|
Reaction rate parameter value for phosphate with transfer with respect to ATP
|
None
|
81.0
nM
|
|
Reaction rate parameter value for phosphate with transfer with respect to ATP
|
None
|
307.0
nM
|
|
Reaction rate parameter value for phosphate with transfer with respect to ATP
|
None
|
37.0
nM
|
|
Journal : J. Med. Chem.
Title : Identification of tricyclic analogs related to ellagic acid as potent/selective tyrosine protein kinase inhibitors.
Year : 1994
Volume : 37
Issue : 14
First Page : 2224
Last Page : 2231
Authors : Dow RL, Chou TT, Bechle BM, Goddard C, Larson ER.
Abstract : The plant-derived natural product ellagic acid (1) has recently been identified as a potent, though nonselective, inhibitor of the tyrosine-specific protein kinase pp60src. This report details efforts directed toward the identification of tricyclic structures related to ellagic acid, with enhanced specificity for inhibition of pp60src over other protein kinases. Phenanthridinone and carbazole core structures were selected for investigation, since N-functionalization allows for the synthesis of numerous analogs which can be utilized to probe enzyme-inhibitor interactions. These ring systems were prepared via a general sequence of biaryl bond formation followed by cyclization to form the desired tricyclic ring systems. N-Alkylation, -acylation, or -sulfonylation and deprotection with boron tribromide afford the target tetraphenolic phenanthridinones 5 and carbazoles 9. Several analogs from both of these series have potencies comparable to that of 1 and exhibit substantially enhanced selectivities for inhibition of pp60src relative to protein kinase A (PKA), a serine/threonine protein kinase. Carbazole-based analogs 9j,m,p are submicromolar inhibitors of pp60src, with potency for the target tyrosine kinase comparable to that of ellagic acid (1), however with 2 orders of magnitude greater selectivity versus that for PKA. As seen for ellagic acid, members of the phenanthridinone-based series (e.g., 5a) exhibited inhibition of pp60src in a manner which is partial mixed noncompetitive with respect to ATP, while analogs in the carbazole series (e.g., 9a) inhibit pp60src in an ATP competitive manner.
|
Inhibition of DNA gyrase supercoiling in Escherichia coli.
|
Escherichia coli
|
47.0
ug.mL-1
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : DNA gyrase inhibitory activity of ellagic acid derivatives.
Year : 1998
Volume : 8
Issue : 1
First Page : 97
Last Page : 100
Authors : Weinder-Wells MA, Altom J, Fernandez J, Fraga-Spano SA, Hilliard J, Ohemeng K, Barrett JF.
Abstract : Ellagic acid was found to inhibit E. coli DNA gyrase supercoiling with approximately the same potency as nalidixic acid. Tricyclic analogs of ellagic acid, which vary in the number and position of the hydroxy groups as well as their replacement with halogens, have been synthesized. The biological activity of these analogs is discussed.
|
In vitro antibacterial activity was determined as inhibitory concentration causing 50% DNA-gyrase supercoiling inhibition (SCI)
|
Escherichia coli
|
3.3
ug.mL-1
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : DNA gyrase inhibitory and antibacterial activity of some flavones(1)
Year : 1993
Volume : 3
Issue : 2
First Page : 225
Last Page : 230
Authors : Ohemeng K, Schwender C, Fu K, Barrett J
|
In vitro inhibitory activity against protein kinase A
|
unidentified
|
600.0
nM
|
|
Journal : J. Med. Chem.
Title : Identification of tricyclic analogs related to ellagic acid as potent/selective tyrosine protein kinase inhibitors.
Year : 1994
Volume : 37
Issue : 14
First Page : 2224
Last Page : 2231
Authors : Dow RL, Chou TT, Bechle BM, Goddard C, Larson ER.
Abstract : The plant-derived natural product ellagic acid (1) has recently been identified as a potent, though nonselective, inhibitor of the tyrosine-specific protein kinase pp60src. This report details efforts directed toward the identification of tricyclic structures related to ellagic acid, with enhanced specificity for inhibition of pp60src over other protein kinases. Phenanthridinone and carbazole core structures were selected for investigation, since N-functionalization allows for the synthesis of numerous analogs which can be utilized to probe enzyme-inhibitor interactions. These ring systems were prepared via a general sequence of biaryl bond formation followed by cyclization to form the desired tricyclic ring systems. N-Alkylation, -acylation, or -sulfonylation and deprotection with boron tribromide afford the target tetraphenolic phenanthridinones 5 and carbazoles 9. Several analogs from both of these series have potencies comparable to that of 1 and exhibit substantially enhanced selectivities for inhibition of pp60src relative to protein kinase A (PKA), a serine/threonine protein kinase. Carbazole-based analogs 9j,m,p are submicromolar inhibitors of pp60src, with potency for the target tyrosine kinase comparable to that of ellagic acid (1), however with 2 orders of magnitude greater selectivity versus that for PKA. As seen for ellagic acid, members of the phenanthridinone-based series (e.g., 5a) exhibited inhibition of pp60src in a manner which is partial mixed noncompetitive with respect to ATP, while analogs in the carbazole series (e.g., 9a) inhibit pp60src in an ATP competitive manner.
|
Tested for in vitro inhibitory activity against tyrosine protein kinase pp60 c-src
|
None
|
300.0
nM
|
|
Journal : J. Med. Chem.
Title : Identification of tricyclic analogs related to ellagic acid as potent/selective tyrosine protein kinase inhibitors.
Year : 1994
Volume : 37
Issue : 14
First Page : 2224
Last Page : 2231
Authors : Dow RL, Chou TT, Bechle BM, Goddard C, Larson ER.
Abstract : The plant-derived natural product ellagic acid (1) has recently been identified as a potent, though nonselective, inhibitor of the tyrosine-specific protein kinase pp60src. This report details efforts directed toward the identification of tricyclic structures related to ellagic acid, with enhanced specificity for inhibition of pp60src over other protein kinases. Phenanthridinone and carbazole core structures were selected for investigation, since N-functionalization allows for the synthesis of numerous analogs which can be utilized to probe enzyme-inhibitor interactions. These ring systems were prepared via a general sequence of biaryl bond formation followed by cyclization to form the desired tricyclic ring systems. N-Alkylation, -acylation, or -sulfonylation and deprotection with boron tribromide afford the target tetraphenolic phenanthridinones 5 and carbazoles 9. Several analogs from both of these series have potencies comparable to that of 1 and exhibit substantially enhanced selectivities for inhibition of pp60src relative to protein kinase A (PKA), a serine/threonine protein kinase. Carbazole-based analogs 9j,m,p are submicromolar inhibitors of pp60src, with potency for the target tyrosine kinase comparable to that of ellagic acid (1), however with 2 orders of magnitude greater selectivity versus that for PKA. As seen for ellagic acid, members of the phenanthridinone-based series (e.g., 5a) exhibited inhibition of pp60src in a manner which is partial mixed noncompetitive with respect to ATP, while analogs in the carbazole series (e.g., 9a) inhibit pp60src in an ATP competitive manner.
|
Inhibition of rat liver CK2
|
Rattus norvegicus
|
20.0
nM
|
|
Inhibition of rat liver CK2
|
Rattus norvegicus
|
40.0
nM
|
|
Journal : J. Med. Chem.
Title : Identification of ellagic acid as potent inhibitor of protein kinase CK2: a successful example of a virtual screening application.
Year : 2006
Volume : 49
Issue : 8
First Page : 2363
Last Page : 2366
Authors : Cozza G, Bonvini P, Zorzi E, Poletto G, Pagano MA, Sarno S, Donella-Deana A, Zagotto G, Rosolen A, Pinna LA, Meggio F, Moro S.
Abstract : Casein kinase 2 (CK2) is a ubiquitous, essential, and highly pleiotropic protein kinase whose abnormally high constitutive activity is suspected to underlie its pathogenic potential in neoplasia and other diseases. Using a virtual screening approach, we have identified the ellagic acid, a naturally occurring tannic acid derivative, as a novel potent CK2 inhibitor. At present, ellagic acid represents the most potent known CK2 inhibitor (K(i) = 20 nM).
|
Antiproliferative activity against SUDHL1 expressing NPM-ALK by MTT assay
|
None
|
85.0
%
|
|
Journal : J. Med. Chem.
Title : Identification of ellagic acid as potent inhibitor of protein kinase CK2: a successful example of a virtual screening application.
Year : 2006
Volume : 49
Issue : 8
First Page : 2363
Last Page : 2366
Authors : Cozza G, Bonvini P, Zorzi E, Poletto G, Pagano MA, Sarno S, Donella-Deana A, Zagotto G, Rosolen A, Pinna LA, Meggio F, Moro S.
