Bernhard Ellinger, Carsten Claussen, Gerd Geisslinger, Angela Corona, Daniela Iaconis, Carmine Talarico, Candida Manelfi, Rolando Cannalire, Giulia Rossetti, Jonas Gossen, Simone Albani, Francesco Musiani, Katja Herzog, Yang Ye, Barbara Giabbai, Nicola Demitri, Dirk Jochmans, Steven De Jonghe, Jasper Rymenants, Vincenzo Summa, Enzo Tramontano, Andrea R. Beccari, Pieter Leyssen, Paola Storici, Johan Neyts, Philip Gribbon, and Andrea Zaliani
Abstract : Compound repurposing is an important strategy being pursued in the identification of effective treatment against the SARS-CoV-2 infection and COVID-19 disease. In this regard, SARS-CoV-2 main protease (M-Pro), also termed 3CL-Pro, is an attractive drug target as it plays a central role in viral replication by processing the viral polyprotein into 11 non-structural proteins. We report the results of a screening campaign involving ca 8.7 K compounds containing marketed drugs, clinical and preclinical candidates, and chemicals regarded as safe in humans. We confirmed previously reported inhibitors of 3CL-Pro, but we have also identified 68 compounds with IC50 lower than 1 uM and 127 compounds with IC50 lower than 5 uM. Profiling showed 67% of confirmed hits were selective (> 5 fold) against other Cys- and Ser- proteases (Chymotrypsin and Cathepsin-L) and MERS 3CL-Pro. Selected compounds were also analysed in their binding characteristics.
|
MERS 3CL-Pro protease inhibition percentage at 10 µM by FRET kind of response from peptide substrate
|
Middle East respiratory syndrome
|
10.0
%
|
|
MERS 3CL-Pro protease inhibition percentage at 10 µM by FRET kind of response from peptide substrate
|
Middle East respiratory syndrome
|
16.0
%
|
|
Title : Identification of inhibitors of SARS-Cov2 M-Pro enzymatic activity using a small molecule repurposing screen
Year : 2020
Authors : Maria Kuzikov, Elisa Costanzi, Jeanette Reinshagen, Francesca Esposito, Laura Vangeel, Markus Wolf, Bernhard Ellinger, Carsten Claussen, Gerd Geisslinger, Angela Corona, Daniela Iaconis, Carmine Talarico, Candida Manelfi, Rolando Cannalire, Giulia Rossetti, Jonas Gossen, Simone Albani, Francesco Musiani, Katja Herzog, Yang Ye, Barbara Giabbai, Nicola Demitri, Dirk Jochmans, Steven De Jonghe, Jasper Rymenants, Vincenzo Summa, Enzo Tramontano, Andrea R. Beccari, Pieter Leyssen, Paola Storici, Johan Neyts, Philip Gribbon, and Andrea Zaliani
Abstract : Compound repurposing is an important strategy being pursued in the identification of effective treatment against the SARS-CoV-2 infection and COVID-19 disease. In this regard, SARS-CoV-2 main protease (M-Pro), also termed 3CL-Pro, is an attractive drug target as it plays a central role in viral replication by processing the viral polyprotein into 11 non-structural proteins. We report the results of a screening campaign involving ca 8.7 K compounds containing marketed drugs, clinical and preclinical candidates, and chemicals regarded as safe in humans. We confirmed previously reported inhibitors of 3CL-Pro, but we have also identified 68 compounds with IC50 lower than 1 uM and 127 compounds with IC50 lower than 5 uM. Profiling showed 67% of confirmed hits were selective (> 5 fold) against other Cys- and Ser- proteases (Chymotrypsin and Cathepsin-L) and MERS 3CL-Pro. Selected compounds were also analysed in their binding characteristics.
|
Chymotrypsin inhibition percentage at 10 µM by FRET kind of response from peptide substrate
|
Homo sapiens
|
-0.5
%
|
|
Title : Identification of inhibitors of SARS-Cov2 M-Pro enzymatic activity using a small molecule repurposing screen
Year : 2020
Authors : Maria Kuzikov, Elisa Costanzi, Jeanette Reinshagen, Francesca Esposito, Laura Vangeel, Markus Wolf, Bernhard Ellinger, Carsten Claussen, Gerd Geisslinger, Angela Corona, Daniela Iaconis, Carmine Talarico, Candida Manelfi, Rolando Cannalire, Giulia Rossetti, Jonas Gossen, Simone Albani, Francesco Musiani, Katja Herzog, Yang Ye, Barbara Giabbai, Nicola Demitri, Dirk Jochmans, Steven De Jonghe, Jasper Rymenants, Vincenzo Summa, Enzo Tramontano, Andrea R. Beccari, Pieter Leyssen, Paola Storici, Johan Neyts, Philip Gribbon, and Andrea Zaliani
Abstract : Compound repurposing is an important strategy being pursued in the identification of effective treatment against the SARS-CoV-2 infection and COVID-19 disease. In this regard, SARS-CoV-2 main protease (M-Pro), also termed 3CL-Pro, is an attractive drug target as it plays a central role in viral replication by processing the viral polyprotein into 11 non-structural proteins. We report the results of a screening campaign involving ca 8.7 K compounds containing marketed drugs, clinical and preclinical candidates, and chemicals regarded as safe in humans. We confirmed previously reported inhibitors of 3CL-Pro, but we have also identified 68 compounds with IC50 lower than 1 uM and 127 compounds with IC50 lower than 5 uM. Profiling showed 67% of confirmed hits were selective (> 5 fold) against other Cys- and Ser- proteases (Chymotrypsin and Cathepsin-L) and MERS 3CL-Pro. Selected compounds were also analysed in their binding characteristics.
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.15
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
0.29
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.15
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
0.29
%
|
|
Title : Cytopathic SARS-Cov2 screening on VERO-E6 cells in a large repurposing effort
Year : 2020
Authors : Andrea Zaliani, Laura Vangeel, Jeanette Reinshagen, Daniela Iaconis, Maria Kuzikov, Oliver Keminer, Markus Wolf, Bernhard Ellinger, Francesca Esposito, Angela Corona, Enzo Tramontano, Candida Manelfi, Katja Herzog, Dirk Jochmans, Steven De Jonghe, Winston Chiu, Thibault Francken, Joost Schepers, Caroline Collard, Kayvan Abbasi, Carsten Claussen , Vincenzo Summa, Andrea R. Beccari, Johan Neyts, Philip Gribbon and Pieter Leyssen
Abstract : Worldwide, there are intensive efforts to identify repurposed drugs as potential therapies against SARS-CoV-2 infection and the associated COVID-19 disease. To date, the anti-inflammatory drug dexamethasone and (to a lesser extent) the RNA-polymerase inhibitor remdesivir have been shown to be effective in reducing mortality and patient time to recovery, respectively, in patients. Here, we report the results of a phenotypic screening campaign within an EU-funded project (H2020-EXSCALATE4COV) aimed at extending the repertoire of anti-COVID therapeutics through repurposing of available compounds and highlighting compounds with new mechanisms of action against viral infection. We screened 8702 molecules from different repurposing libraries, to reveal 110 compounds with an anti-cytopathic IC50 < 20 µM. From this group, 18 with a safety index greater than 2 are also marketed drugs, making them suitable for further study as potential therapies against COVID-19. Our result supports the idea that a systematic approach to repurposing is a valid strategy to accelerate the necessary drug discovery process.
|
Modulation of NF-kappaB in Sprague-Dawley rat BMM assessed as inhibition of M-CSF/RANKL-induced osteoclast differentiation by measuring decrease in TRAP-positive multinucleated cells at 100 uM measured after 5 days by TRAP-staining based assay relative to control
|
Rattus norvegicus
|
92.0
%
|
|
Journal : Bioorg Med Chem Lett
Title : Inhibitory effect of oolonghomobisflavan B on osteoclastogenesis by suppressing p38 MAPK activation.