Abstract : Casein kinase 2 (CK2) is a ubiquitous, essential, and highly pleiotropic protein kinase whose abnormally high constitutive activity is suspected to underlie its pathogenic potential in neoplasia and other diseases. Using a virtual screening approach, we have identified the ellagic acid, a naturally occurring tannic acid derivative, as a novel potent CK2 inhibitor. At present, ellagic acid represents the most potent known CK2 inhibitor (K(i) = 20 nM).
|
Antiproliferative activity against FEPD by MTT assay
|
Homo sapiens
|
70.0
%
|
|
Journal : J. Med. Chem.
Title : Identification of ellagic acid as potent inhibitor of protein kinase CK2: a successful example of a virtual screening application.
Year : 2006
Volume : 49
Issue : 8
First Page : 2363
Last Page : 2366
Authors : Cozza G, Bonvini P, Zorzi E, Poletto G, Pagano MA, Sarno S, Donella-Deana A, Zagotto G, Rosolen A, Pinna LA, Meggio F, Moro S.
Abstract : Casein kinase 2 (CK2) is a ubiquitous, essential, and highly pleiotropic protein kinase whose abnormally high constitutive activity is suspected to underlie its pathogenic potential in neoplasia and other diseases. Using a virtual screening approach, we have identified the ellagic acid, a naturally occurring tannic acid derivative, as a novel potent CK2 inhibitor. At present, ellagic acid represents the most potent known CK2 inhibitor (K(i) = 20 nM).
|
Antiproliferative activity against KARPAS299 expressing NPM-ALK by MTT assay
|
None
|
60.0
%
|
|
Journal : J. Med. Chem.
Title : Identification of ellagic acid as potent inhibitor of protein kinase CK2: a successful example of a virtual screening application.
Year : 2006
Volume : 49
Issue : 8
First Page : 2363
Last Page : 2366
Authors : Cozza G, Bonvini P, Zorzi E, Poletto G, Pagano MA, Sarno S, Donella-Deana A, Zagotto G, Rosolen A, Pinna LA, Meggio F, Moro S.
Abstract : Casein kinase 2 (CK2) is a ubiquitous, essential, and highly pleiotropic protein kinase whose abnormally high constitutive activity is suspected to underlie its pathogenic potential in neoplasia and other diseases. Using a virtual screening approach, we have identified the ellagic acid, a naturally occurring tannic acid derivative, as a novel potent CK2 inhibitor. At present, ellagic acid represents the most potent known CK2 inhibitor (K(i) = 20 nM).
|
Antiproliferative activity against SR786 expressing NPM-ALK by MTT assay
|
None
|
40.0
%
|
|
Journal : J. Med. Chem.
Title : Identification of ellagic acid as potent inhibitor of protein kinase CK2: a successful example of a virtual screening application.
Year : 2006
Volume : 49
Issue : 8
First Page : 2363
Last Page : 2366
Authors : Cozza G, Bonvini P, Zorzi E, Poletto G, Pagano MA, Sarno S, Donella-Deana A, Zagotto G, Rosolen A, Pinna LA, Meggio F, Moro S.
Abstract : Casein kinase 2 (CK2) is a ubiquitous, essential, and highly pleiotropic protein kinase whose abnormally high constitutive activity is suspected to underlie its pathogenic potential in neoplasia and other diseases. Using a virtual screening approach, we have identified the ellagic acid, a naturally occurring tannic acid derivative, as a novel potent CK2 inhibitor. At present, ellagic acid represents the most potent known CK2 inhibitor (K(i) = 20 nM).
|
Inhibition of CK2 in rat liver
|
Rattus norvegicus
|
40.0
nM
|
|
Journal : J. Med. Chem.
Title : Coumarin as attractive casein kinase 2 (CK2) inhibitor scaffold: an integrate approach to elucidate the putative binding motif and explain structure-activity relationships.
Year : 2008
Volume : 51
Issue : 4
First Page : 752
Last Page : 759
Authors : Chilin A, Battistutta R, Bortolato A, Cozza G, Zanatta S, Poletto G, Mazzorana M, Zagotto G, Uriarte E, Guiotto A, Pinna LA, Meggio F, Moro S.
Abstract : Casein kinase 2 (CK2) is an ubiquitous, essential, and highly pleiotropic protein kinase whose abnormally high constitutive activity is suspected to underlie its pathogenic potential in neoplasia and other diseases. Recently, using different virtual screening approaches, we have identified several novel CK2 inhibitors. In particular, we have discovered that coumarin moiety can be considered an attractive CK2 inhibitor scaffold. In the present work, we have synthetized and tested a small library of coumarins (more than 60), rationalizing the observed structure-activity relationship. Moreover, the most promising inhibitor, 3,8-dibromo-7-hydroxy-4-methylchromen-2-one (DBC), has been also crystallized in complex with CK2, and the experimental binding mode has been used to derive a linear interaction energy (LIE) model.
|
Inhibition of H(+)/K(+) ATPase from pig gastric mucosa
|
Sus scrofa
|
210.0
nM
|
|
Journal : J. Nat. Prod.
Title : Inhibitory effect of tannic acid on gastric H+,K(+)-ATPase.
Year : 1992
Volume : 55
Issue : 4
First Page : 513
Last Page : 516
Authors : Murakami S, Muramatsu M, Otomo S.
Abstract : The effect of tannic acid on gastric H+,K(+)-ATPase was studied. Tannic acid dose-dependently inhibited pig gastric H+,K(+)-ATPase activity with an IC50 value of 2.9 x 10(-8) M. Tannic acid also inhibited K(+)-stimulated p-nitrophenyl phosphatase (K(+)-pNPPase) activity, which is found in gastric H+,K(+)-ATPase preparations, as well as H+,K(+)-ATPase activity, with an IC50 value of 4.1 x 10(-7) M. Kinetic studies showed that the inhibition of H+,K(+)-ATPase activity by tannic acid was competitive with respect to ATP and noncompetitive with respect to K+. These results show that tannic acid is a potent inhibitor of gastric H+,K(+)-ATPase; this may be related to its anti-secretory and anti-ulcerogenic effects.
|
Inhibition of rat liver CK2 by Lineweaver-Burke double reciprocal plot analysis
|
Rattus norvegicus
|
20.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Structural insight into human CK2alpha in complex with the potent inhibitor ellagic acid.
Year : 2009
Volume : 19
Issue : 11
First Page : 2920
Last Page : 2923
Authors : Sekiguchi Y, Nakaniwa T, Kinoshita T, Nakanishi I, Kitaura K, Hirasawa A, Tsujimoto G, Tada T.
Abstract : We determined the 2.35-A crystal structure of a human CK2 catalytic subunit (referred to as CK2alpha complexed with the ATP-competitive, potent CK2 inhibitor ellagic acid. The inhibitor binds to CK2alpha with a novel binding mode, including water-mediated hydrogen bonds. This structural information may support discovery of potent CK2 inhibitors.
|
Inhibition of rat liver CK2 catalytic activity
|
Rattus norvegicus
|
40.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Structural insight into human CK2alpha in complex with the potent inhibitor ellagic acid.
Year : 2009
Volume : 19
Issue : 11
First Page : 2920
Last Page : 2923
Authors : Sekiguchi Y, Nakaniwa T, Kinoshita T, Nakanishi I, Kitaura K, Hirasawa A, Tsujimoto G, Tada T.
Abstract : We determined the 2.35-A crystal structure of a human CK2 catalytic subunit (referred to as CK2alpha complexed with the ATP-competitive, potent CK2 inhibitor ellagic acid. The inhibitor binds to CK2alpha with a novel binding mode, including water-mediated hydrogen bonds. This structural information may support discovery of potent CK2 inhibitors.
|
Inhibition of GST-fused human recombinant CK2alpha expressed in Escherichia coli HMS174 (DE3)
|
Homo sapiens
|
40.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Structural insight into human CK2alpha in complex with the potent inhibitor ellagic acid.
Year : 2009
Volume : 19
Issue : 11
First Page : 2920
Last Page : 2923
Authors : Sekiguchi Y, Nakaniwa T, Kinoshita T, Nakanishi I, Kitaura K, Hirasawa A, Tsujimoto G, Tada T.
Abstract : We determined the 2.35-A crystal structure of a human CK2 catalytic subunit (referred to as CK2alpha complexed with the ATP-competitive, potent CK2 inhibitor ellagic acid. The inhibitor binds to CK2alpha with a novel binding mode, including water-mediated hydrogen bonds. This structural information may support discovery of potent CK2 inhibitors.
|
Inhibition of Saccharomyces cerevisiae fatty acid synthase
|
Saccharomyces cerevisiae
|
20.0
ug.mL-1
|
|
Journal : J. Nat. Prod.
Title : Fatty acid synthase inhibitors from plants: isolation, structure elucidation, and SAR studies.
Year : 2002
Volume : 65
Issue : 12
First Page : 1909
Last Page : 1914
Authors : Li XC, Joshi AS, ElSohly HN, Khan SI, Jacob MR, Zhang Z, Khan IA, Ferreira D, Walker LA, Broedel SE, Raulli RE, Cihlar RL.
Abstract : Fatty acid synthase (FAS) has been identified as a potential antifungal target. FAS prepared from Saccharomyces cerevisiae was employed for bioactivity-guided fractionation of Chlorophora tinctoria,Paspalum conjugatum, Symphonia globulifera, Buchenavia parviflora, and Miconia pilgeriana. Thirteen compounds (1-13), including three new natural products (1, 4, 12), were isolated and their structures identified by spectroscopic interpretation. They represented five chemotypes, namely, isoflavones, flavones, biflavonoids, hydrolyzable tannin-related derivatives, and triterpenoids. 3'-Formylgenistein (1) and ellagic acid 4-O-alpha-l-rhamnopyranoside (9) were the most potent compounds against FAS, with IC(50) values of 2.3 and 7.5 microg/mL, respectively. Furthermore, 43 (14-56) analogues of the five chemotypes from our natural product repository and commercial sources were tested for their FAS inhibitory activity. Structure-activity relationships for some chemotypes were investigated. All these compounds were further evaluated for antifungal activity against Candida albicans and Cryptococcus neoformans. Although there were several antifungal compounds in the set, correlation between the FAS inhibitory activity and antifungal activity could not be defined.
|
Antifungal activity against Candida albicans ATCC 90028
|
Candida albicans
|
50.0
ug.mL-1
|
|
Journal : J. Nat. Prod.
Title : Fatty acid synthase inhibitors from plants: isolation, structure elucidation, and SAR studies.
Year : 2002
Volume : 65
Issue : 12
First Page : 1909
Last Page : 1914
Authors : Li XC, Joshi AS, ElSohly HN, Khan SI, Jacob MR, Zhang Z, Khan IA, Ferreira D, Walker LA, Broedel SE, Raulli RE, Cihlar RL.
Abstract : Fatty acid synthase (FAS) has been identified as a potential antifungal target. FAS prepared from Saccharomyces cerevisiae was employed for bioactivity-guided fractionation of Chlorophora tinctoria,Paspalum conjugatum, Symphonia globulifera, Buchenavia parviflora, and Miconia pilgeriana. Thirteen compounds (1-13), including three new natural products (1, 4, 12), were isolated and their structures identified by spectroscopic interpretation. They represented five chemotypes, namely, isoflavones, flavones, biflavonoids, hydrolyzable tannin-related derivatives, and triterpenoids. 3'-Formylgenistein (1) and ellagic acid 4-O-alpha-l-rhamnopyranoside (9) were the most potent compounds against FAS, with IC(50) values of 2.3 and 7.5 microg/mL, respectively. Furthermore, 43 (14-56) analogues of the five chemotypes from our natural product repository and commercial sources were tested for their FAS inhibitory activity. Structure-activity relationships for some chemotypes were investigated. All these compounds were further evaluated for antifungal activity against Candida albicans and Cryptococcus neoformans. Although there were several antifungal compounds in the set, correlation between the FAS inhibitory activity and antifungal activity could not be defined.
|
Antifungal activity against Cryptococcus neoformans ATCC 90113
|
Cryptococcus neoformans
|
5.5
ug.mL-1
|
|
Journal : J. Nat. Prod.
Title : Fatty acid synthase inhibitors from plants: isolation, structure elucidation, and SAR studies.
Year : 2002
Volume : 65
Issue : 12
First Page : 1909
Last Page : 1914
Authors : Li XC, Joshi AS, ElSohly HN, Khan SI, Jacob MR, Zhang Z, Khan IA, Ferreira D, Walker LA, Broedel SE, Raulli RE, Cihlar RL.
Abstract : Fatty acid synthase (FAS) has been identified as a potential antifungal target. FAS prepared from Saccharomyces cerevisiae was employed for bioactivity-guided fractionation of Chlorophora tinctoria,Paspalum conjugatum, Symphonia globulifera, Buchenavia parviflora, and Miconia pilgeriana. Thirteen compounds (1-13), including three new natural products (1, 4, 12), were isolated and their structures identified by spectroscopic interpretation. They represented five chemotypes, namely, isoflavones, flavones, biflavonoids, hydrolyzable tannin-related derivatives, and triterpenoids. 3'-Formylgenistein (1) and ellagic acid 4-O-alpha-l-rhamnopyranoside (9) were the most potent compounds against FAS, with IC(50) values of 2.3 and 7.5 microg/mL, respectively. Furthermore, 43 (14-56) analogues of the five chemotypes from our natural product repository and commercial sources were tested for their FAS inhibitory activity. Structure-activity relationships for some chemotypes were investigated. All these compounds were further evaluated for antifungal activity against Candida albicans and Cryptococcus neoformans. Although there were several antifungal compounds in the set, correlation between the FAS inhibitory activity and antifungal activity could not be defined.
|
Antiplasmodial activity after 24 hrs against chloroquine-sensitive, mefloquine-resistant Plasmodium falciparum D6 infected human erythrocytes by [G-3H]hypoxanthine uptake
|
Plasmodium falciparum D6
|
0.145
ug.mL-1
|
|
Journal : J. Nat. Prod.
Title : In vitro antiplasmodial activity of extracts of Tristaniopsis species and identification of the active constituents: ellagic acid and 3,4,5-trimethoxyphenyl-(6'-O-galloyl)-O-beta-D-glucopyranoside.
Year : 2001
Volume : 64
Issue : 5
First Page : 603
Last Page : 607
Authors : Verotta L, Dell'Agli M, Giolito A, Guerrini M, Cabalion P, Bosisio E.
Abstract : Screening of plants from New Caledonia for antiplasmodial activity against Plasmodium falciparum revealed that methanolic extracts of the leaves and bark of Tristaniopsis calobuxus, T. yateensis, and T.glauca inhibited the growth of chloroquine-sensitive and -resistant clones. Ellagic acid and the new compound 3,4,5-trimethoxyphenyl-(6'-O-galloyl)-O-beta-D-glucopyranoside were identified as the active constituents (IC50 0.5 and 3.2 microM, respectively). The growth inhibition of both clones was comparable. The compounds showed negligible or very low cytotoxicity to human skin fibroblasts and Hep G2 cells when tested at concentrations ranging from 0.5 to 100 microM.
|
Antiplasmodial activity after 24 hrs against chloroquine-resistant, mefloquine-sensitive Plasmodium falciparum W2 infected human erythrocytes by [G-3H]hypoxanthine uptake
|
Plasmodium falciparum
|
0.103
ug.mL-1
|
|
Journal : J. Nat. Prod.
Title : In vitro antiplasmodial activity of extracts of Tristaniopsis species and identification of the active constituents: ellagic acid and 3,4,5-trimethoxyphenyl-(6'-O-galloyl)-O-beta-D-glucopyranoside.
Year : 2001
Volume : 64
Issue : 5
First Page : 603
Last Page : 607
Authors : Verotta L, Dell'Agli M, Giolito A, Guerrini M, Cabalion P, Bosisio E.
Abstract : Screening of plants from New Caledonia for antiplasmodial activity against Plasmodium falciparum revealed that methanolic extracts of the leaves and bark of Tristaniopsis calobuxus, T. yateensis, and T.glauca inhibited the growth of chloroquine-sensitive and -resistant clones. Ellagic acid and the new compound 3,4,5-trimethoxyphenyl-(6'-O-galloyl)-O-beta-D-glucopyranoside were identified as the active constituents (IC50 0.5 and 3.2 microM, respectively). The growth inhibition of both clones was comparable. The compounds showed negligible or very low cytotoxicity to human skin fibroblasts and Hep G2 cells when tested at concentrations ranging from 0.5 to 100 microM.
|
Inhibition of HIV1 RT
|
Human immunodeficiency virus 1
|
150.0
ug.mL-1
|
|
Journal : J. Nat. Prod.
Title : Evaluation of natural products as inhibitors of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase.
Year : 1991
Volume : 54
Issue : 1
First Page : 143
Last Page : 154
Authors : Tan GT, Pezzuto JM, Kinghorn AD, Hughes SH.