Year : 2020
Volume : 30
Issue : 18.0
First Page : 127429
Last Page : 127429
Authors : Lim S,Kim TH,Ihn HJ,Lim J,Kim GY,Choi YH,Bae JS,Jung JC,Shin HI,Kim JE,Park EK
Abstract : Suppression of differentiation and/or function of osteoclasts is considered an effective therapeutic strategy for osteolytic bone diseases such as periodontitis and osteoporosis. Evidence regarding the health benefits of oolong tea consumption is accumulating, and tea polyphenols have various pharmacological properties such as anti-cancer and anti-diabetes effects. In this study, we investigated the effect of oolonghomobisflavan B (OFB), a polyphenolic compound in oolong tea, on osteoclast differentiation. OFB suppressed receptor activator of nuclear factor-κB (RANKL)-induced formation of tartate-resistant acid phosphatase-positive multinuclear cells without cytotoxicity. OFB also significantly attenuated p38 phosphorylation, which is essential for RANKL-induced osteoclastogenesis, and inhibited the expressions of nuclear factor of activated T cells, cytoplasmic 1 (NFATc1) and osteoclast-specific target genes, including dendritic cell-specific transmembrane protein and cathepsin K. Our findings suggest that OFB exhibits an anti-osteoclastogenic activity by inhibiting RANKL-mediated p38 activation, which is useful for the prevention and treatment of osteolytic bone diseases.
|
Binding affinity to recombinant Influenza A virus (A/USA:Huston/AA/1945 H1N1)) N-terminal His6-tagged PA endonuclease assessed as dissociation constant by SPR analysis
|
influenza A virus
|
956.32
nM
|
|
Journal : Eur J Med Chem
Title : Synthesis and SARs of dopamine derivatives as potential inhibitors of influenza virus PA endonuclease.
Year : 2020
Volume : 189
First Page : 112048
Last Page : 112048
Authors : Liao Y,Ye Y,Li S,Zhuang Y,Chen L,Chen J,Cui Z,Huo L,Liu S,Song G
Abstract : Currently, influenza PA endonuclease has become an attractive target for development of new drugs to treat influenza infections. Herein we report the discovery of new PA endonuclease inhibitors derived from a chelating agent dopamine moiety. A series of dopamine amide derivatives and their conformationally constrained 1,2,3,4-tetrahydroisoquinoline-6,7-diol-based analogs were elaborated and assayed against influenza virus A/WSN/33 (H1N1). Most compounds exhibited moderate to excellent antiviral activities, generating a preliminary SARs. Among them, compounds 14 and 19 showed stronger anti-IAV activity compared with the reference Peramivir. Moreover, 14 and 19 demonstrated a concentration-dependent inhibition of PA endonuclease based on both FRET assay and SPR assay. Docking studies were also performed to elucidate the binding mode of 14 and 19 with the PA protein and to identify amino acids involved in their mechanism of action, which were well consistent with the biological data. This finding was beneficial to laying the foundation for the rational development of more effective PA endonuclease inhibitors.
|
Inhibition of biotinylated 5-(4-((Z)-3-Carboxy-3-hydroxyacryloyl)-4-(4-chlorobenzyl)piperidine-1-carbonyl)-2-((13,35-dioxo-39-((3aR,4R,6aS)-2-oxohexahydro-1H-thieno[3,4-d]imidazole-4-yl)-3,6,9,16,19,22,25,28,31-nonaoxa-12,34-diazanonatriacontyl)oxy)benzoic acid binding to Influenza A virus (A/California/07/2009(H1N1)) N-terminal GST-tagged polymerase acidic subunit N-terminal domain expressed in Escherichia coli BL21 (DE3) RIL cells measured after 120 mins by Alphascreen assay
|
Influenza A virus (A/California/07/2009(H1N1))
|
870.0
nM
|
|
Journal : Eur J Med Chem
Title : Unraveling the anti-influenza effect of flavonoids: Experimental validation of luteolin and its congeners as potent influenza endonuclease inhibitors.
Year : 2020
Volume : 208
First Page : 112754
Last Page : 112754
Authors : Zima V,Radilová K,Kožíšek M,Albiñana CB,Karlukova E,Brynda J,Fanfrlík J,Flieger M,Hodek J,Weber J,Majer P,Konvalinka J,Machara A
Abstract : The biological effects of flavonoids on mammal cells are diverse, ranging from scavenging free radicals and anti-cancer activity to anti-influenza activity. Despite appreciable effort to understand the anti-influenza activity of flavonoids, there is no clear consensus about their precise mode-of-action at a cellular level. Here, we report the development and validation of a screening assay based on AlphaScreen technology and illustrate its application for determination of the inhibitory potency of a large set of polyols against PA N-terminal domain (PA-Nter) of influenza RNA-dependent RNA polymerase featuring endonuclease activity. The most potent inhibitors we identified were luteolin with an IC of 72 ± 2 nM and its 8-C-glucoside orientin with an IC of 43 ± 2 nM. Submicromolar inhibitors were also evaluated by an in vitro endonuclease activity assay using single-stranded DNA, and the results were in full agreement with data from the competitive AlphaScreen assay. Using X-ray crystallography, we analyzed structures of the PA-Nter in complex with luteolin at 2.0 Å resolution and quambalarine B at 2.5 Å resolution, which clearly revealed the binding pose of these polyols coordinated to two manganese ions in the endonuclease active site. Using two distinct assays along with the structural work, we have presumably identified and characterized the molecular mode-of-action of flavonoids in influenza-infected cells.