Abstract : Inhibition of human immunodeficiency virus reverse transcriptase is currently considered a useful approach in the prophylaxis and intervention of acquired immunodeficiency syndrome (AIDS), and natural products have not been extensively explored as inhibitors of this enzyme. We currently report that the reverse transcriptase assay developed for the detection of the enzyme in virions involving polyadenylic acid.oligodeoxythymidylic acid (poly rA.oligo dT) and radiolabeled thymidine 5'-triphosphate (TTP), can be applied as a simple method for screening the human immunodeficiency virus type 1 reverse transcriptase (HIV-1 RT) inhibitory potential of natural products. As reported herein, 156 pure natural products have been examined in this system. Benzophenanthridine alkaloids such as faragaronine chloride [1] and nitidine chloride, which are known inhibitors of avian myeloblastosis virus reverse transcriptase, demonstrated potent activity in the HIV-1 RT system, and 1 (IC50 10 micrograms/ml) was adopted as a positive-control substance. Additional inhibitors found were columbamine iodide [2] and other protoberberine alkaloids, the isoquinoline alkaloid O-methylpsychotrine sulfate [3], and the iridoid fulvoplumierin [4]. A number of indolizidine, pyrrolizidine, quinolizidine, indole, and other alkaloids, as well as compounds of many other structural classes, were tested and found to be inactive. A total of 100 plant extracts have also been evaluated, and 15 of these extracts showed significant inhibitory activity. Because tannins and other polyphenolic compounds are potent reverse transcriptase inhibitors, methods were evaluated for the removal of these from plant extracts prior to testing. Polyphenolic compounds were found to be responsible for the activity demonstrated by the majority of plant extracts. After appropriate tannin removal procedures were established, the bioassay system was shown to be generally applicable to both pure natural products and plant extracts. The method also proved useful in directing an isolation procedure with Plumeria rubra to yield fulvoplumierin [4] as an active compound (IC50 45 micrograms/ml).
|
Antiinflammatory activity in human neutrophils assessed as respiratory burst inhibition at 1000 ug/ml by WST-1 assay
|
Homo sapiens
|
27.1
%
|
|
Journal : J. Nat. Prod.
Title : Inhibitory effect of macabarterin, a polyoxygenated ellagitannin from Macaranga barteri, on human neutrophil respiratory burst activity.
Year : 2008
Volume : 71
Issue : 11
First Page : 1906
Last Page : 1910
Authors : Ngoumfo RM, Ngounou GE, Tchamadeu CV, Qadir MI, Mbazoa CD, Begum A, Ngninzeko FN, Lontsi D, Choudhary MI.
Abstract : An ellagitannin with a 2,4-acyl group, named macabarterin (1), and a new ellagic acid glycoside, 3-O-methylellagic acid 4-O-β-d-xylopyranoside (2), were isolated from the stem bark extract of Macaranga barteri along with five known phenolic compounds, ellagic acid (3), 3-O-methylellagic acid (4), gallic acid (5), methyl gallate (6), and scopoletin (7). The structures of 1 and 2, as well as those of the known compounds, were elucidated on the basis of spectroscopic data and by comparison with reported data. Compounds 1-5 and 7 were tested for their anti-inflammatory potential in a cell-based respiratory burst assay, compound 1 being found an inhibitor of the superoxides produced in the cellular system.
|
PUBCHEM_BIOASSAY: SMAD Transcription Factor Inhibitors Dose Response Confirmation. (Class of assay: confirmatory) [Related pubchem assays: 630 (Primary screen preceding this dose response confirmation assay.)]
|
Homo sapiens
|
142.0
nM
|
|
Title : PubChem BioAssay data set
|
PUBCHEM_BIOASSAY: High Throughput Screening Assay for Hsp70 Inhibitors. (Class of assay: confirmatory) [Related pubchem assays: 786 ]
|
Homo sapiens
|
760.0
nM
|
|
Title : PubChem BioAssay data set
|
PUBCHEM_BIOASSAY: Fluorescence polarization-based biochemical high throughput dose response assay to identify inhibitors of tRNA 2'-phosphotransferase (TPT1). (Class of assay: confirmatory) [Related pubchem assays: 1963 (Summary AID.), 1962 (Primary screen (TPT1 inhibitors).), 2153 (Counterscreen (RNase inhibitors).), 2149 (Confirmation screen (TPT1 inhibitors).)]
|
Candida albicans SC5314
|
540.68
nM
|
|
Title : PubChem BioAssay data set
|
Antiplasmodial activity against Plasmodium falciparum F32
|
Plasmodium falciparum
|
330.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro and in vivo properties of ellagic acid in malaria treatment.
Year : 2009
Volume : 53
Issue : 3
First Page : 1100
Last Page : 1106
Authors : Soh PN, Witkowski B, Olagnier D, Nicolau ML, Garcia-Alvarez MC, Berry A, Benoit-Vical F.
Abstract : Malaria is one of the most significant causes of infectious disease in the world. The search for new antimalarial chemotherapies has become increasingly urgent due to the parasites' resistance to current drugs. Ellagic acid is a polyphenol found in various plant products. In this study, antimalarial properties of ellagic acid were explored. The results obtained have shown high activity in vitro against all Plasmodium falciparum strains whatever their levels of chloroquine and mefloquine resistance (50% inhibitory concentrations ranging from 105 to 330 nM). Ellagic acid was also active in vivo against Plamodium vinckei petteri in suppressive, curative, and prophylactic murine tests, without any toxicity (50% effective dose by the intraperitoneal route inferior to 1 mg/kg/day). The study of the point of action of its antimalarial activity in the erythrocytic cycle of Plasmodium falciparum demonstrated that it occurred at the mature trophozoite and young schizont stages. Moreover, ellagic acid has been shown to potentiate the activity of current antimalarial drugs such as chloroquine, mefloquine, artesunate, and atovaquone. This study also proved the antioxidant activity of ellagic acid and, in contrast, the inhibitory effect of the antioxidant compound N-acetyl-l-cysteine on its antimalarial efficacy. The possible mechanisms of action of ellagic acid on P. falciparum are discussed in light of the results. Ellagic acid has in vivo activity against plasmodia, but modification of the compound could lead to improved pharmacological properties, principally for the oral route.
|
Antiplasmodial activity against Plasmodium falciparum Dd2
|
Plasmodium falciparum
|
105.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro and in vivo properties of ellagic acid in malaria treatment.
Year : 2009
Volume : 53
Issue : 3
First Page : 1100
Last Page : 1106
Authors : Soh PN, Witkowski B, Olagnier D, Nicolau ML, Garcia-Alvarez MC, Berry A, Benoit-Vical F.
Abstract : Malaria is one of the most significant causes of infectious disease in the world. The search for new antimalarial chemotherapies has become increasingly urgent due to the parasites' resistance to current drugs. Ellagic acid is a polyphenol found in various plant products. In this study, antimalarial properties of ellagic acid were explored. The results obtained have shown high activity in vitro against all Plasmodium falciparum strains whatever their levels of chloroquine and mefloquine resistance (50% inhibitory concentrations ranging from 105 to 330 nM). Ellagic acid was also active in vivo against Plamodium vinckei petteri in suppressive, curative, and prophylactic murine tests, without any toxicity (50% effective dose by the intraperitoneal route inferior to 1 mg/kg/day). The study of the point of action of its antimalarial activity in the erythrocytic cycle of Plasmodium falciparum demonstrated that it occurred at the mature trophozoite and young schizont stages. Moreover, ellagic acid has been shown to potentiate the activity of current antimalarial drugs such as chloroquine, mefloquine, artesunate, and atovaquone. This study also proved the antioxidant activity of ellagic acid and, in contrast, the inhibitory effect of the antioxidant compound N-acetyl-l-cysteine on its antimalarial efficacy. The possible mechanisms of action of ellagic acid on P. falciparum are discussed in light of the results. Ellagic acid has in vivo activity against plasmodia, but modification of the compound could lead to improved pharmacological properties, principally for the oral route.
|
Antiplasmodial activity against Plasmodium falciparum FcB1
|
Plasmodium falciparum FcB1/Columbia
|
300.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro and in vivo properties of ellagic acid in malaria treatment.
Year : 2009
Volume : 53
Issue : 3
First Page : 1100
Last Page : 1106
Authors : Soh PN, Witkowski B, Olagnier D, Nicolau ML, Garcia-Alvarez MC, Berry A, Benoit-Vical F.