|
Binding affinity to wild type TTR (unknown origin) expressed in bacterial expression system by isothermal titration calorimetry
|
Homo sapiens
|
400.0
nM
|
|
Journal : J Med Chem
Title : Transthyretin Amyloidogenesis Inhibitors: From Discovery to Current Developments.
Year : 2020
Volume : 63
Issue : 23.0
First Page : 14228
Last Page : 14242
Authors : Yokoyama T,Mizuguchi M
Abstract : Transthyretin (TTR) is a homotetrameric protein in human plasma. The dissociation of the TTR tetramer and misfolding of the TTR monomer result in the formation of amyloid fibrils. Hereditary TTR amyloidosis is characterized by the extracellular deposition of amyloid fibrils containing TTR variants. The development of small molecules that kinetically stabilize the TTR tetramer is one of the effective strategies for the treatment of hereditary TTR amyloidosis. So far, several stabilizers have been discovered. Tafamidis is the only approved stabilizer for treatment of hereditary TTR amyloidosis, although two nucleic acid medicines that inhibit TTR synthesis, inotersen and patisiran, were recently approved for treatment of this disorder. In this Perspective, we seek to describe the representative kinetic stabilizers from discovery to development, interweaving the crystallographic study of the complex structures.
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Inhibition of recombinant His-tagged PGAM1 (unknown origin) expressed in Escherichia coli BL21 using 3-PG as substrate in presence of ADP by Kinase-Glo max luminescent assay
|
Homo sapiens
|
490.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Design, synthesis, and biological evaluation of 1,3,6,7-tetrahydroxyxanthone derivatives as phosphoglycerate mutase 1 inhibitors.
Year : 2021
Volume : 36
First Page : 127820
Last Page : 127820
Authors : Jiang K,Gao B,Yu J,Jiang L,Niu A,Jia Y,Meng T,Zhou L,Wang J
Abstract : Phosphoglycerate mutase 1 (PGAM1) is a promising target for cancer treatment. Herein, we found that α-mangostin and γ-mangostin exhibited moderate PGAM1 inhibitory activities, with IC of 7.2 μM and 1.2 µM, respectively. Based on α-mangostin, a series of 1,3,6,7-tetrahydroxyxanthone derivatives were designed, synthesized and evaluated in vitro for PGAM1 inhibition. The significant structure-activity relationships (SAR) and a fresh binding mode of this kind of new compounds were also clearly described. This study provides valuable information for further optimization of PGAM1 inhibitors with 1,3,6,7-tetrahydroxyxanthone backbone or de novo design of novel inhibitor.
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Stabilization of wild type human transthyretin expressed in Escherichia coli BL21(DE3) assessed as decrease in TTR-amyloid beta fibril formation at 10 uM preincubated for 6 hrs with transthyretin followed by measuring after 96 hrs maintaining pH of 4.4 by thioflavin T binding assay relative to control
|
Homo sapiens
|
53.0
%
|
|
Journal : Bioorg Med Chem
Title : Monoaryl derivatives as transthyretin fibril formation inhibitors: Design, synthesis, biological evaluation and structural analysis.
Year : 2020
Volume : 28
Issue : 18
First Page : 115673
Last Page : 115673
Authors : Ciccone L,Nencetti S,Tonali N,Fruchart-Gaillard C,Shepard W,Nuti E,Camodeca C,Rossello A,Orlandini E
Abstract : Transthyretin (TTR) is a ß-sheet-rich homotetrameric protein that transports thyroxine (T4) and retinol both in plasma and in cerebrospinal fluid. TTR also interacts with amyloid-β, playing a protective role in Alzheimer's disease. Dissociation of the native transthyretin (TTR) tetramer is widely accepted as the critical step in TTR amyloids fibrillogenesis, and is responsible for extracellular deposition of amyloid fibrils. Small molecules, able to bind in T4 binding sites and stabilize the TTR tetramer, are interesting tools to treat and prevent systemic ATTR amyloidosis. We report here the synthesis, in vitro evaluation and three-dimensional crystallographic analyses of new monoaryl-derivatives in complex with TTR. Of the derivatives reported here, the best inhibitor of TTR fibrillogenesis, 1d, exhibits an activity similar to diflunisal.
|
Inhibition of 6His-tagged human RD52 assessed as reduction in RD52 binding to Cy3-dT30-Cy5 ssDNA incubated for 30 mins by FRET assay
|
Homo sapiens
|
277.0
nM
|
|
Journal : J Med Chem
Title : Synthetic Lethality through the Lens of Medicinal Chemistry.
Year : 2020
Volume : 63
Issue : 23.0
First Page : 14151
Last Page : 14183
Authors : Myers SH,Ortega JA,Cavalli A
Abstract : Personalized medicine and therapies represent the goal of modern medicine, as drug discovery strives to move away from one-cure-for-all and makes use of the various targets and biomarkers within differing disease areas. This approach, especially in oncology, is often undermined when the cells make use of alternative survival pathways. As such, acquired resistance is unfortunately common. In order to combat this phenomenon, synthetic lethality is being investigated, making use of existing genetic fragilities within the cancer cell. This Perspective highlights exciting targets within synthetic lethality, (PARP, ATR, ATM, DNA-PKcs, WEE1, CDK12, RAD51, RAD52, and PD-1) and discusses the medicinal chemistry programs being used to interrogate them, the challenges these programs face, and what the future holds for this promising field.
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Inhibition of cytochrome c (unknown origin) assessed as reduction in cyt c-CL complex formation at 10 uM incubated for 15 mins in presence of cardiolipin by Trp-59 fluorescence assay relative to control
|
Homo sapiens
|
63.0
%
|
|
Journal : Bioorg Med Chem
Title : A role of flavonoids in cytochrome c-cardiolipin interactions.
Year : 2021
Volume : 33
First Page : 116043
Last Page : 116043
Authors : Rice M,Wong B,Oja M,Samuels K,Williams AK,Fong J,Sapse AM,Maran U,Korobkova EA
Abstract : The processes preceding the detachment of cytochrome c (cyt c) from the inner mitochondrial membrane in intrinsic apoptosis involve peroxidation of cardiolipin (CL) catalyzed by cyt c-CL complex. In the present work, we studied the effect of 17 dietary flavonoids on the peroxidase activity of cyt c bound to liposomes. Specifically, we explored the relationship between peroxidase activity and flavonoids' (1) potential to modulate cyt c unfolding, (2) effect on the oxidation state of heme iron, (3) membrane permeability, (4) membrane binding energy, and (5) structure. The measurements revealed that flavones, flavonols, and flavanols were the strongest, while isoflavones were the weakest inhibitors of the oxidation. Flavonoids' peroxidase inhibition activity correlated positively with their potential to suppress Trp-59 fluorescence in cyt c as well as the number of OH groups. Hydrophilic flavonoids, such as catechin, having the lowest membrane permeability and the strongest binding with phosphocholine (PC) based on the quantum chemical calculations exhibited the strongest inhibition of Amplex Red (AR) peroxidation, suggesting a membrane-protective function of flavonoids at the surface. The results of the present research specify basic principles for the design of molecules that will control the catalytic oxidation of lipids in mitochondrial membranes. These principles take into account the number of hydroxyl groups and hydrophilicity of flavonoids.
|
Inhibition of cytochrome c (unknown origin) assessed as reduction in cyt c-CL peroxidase activity at 10 uM up to 20 mins in presence of cardiolipin by Amplex red staining based fluorescence assay relative to control
|
Homo sapiens
|
50.0
%
|
|
Journal : Bioorg Med Chem
Title : A role of flavonoids in cytochrome c-cardiolipin interactions.