Abstract : Malaria is one of the most significant causes of infectious disease in the world. The search for new antimalarial chemotherapies has become increasingly urgent due to the parasites' resistance to current drugs. Ellagic acid is a polyphenol found in various plant products. In this study, antimalarial properties of ellagic acid were explored. The results obtained have shown high activity in vitro against all Plasmodium falciparum strains whatever their levels of chloroquine and mefloquine resistance (50% inhibitory concentrations ranging from 105 to 330 nM). Ellagic acid was also active in vivo against Plamodium vinckei petteri in suppressive, curative, and prophylactic murine tests, without any toxicity (50% effective dose by the intraperitoneal route inferior to 1 mg/kg/day). The study of the point of action of its antimalarial activity in the erythrocytic cycle of Plasmodium falciparum demonstrated that it occurred at the mature trophozoite and young schizont stages. Moreover, ellagic acid has been shown to potentiate the activity of current antimalarial drugs such as chloroquine, mefloquine, artesunate, and atovaquone. This study also proved the antioxidant activity of ellagic acid and, in contrast, the inhibitory effect of the antioxidant compound N-acetyl-l-cysteine on its antimalarial efficacy. The possible mechanisms of action of ellagic acid on P. falciparum are discussed in light of the results. Ellagic acid has in vivo activity against plasmodia, but modification of the compound could lead to improved pharmacological properties, principally for the oral route.
|
Antiplasmodial activity against Plasmodium falciparum W2
|
Plasmodium falciparum
|
330.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro and in vivo properties of ellagic acid in malaria treatment.
Year : 2009
Volume : 53
Issue : 3
First Page : 1100
Last Page : 1106
Authors : Soh PN, Witkowski B, Olagnier D, Nicolau ML, Garcia-Alvarez MC, Berry A, Benoit-Vical F.
Abstract : Malaria is one of the most significant causes of infectious disease in the world. The search for new antimalarial chemotherapies has become increasingly urgent due to the parasites' resistance to current drugs. Ellagic acid is a polyphenol found in various plant products. In this study, antimalarial properties of ellagic acid were explored. The results obtained have shown high activity in vitro against all Plasmodium falciparum strains whatever their levels of chloroquine and mefloquine resistance (50% inhibitory concentrations ranging from 105 to 330 nM). Ellagic acid was also active in vivo against Plamodium vinckei petteri in suppressive, curative, and prophylactic murine tests, without any toxicity (50% effective dose by the intraperitoneal route inferior to 1 mg/kg/day). The study of the point of action of its antimalarial activity in the erythrocytic cycle of Plasmodium falciparum demonstrated that it occurred at the mature trophozoite and young schizont stages. Moreover, ellagic acid has been shown to potentiate the activity of current antimalarial drugs such as chloroquine, mefloquine, artesunate, and atovaquone. This study also proved the antioxidant activity of ellagic acid and, in contrast, the inhibitory effect of the antioxidant compound N-acetyl-l-cysteine on its antimalarial efficacy. The possible mechanisms of action of ellagic acid on P. falciparum are discussed in light of the results. Ellagic acid has in vivo activity against plasmodia, but modification of the compound could lead to improved pharmacological properties, principally for the oral route.
|
Antiplasmodial activity against Plasmodium falciparum FcM29
|
Plasmodium falciparum
|
180.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro and in vivo properties of ellagic acid in malaria treatment.
Year : 2009
Volume : 53
Issue : 3
First Page : 1100
Last Page : 1106
Authors : Soh PN, Witkowski B, Olagnier D, Nicolau ML, Garcia-Alvarez MC, Berry A, Benoit-Vical F.
Abstract : Malaria is one of the most significant causes of infectious disease in the world. The search for new antimalarial chemotherapies has become increasingly urgent due to the parasites' resistance to current drugs. Ellagic acid is a polyphenol found in various plant products. In this study, antimalarial properties of ellagic acid were explored. The results obtained have shown high activity in vitro against all Plasmodium falciparum strains whatever their levels of chloroquine and mefloquine resistance (50% inhibitory concentrations ranging from 105 to 330 nM). Ellagic acid was also active in vivo against Plamodium vinckei petteri in suppressive, curative, and prophylactic murine tests, without any toxicity (50% effective dose by the intraperitoneal route inferior to 1 mg/kg/day). The study of the point of action of its antimalarial activity in the erythrocytic cycle of Plasmodium falciparum demonstrated that it occurred at the mature trophozoite and young schizont stages. Moreover, ellagic acid has been shown to potentiate the activity of current antimalarial drugs such as chloroquine, mefloquine, artesunate, and atovaquone. This study also proved the antioxidant activity of ellagic acid and, in contrast, the inhibitory effect of the antioxidant compound N-acetyl-l-cysteine on its antimalarial efficacy. The possible mechanisms of action of ellagic acid on P. falciparum are discussed in light of the results. Ellagic acid has in vivo activity against plasmodia, but modification of the compound could lead to improved pharmacological properties, principally for the oral route.
|
Antiplasmodial activity against Plasmodium vinckei petteri infected in Swiss mouse assessed as inhibition of parasite growth at 50 mg/kg/day, ip measured on day 4 postinfection
|
Plasmodium vinckei petteri
|
100.0
%
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro and in vivo properties of ellagic acid in malaria treatment.
Year : 2009
Volume : 53
Issue : 3
First Page : 1100
Last Page : 1106
Authors : Soh PN, Witkowski B, Olagnier D, Nicolau ML, Garcia-Alvarez MC, Berry A, Benoit-Vical F.
Abstract : Malaria is one of the most significant causes of infectious disease in the world. The search for new antimalarial chemotherapies has become increasingly urgent due to the parasites' resistance to current drugs. Ellagic acid is a polyphenol found in various plant products. In this study, antimalarial properties of ellagic acid were explored. The results obtained have shown high activity in vitro against all Plasmodium falciparum strains whatever their levels of chloroquine and mefloquine resistance (50% inhibitory concentrations ranging from 105 to 330 nM). Ellagic acid was also active in vivo against Plamodium vinckei petteri in suppressive, curative, and prophylactic murine tests, without any toxicity (50% effective dose by the intraperitoneal route inferior to 1 mg/kg/day). The study of the point of action of its antimalarial activity in the erythrocytic cycle of Plasmodium falciparum demonstrated that it occurred at the mature trophozoite and young schizont stages. Moreover, ellagic acid has been shown to potentiate the activity of current antimalarial drugs such as chloroquine, mefloquine, artesunate, and atovaquone. This study also proved the antioxidant activity of ellagic acid and, in contrast, the inhibitory effect of the antioxidant compound N-acetyl-l-cysteine on its antimalarial efficacy. The possible mechanisms of action of ellagic acid on P. falciparum are discussed in light of the results. Ellagic acid has in vivo activity against plasmodia, but modification of the compound could lead to improved pharmacological properties, principally for the oral route.
|
Antiplasmodial activity against Plasmodium vinckei petteri infected in Swiss mouse assessed as inhibition of parasite growth at 100 mg/kg/day, ip measured on day 5 postinfection
|
Plasmodium vinckei petteri
|
100.0
%
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro and in vivo properties of ellagic acid in malaria treatment.
Year : 2009
Volume : 53
Issue : 3
First Page : 1100
Last Page : 1106
Authors : Soh PN, Witkowski B, Olagnier D, Nicolau ML, Garcia-Alvarez MC, Berry A, Benoit-Vical F.
Abstract : Malaria is one of the most significant causes of infectious disease in the world. The search for new antimalarial chemotherapies has become increasingly urgent due to the parasites' resistance to current drugs. Ellagic acid is a polyphenol found in various plant products. In this study, antimalarial properties of ellagic acid were explored. The results obtained have shown high activity in vitro against all Plasmodium falciparum strains whatever their levels of chloroquine and mefloquine resistance (50% inhibitory concentrations ranging from 105 to 330 nM). Ellagic acid was also active in vivo against Plamodium vinckei petteri in suppressive, curative, and prophylactic murine tests, without any toxicity (50% effective dose by the intraperitoneal route inferior to 1 mg/kg/day). The study of the point of action of its antimalarial activity in the erythrocytic cycle of Plasmodium falciparum demonstrated that it occurred at the mature trophozoite and young schizont stages. Moreover, ellagic acid has been shown to potentiate the activity of current antimalarial drugs such as chloroquine, mefloquine, artesunate, and atovaquone. This study also proved the antioxidant activity of ellagic acid and, in contrast, the inhibitory effect of the antioxidant compound N-acetyl-l-cysteine on its antimalarial efficacy. The possible mechanisms of action of ellagic acid on P. falciparum are discussed in light of the results. Ellagic acid has in vivo activity against plasmodia, but modification of the compound could lead to improved pharmacological properties, principally for the oral route.
|
Antiplasmodial activity against chloroquine-sensitive Plasmodium falciparum 3D7
|
Plasmodium falciparum
|
819.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Compounds structurally related to ellagic acid show improved antiplasmodial activity.
Year : 2009
Volume : 53
Issue : 2
First Page : 622
Last Page : 630
Authors : Sturm N, Hu Y, Zimmermann H, Fritz-Wolf K, Wittlin S, Rahlfs S, Becker K.
Abstract : The cancer chemopreventive agent ellagic acid (EA) is a known inhibitor of glutathione S-transferases (GSTs) and possesses antiplasmodial activities in the upper-nanomolar range. In the recent drug development approach, the properties of the active site of Plasmodium falciparum GST were exploited for inhibitor design by introducing one or two additional hydroxyl groups into EA, yielding flavellagic acid (FEA) and coruleoellagic acid (CEA), respectively. Indeed, the inhibition of P. falciparum GST was improved with the increasing hydrophilicity of the planar polyaromatic ring system. Studying the effects of the two compounds on the central redox enzymes of Plasmodium revealed that glutathione reductase and thioredoxin reductase also are inhibited in the lower-micromolar range. Both compounds had strong antiplasmodial activity in the lower-nanomolar range and were particularly effective against chloroquine (CQ)-resistant P. falciparum strains. Neither FEA nor CEA showed cytotoxic effects on human cells. This was supported by negligible changes in transcript levels and enzyme activities of redox enzymes in human A549 cells upon treatment with the compounds. In Plasmodium, however, CEA treatment resulted in a marked downregulation of most antioxidant genes studied and impaired mainly the trophozoite stage of the parasites. In addition, EA, CEA, and FEA were found to strongly inhibit in vitro heme aggregation. In vitro and preliminary in vivo studies indicated that, compared to CQ, CEA is a slowly acting compound and is able to significantly improve the survival of Plasmodium berghei-infected mice. We conclude that FEA and CEA are promising antimalarial compounds that deserve to be studied further.
|
Antiplasmodial activity against chloroquine-resistant Plasmodium falciparum Dd2
|
Plasmodium falciparum
|
351.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Compounds structurally related to ellagic acid show improved antiplasmodial activity.
Year : 2009
Volume : 53
Issue : 2
First Page : 622
Last Page : 630
Authors : Sturm N, Hu Y, Zimmermann H, Fritz-Wolf K, Wittlin S, Rahlfs S, Becker K.
Abstract : The cancer chemopreventive agent ellagic acid (EA) is a known inhibitor of glutathione S-transferases (GSTs) and possesses antiplasmodial activities in the upper-nanomolar range. In the recent drug development approach, the properties of the active site of Plasmodium falciparum GST were exploited for inhibitor design by introducing one or two additional hydroxyl groups into EA, yielding flavellagic acid (FEA) and coruleoellagic acid (CEA), respectively. Indeed, the inhibition of P. falciparum GST was improved with the increasing hydrophilicity of the planar polyaromatic ring system. Studying the effects of the two compounds on the central redox enzymes of Plasmodium revealed that glutathione reductase and thioredoxin reductase also are inhibited in the lower-micromolar range. Both compounds had strong antiplasmodial activity in the lower-nanomolar range and were particularly effective against chloroquine (CQ)-resistant P. falciparum strains. Neither FEA nor CEA showed cytotoxic effects on human cells. This was supported by negligible changes in transcript levels and enzyme activities of redox enzymes in human A549 cells upon treatment with the compounds. In Plasmodium, however, CEA treatment resulted in a marked downregulation of most antioxidant genes studied and impaired mainly the trophozoite stage of the parasites. In addition, EA, CEA, and FEA were found to strongly inhibit in vitro heme aggregation. In vitro and preliminary in vivo studies indicated that, compared to CQ, CEA is a slowly acting compound and is able to significantly improve the survival of Plasmodium berghei-infected mice. We conclude that FEA and CEA are promising antimalarial compounds that deserve to be studied further.
|
Antiplasmodial activity against chloroquine-resistant Plasmodium falciparum K1
|
Plasmodium falciparum K1
|
970.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Compounds structurally related to ellagic acid show improved antiplasmodial activity.
Year : 2009
Volume : 53
Issue : 2
First Page : 622
Last Page : 630
Authors : Sturm N, Hu Y, Zimmermann H, Fritz-Wolf K, Wittlin S, Rahlfs S, Becker K.
Abstract : The cancer chemopreventive agent ellagic acid (EA) is a known inhibitor of glutathione S-transferases (GSTs) and possesses antiplasmodial activities in the upper-nanomolar range. In the recent drug development approach, the properties of the active site of Plasmodium falciparum GST were exploited for inhibitor design by introducing one or two additional hydroxyl groups into EA, yielding flavellagic acid (FEA) and coruleoellagic acid (CEA), respectively. Indeed, the inhibition of P. falciparum GST was improved with the increasing hydrophilicity of the planar polyaromatic ring system. Studying the effects of the two compounds on the central redox enzymes of Plasmodium revealed that glutathione reductase and thioredoxin reductase also are inhibited in the lower-micromolar range. Both compounds had strong antiplasmodial activity in the lower-nanomolar range and were particularly effective against chloroquine (CQ)-resistant P. falciparum strains. Neither FEA nor CEA showed cytotoxic effects on human cells. This was supported by negligible changes in transcript levels and enzyme activities of redox enzymes in human A549 cells upon treatment with the compounds. In Plasmodium, however, CEA treatment resulted in a marked downregulation of most antioxidant genes studied and impaired mainly the trophozoite stage of the parasites. In addition, EA, CEA, and FEA were found to strongly inhibit in vitro heme aggregation. In vitro and preliminary in vivo studies indicated that, compared to CQ, CEA is a slowly acting compound and is able to significantly improve the survival of Plasmodium berghei-infected mice. We conclude that FEA and CEA are promising antimalarial compounds that deserve to be studied further.
|
PUBCHEM_BIOASSAY: uHTS absorbance assay for the identification of compounds that inhibit VHR1. (Class of assay: confirmatory) [Related pubchem assays (depositor defined):AID1661, AID1878, AID1957, AID1958, AID1992, AID2004, AID2070, AID2074, AID2684]
|
Homo sapiens
|
980.0
nM
|
|
Title : PubChem BioAssay data set
|
Antioxidant activity assessed as DPPH free radical scavenging activity
|
None
|
4.8
ug
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and antioxygenic activities of seabuckthorn flavone-3-ols and analogs.
Year : 2011
Volume : 21
Issue : 18
First Page : 5328
Last Page : 5330
Authors : Pandurangan N, Bose C, Banerji A.
Abstract : A practical synthesis of polyhydroxy- and regiospecifically methylated flavone-3-ols which are components of commercial 'seabuckthorn flavone' has been achieved by modified Algar-Flynn-Oyamada method. Antioxidant activities of seabuckthorn extracts, isolated products and a number of flavone-3-ols have been determined. Structure-activity relationships have been discussed. Amongst the compounds tested, gallic acid, which is also present in seabuckthorn, was found to be the most effective antioxidant and radioprotectant.
|
Inhibition of human recombinant aldose reductase using D-glyceraldehyde as substrate preincubated for 10 mins before substrate addition measured for every 10 secs for 50 mins by spectrophotometry
|
Homo sapiens
|
200.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Construction of an Indonesian herbal constituents database and its use in Random Forest modelling in a search for inhibitors of aldose reductase.
Year : 2012
Volume : 20
Issue : 3
First Page : 1251
Last Page : 1258
Authors : Naeem S, Hylands P, Barlow D.
Abstract : Data on phytochemical constituents of plants commonly used in traditional Indonesian medicine have been compiled as a computer database. This database (the Indonesian Herbal constituents database, IHD) currently contains details on ∼1,000 compounds found in 33 different plants. For each entry, the IHD gives details of chemical structure, trivial and systematic name, CAS registry number, pharmacology (where known), toxicology (LD(50)), botanical species, the part(s) of the plant(s) where the compounds are found, typical dosage(s) and reference(s). A second database has been also been compiled for plant-derived compounds with known activity against the enzyme, aldose reductase (AR). This database (the aldose reductase inhibitors database, ARID) contains the same details as the IHD, and currently comprises information on 120 different AR inhibitors. Virtual screening of all compounds in the IHD has been performed using Random Forest (RF) modelling, in a search for novel leads active against AR-to provide for new forms of symptomatic relief in diabetic patients. For the RF modelling, a set of simple 2D chemical descriptors were employed to classify all compounds in the combined ARID and IHD databases as either active or inactive as AR inhibitors. The resulting RF models (which gave misclassification rates of 21%) were used to identify putative new AR inhibitors in the IHD, with such compounds being identified as those giving RF scores >0.5 (in each of the three different RF models developed). In vitro assays were subsequently performed for four of the compounds obtained as hits in this in silico screening, to determine their inhibitory activity against human recombinant AR. The two compounds having the highest RF scores (prunetin and ononin) were shown to have the highest activities experimentally (giving ∼58% and ∼52% inhibition at a concentration of 15μM, respectively), while the compounds with lowest RF scores (vanillic acid and cinnamic acid) showed the lowest activities experimentally (giving ∼29% and ∼44% inhibition at a concentration of 15μM, respectively). These simple virtual screening studies were thus helpful in identifying novel inhibitors of AR, but yielded compounds with only very modest (micromolar) potency.
|
Inhibition of human recombinant ARK5 expressed in Sf9 cells assessed as autophosphorylation after 80 mins by scintillation counting
|
Homo sapiens
|
510.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Indeno[1,2-b]indole derivatives as a novel class of potent human protein kinase CK2 inhibitors.