Year : 2021
Volume : 33
First Page : 116043
Last Page : 116043
Authors : Rice M,Wong B,Oja M,Samuels K,Williams AK,Fong J,Sapse AM,Maran U,Korobkova EA
Abstract : The processes preceding the detachment of cytochrome c (cyt c) from the inner mitochondrial membrane in intrinsic apoptosis involve peroxidation of cardiolipin (CL) catalyzed by cyt c-CL complex. In the present work, we studied the effect of 17 dietary flavonoids on the peroxidase activity of cyt c bound to liposomes. Specifically, we explored the relationship between peroxidase activity and flavonoids' (1) potential to modulate cyt c unfolding, (2) effect on the oxidation state of heme iron, (3) membrane permeability, (4) membrane binding energy, and (5) structure. The measurements revealed that flavones, flavonols, and flavanols were the strongest, while isoflavones were the weakest inhibitors of the oxidation. Flavonoids' peroxidase inhibition activity correlated positively with their potential to suppress Trp-59 fluorescence in cyt c as well as the number of OH groups. Hydrophilic flavonoids, such as catechin, having the lowest membrane permeability and the strongest binding with phosphocholine (PC) based on the quantum chemical calculations exhibited the strongest inhibition of Amplex Red (AR) peroxidation, suggesting a membrane-protective function of flavonoids at the surface. The results of the present research specify basic principles for the design of molecules that will control the catalytic oxidation of lipids in mitochondrial membranes. These principles take into account the number of hydroxyl groups and hydrophilicity of flavonoids.
|
Inhibition of cytochrome c (unknown origin) assessed as reduction reduction of cyt c from its ferric state to ferrous state at 10 uM incubated for 20 mins in presence of cardiolipin by UV-vis Spectrophotometric assay relative to control
|
Homo sapiens
|
62.0
%
|
|
Journal : Bioorg Med Chem
Title : A role of flavonoids in cytochrome c-cardiolipin interactions.
Year : 2021
Volume : 33
First Page : 116043
Last Page : 116043
Authors : Rice M,Wong B,Oja M,Samuels K,Williams AK,Fong J,Sapse AM,Maran U,Korobkova EA
Abstract : The processes preceding the detachment of cytochrome c (cyt c) from the inner mitochondrial membrane in intrinsic apoptosis involve peroxidation of cardiolipin (CL) catalyzed by cyt c-CL complex. In the present work, we studied the effect of 17 dietary flavonoids on the peroxidase activity of cyt c bound to liposomes. Specifically, we explored the relationship between peroxidase activity and flavonoids' (1) potential to modulate cyt c unfolding, (2) effect on the oxidation state of heme iron, (3) membrane permeability, (4) membrane binding energy, and (5) structure. The measurements revealed that flavones, flavonols, and flavanols were the strongest, while isoflavones were the weakest inhibitors of the oxidation. Flavonoids' peroxidase inhibition activity correlated positively with their potential to suppress Trp-59 fluorescence in cyt c as well as the number of OH groups. Hydrophilic flavonoids, such as catechin, having the lowest membrane permeability and the strongest binding with phosphocholine (PC) based on the quantum chemical calculations exhibited the strongest inhibition of Amplex Red (AR) peroxidation, suggesting a membrane-protective function of flavonoids at the surface. The results of the present research specify basic principles for the design of molecules that will control the catalytic oxidation of lipids in mitochondrial membranes. These principles take into account the number of hydroxyl groups and hydrophilicity of flavonoids.
|
Inhibition of COL1A1 promotor activity in human LX2 cells at 20 uM incubated for 24 hrs by luciferase reporter gene assay
|
Homo sapiens
|
19.19
%
|
|
|
Inhibition of COL1A1 promotor activity in human LX2 cells at 50 uM incubated for 24 hrs by luciferase reporter gene assay
|
Homo sapiens
|
32.25
%
|
|
|
Reversal of Pgp-mediated paclitaxel resistance in human LCC6MDR cells assessed as paclitaxel IC50 at 1 uM after 5 days by Cell Titer-Glo luminescence assay (Rvb = 152.5 +/- 9.7 uM)
|
Homo sapiens
|
124.1
nM
|
|
|
Reversal of Pgp-mediated paclitaxel resistance in human LCC6MDR cells assessed as paclitaxel IC50 at 10 uM after 5 days by Cell Titer-Glo luminescence assay (Rvb = 152.5 +/- 9.7 uM)
|
Homo sapiens
|
122.6
nM
|
|