Year : 2012
Volume : 20
Issue : 7
First Page : 2282
Last Page : 2289
Authors : Hundsdörfer C, Hemmerling HJ, Götz C, Totzke F, Bednarski P, Le Borgne M, Jose J.
Abstract : Herein we describe the synthesis and properties of indeno[1,2-b]indole derivatives as a novel class of potent inhibitors of the human protein kinase CK2. A set of 19 compounds was obtained using a convenient and straightforward synthesis protocol. The compounds were tested for inhibition of human protein kinase CK2, which was recombinantly expressed in Escherichia coli. New inhibitors with IC(50) in the micro- and sub-micromolar range were identified. Compound 4b (5-isopropyl-7,8-dihydroindeno[1,2-b]indole-9,10(5H,6H)-dione) inhibited human CK2 with an IC(50) of 0.11 μM and did not significantly inhibit 22 other human protein kinases, suggesting selectivity towards CK2. ATP-competitive inhibition by compound 4b was shown and a K(i) of 0.06 μM was determined. Our findings indicate that indeno[1,2-b]indoles are a promising starting point for further development and optimization of human protein kinase CK2 inhibitors.
|
Inhibition of human recombinant EGF-R expressed in Sf9 cells using poly(E,Y)4:1 as substrate after 80 mins by scintillation counting
|
Homo sapiens
|
690.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Indeno[1,2-b]indole derivatives as a novel class of potent human protein kinase CK2 inhibitors.
Year : 2012
Volume : 20
Issue : 7
First Page : 2282
Last Page : 2289
Authors : Hundsdörfer C, Hemmerling HJ, Götz C, Totzke F, Bednarski P, Le Borgne M, Jose J.
Abstract : Herein we describe the synthesis and properties of indeno[1,2-b]indole derivatives as a novel class of potent inhibitors of the human protein kinase CK2. A set of 19 compounds was obtained using a convenient and straightforward synthesis protocol. The compounds were tested for inhibition of human protein kinase CK2, which was recombinantly expressed in Escherichia coli. New inhibitors with IC(50) in the micro- and sub-micromolar range were identified. Compound 4b (5-isopropyl-7,8-dihydroindeno[1,2-b]indole-9,10(5H,6H)-dione) inhibited human CK2 with an IC(50) of 0.11 μM and did not significantly inhibit 22 other human protein kinases, suggesting selectivity towards CK2. ATP-competitive inhibition by compound 4b was shown and a K(i) of 0.06 μM was determined. Our findings indicate that indeno[1,2-b]indoles are a promising starting point for further development and optimization of human protein kinase CK2 inhibitors.
|
Inhibition of human recombinant IGF1R expressed in Sf9 cells using poly(E,Y)4:1 as substrate after 80 mins by scintillation counting
|
Homo sapiens
|
250.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Indeno[1,2-b]indole derivatives as a novel class of potent human protein kinase CK2 inhibitors.
Year : 2012
Volume : 20
Issue : 7
First Page : 2282
Last Page : 2289
Authors : Hundsdörfer C, Hemmerling HJ, Götz C, Totzke F, Bednarski P, Le Borgne M, Jose J.
Abstract : Herein we describe the synthesis and properties of indeno[1,2-b]indole derivatives as a novel class of potent inhibitors of the human protein kinase CK2. A set of 19 compounds was obtained using a convenient and straightforward synthesis protocol. The compounds were tested for inhibition of human protein kinase CK2, which was recombinantly expressed in Escherichia coli. New inhibitors with IC(50) in the micro- and sub-micromolar range were identified. Compound 4b (5-isopropyl-7,8-dihydroindeno[1,2-b]indole-9,10(5H,6H)-dione) inhibited human CK2 with an IC(50) of 0.11 μM and did not significantly inhibit 22 other human protein kinases, suggesting selectivity towards CK2. ATP-competitive inhibition by compound 4b was shown and a K(i) of 0.06 μM was determined. Our findings indicate that indeno[1,2-b]indoles are a promising starting point for further development and optimization of human protein kinase CK2 inhibitors.
|
Inhibition of human recombinant SRC expressed in Sf9 cells using poly(E,Y)4:1 as substrate after 80 mins by scintillation counting
|
Homo sapiens
|
800.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Indeno[1,2-b]indole derivatives as a novel class of potent human protein kinase CK2 inhibitors.
Year : 2012
Volume : 20
Issue : 7
First Page : 2282
Last Page : 2289
Authors : Hundsdörfer C, Hemmerling HJ, Götz C, Totzke F, Bednarski P, Le Borgne M, Jose J.
Abstract : Herein we describe the synthesis and properties of indeno[1,2-b]indole derivatives as a novel class of potent inhibitors of the human protein kinase CK2. A set of 19 compounds was obtained using a convenient and straightforward synthesis protocol. The compounds were tested for inhibition of human protein kinase CK2, which was recombinantly expressed in Escherichia coli. New inhibitors with IC(50) in the micro- and sub-micromolar range were identified. Compound 4b (5-isopropyl-7,8-dihydroindeno[1,2-b]indole-9,10(5H,6H)-dione) inhibited human CK2 with an IC(50) of 0.11 μM and did not significantly inhibit 22 other human protein kinases, suggesting selectivity towards CK2. ATP-competitive inhibition by compound 4b was shown and a K(i) of 0.06 μM was determined. Our findings indicate that indeno[1,2-b]indoles are a promising starting point for further development and optimization of human protein kinase CK2 inhibitors.
|
Inhibition of human recombinant VEGF-R2 expressed in Sf9 cells using poly(E,Y)4:1 as substrate after 80 mins by scintillation counting
|
Homo sapiens
|
790.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Indeno[1,2-b]indole derivatives as a novel class of potent human protein kinase CK2 inhibitors.
Year : 2012
Volume : 20
Issue : 7
First Page : 2282
Last Page : 2289
Authors : Hundsdörfer C, Hemmerling HJ, Götz C, Totzke F, Bednarski P, Le Borgne M, Jose J.
Abstract : Herein we describe the synthesis and properties of indeno[1,2-b]indole derivatives as a novel class of potent inhibitors of the human protein kinase CK2. A set of 19 compounds was obtained using a convenient and straightforward synthesis protocol. The compounds were tested for inhibition of human protein kinase CK2, which was recombinantly expressed in Escherichia coli. New inhibitors with IC(50) in the micro- and sub-micromolar range were identified. Compound 4b (5-isopropyl-7,8-dihydroindeno[1,2-b]indole-9,10(5H,6H)-dione) inhibited human CK2 with an IC(50) of 0.11 μM and did not significantly inhibit 22 other human protein kinases, suggesting selectivity towards CK2. ATP-competitive inhibition by compound 4b was shown and a K(i) of 0.06 μM was determined. Our findings indicate that indeno[1,2-b]indoles are a promising starting point for further development and optimization of human protein kinase CK2 inhibitors.
|
Inhibition of human recombinant INS-R expressed in Sf9 cells using poly(A,E,K,Y)6:2:5:1 as substrate after 80 mins by scintillation counting
|
Homo sapiens
|
340.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Indeno[1,2-b]indole derivatives as a novel class of potent human protein kinase CK2 inhibitors.
Year : 2012
Volume : 20
Issue : 7
First Page : 2282
Last Page : 2289
Authors : Hundsdörfer C, Hemmerling HJ, Götz C, Totzke F, Bednarski P, Le Borgne M, Jose J.
Abstract : Herein we describe the synthesis and properties of indeno[1,2-b]indole derivatives as a novel class of potent inhibitors of the human protein kinase CK2. A set of 19 compounds was obtained using a convenient and straightforward synthesis protocol. The compounds were tested for inhibition of human protein kinase CK2, which was recombinantly expressed in Escherichia coli. New inhibitors with IC(50) in the micro- and sub-micromolar range were identified. Compound 4b (5-isopropyl-7,8-dihydroindeno[1,2-b]indole-9,10(5H,6H)-dione) inhibited human CK2 with an IC(50) of 0.11 μM and did not significantly inhibit 22 other human protein kinases, suggesting selectivity towards CK2. ATP-competitive inhibition by compound 4b was shown and a K(i) of 0.06 μM was determined. Our findings indicate that indeno[1,2-b]indoles are a promising starting point for further development and optimization of human protein kinase CK2 inhibitors.
|
Inhibition of human recombinant MET expressed in Sf9 cells using poly(A,E,K,Y)6:2:5:1 as substrate after 80 mins by scintillation counting
|
Homo sapiens
|
580.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Indeno[1,2-b]indole derivatives as a novel class of potent human protein kinase CK2 inhibitors.
Year : 2012
Volume : 20
Issue : 7
First Page : 2282
Last Page : 2289
Authors : Hundsdörfer C, Hemmerling HJ, Götz C, Totzke F, Bednarski P, Le Borgne M, Jose J.
Abstract : Herein we describe the synthesis and properties of indeno[1,2-b]indole derivatives as a novel class of potent inhibitors of the human protein kinase CK2. A set of 19 compounds was obtained using a convenient and straightforward synthesis protocol. The compounds were tested for inhibition of human protein kinase CK2, which was recombinantly expressed in Escherichia coli. New inhibitors with IC(50) in the micro- and sub-micromolar range were identified. Compound 4b (5-isopropyl-7,8-dihydroindeno[1,2-b]indole-9,10(5H,6H)-dione) inhibited human CK2 with an IC(50) of 0.11 μM and did not significantly inhibit 22 other human protein kinases, suggesting selectivity towards CK2. ATP-competitive inhibition by compound 4b was shown and a K(i) of 0.06 μM was determined. Our findings indicate that indeno[1,2-b]indoles are a promising starting point for further development and optimization of human protein kinase CK2 inhibitors.
|
Inhibition of human recombinant TIE2 expressed in Sf9 cells using poly(E,Y)4:1 as substrate after 80 mins by scintillation counting
|
Homo sapiens
|
260.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Indeno[1,2-b]indole derivatives as a novel class of potent human protein kinase CK2 inhibitors.
Year : 2012
Volume : 20
Issue : 7
First Page : 2282
Last Page : 2289
Authors : Hundsdörfer C, Hemmerling HJ, Götz C, Totzke F, Bednarski P, Le Borgne M, Jose J.
Abstract : Herein we describe the synthesis and properties of indeno[1,2-b]indole derivatives as a novel class of potent inhibitors of the human protein kinase CK2. A set of 19 compounds was obtained using a convenient and straightforward synthesis protocol. The compounds were tested for inhibition of human protein kinase CK2, which was recombinantly expressed in Escherichia coli. New inhibitors with IC(50) in the micro- and sub-micromolar range were identified. Compound 4b (5-isopropyl-7,8-dihydroindeno[1,2-b]indole-9,10(5H,6H)-dione) inhibited human CK2 with an IC(50) of 0.11 μM and did not significantly inhibit 22 other human protein kinases, suggesting selectivity towards CK2. ATP-competitive inhibition by compound 4b was shown and a K(i) of 0.06 μM was determined. Our findings indicate that indeno[1,2-b]indoles are a promising starting point for further development and optimization of human protein kinase CK2 inhibitors.
|
Agonist activity at GPR35 receptor in human HT-29 cells after 10 mins by dynamic mass redistribution assay
|
Homo sapiens
|
110.0
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Discovery of Natural Phenols as G Protein-Coupled Receptor-35 (GPR35) Agonists.
Year : 2012
Volume : 3
Issue : 2
First Page : 165
Last Page : 169
Authors : Deng H, Hu H, Ling S, Ferrie AM, Fang Y.
Abstract : We report the discovery and characterization of natural phenols as G protein-coupled receptor-35 (GPR35) agonists. Pharmacological characterization using label-free dynamic mass redistribution and Tango β-arrestin translocation assays revealed that GPR35-active natural phenols are divergent in their biased agonism.
|
Desensitization of GPR35 receptor in human HT-29 cells assessed as inhibition of zaprinast-induced dynamic mass redistribution after 10 mins
|
Homo sapiens
|
100.0
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Discovery of Natural Phenols as G Protein-Coupled Receptor-35 (GPR35) Agonists.
Year : 2012
Volume : 3
Issue : 2
First Page : 165
Last Page : 169
Authors : Deng H, Hu H, Ling S, Ferrie AM, Fang Y.
Abstract : We report the discovery and characterization of natural phenols as G protein-coupled receptor-35 (GPR35) agonists. Pharmacological characterization using label-free dynamic mass redistribution and Tango β-arrestin translocation assays revealed that GPR35-active natural phenols are divergent in their biased agonism.
|
TP_TRANSPORTER: inhibition of ochratoxin A uptake (ochratoxin A / 1uM) in Xenopus laevis oocytes
|
Xenopus laevis
|
270.0
nM
|
|
Journal : Drug Metab. Dispos.
Title : The dietary polyphenol ellagic acid is a potent inhibitor of hOAT1.
Year : 2005
Volume : 33
Issue : 1
First Page : 1097
Last Page : 1100
Authors : Whitley AC, Sweet DH, Walle T.
Abstract : Ellagic acid (EA), a polyphenol present in berries, has been demonstrated to be preventive of esophageal and colon cancer in animals. Here, we have studied the ability of organic anion transporters (OATs) and organic anion-transporting polypeptides (OATPs) to transport EA. The accumulation of radiolabeled (14)C]EA, [(3)H]p-aminohippuric acid (PAH), [(14)C]glutarate, [(3)H]estrone sulfate, [(3)H]ochratoxin A, and [(3)H]taurocholic acid +/- inhibitor(s) was tested in OAT- and OATP-expressing oocytes. Oocytes expressing human (h)OAT1, rat (r)Oat1, and hOAT4 accumulated 6.5-, 7.1-, and 8.9-fold more EA, respectively, than did water-injected oocytes. This accumulation was prevented by the prototype OAT inhibitors bromosulfophthalein and probenecid. rOatp1, mouse (m)Oat2, hOAT3, and mOat5 showed no EA transport. The uptake of the prototype OAT substrate PAH in hOAT1-expressing oocytes was dose dependently and potently inhibited by EA with an IC(50)of 207 nM. In conclusion, we have demonstrated that the OAT family members hOAT1, rOat1, and hOAT4 mediate transport of EA, with a very high affinity for hOAT1.
|
Inhibition of electric eel AChE at 2 mg/ml by Ellman's method
|
Electrophorus electricus
|
-6.13
%
|
|
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
|
4.4
%
|
|
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 Rattus norvegicus (rat) lens aldose reductase
|
Rattus norvegicus
|
199.53
nM
|
|
Journal : Med Chem Res
Title : QSAR and flexible docking studies of some aldose reductase inhibitors obtained from natural origin
Year : 2012
Volume : 21
Issue : 8
First Page : 1665
Last Page : 1676
Authors : Jain SV, Bhadoriya KS, Bari SB
|
Inhibition of human recombinant CK2 expressed in Escherichia coli BL21(DE3) using RRRDDDSDDD as substrate after 15 mins by capillary electrophoretic analysis
|
Homo sapiens
|
40.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis and biological evaluation of novel substituted pyrrolo[1,2-a]quinoxaline derivatives as inhibitors of the human protein kinase CK2.
Year : 2013
Volume : 65
First Page : 205
Last Page : 222
Authors : Guillon J, Le Borgne M, Rimbault C, Moreau S, Savrimoutou S, Pinaud N, Baratin S, Marchivie M, Roche S, Bollacke A, Pecci A, Alvarez L, Desplat V, Jose J.
Abstract : Herein we describe the synthesis and properties of substituted phenylaminopyrrolo[1,2-a]quinoxaline-carboxylic acid derivatives as a novel class of potent inhibitors of the human protein kinase CK2. A set of 15 compounds was designed and synthesized using convenient and straightforward synthesis protocols. The compounds were tested for inhibition of human protein kinase CK2, which is a potential drug target for many diseases including inflammatory disorders and cancer. New inhibitors with IC50 in the micro- and sub-micromolar range were identified. The most promising compound, the 4-[(3-chlorophenyl)amino]pyrrolo[1,2-a]quinoxaline-3-carboxylic acid 1c inhibited human CK2 with an IC50 of 49 nM. Our findings indicate that pyrrolo[1,2-a]quinoxalines are a promising starting scaffold for further development and optimization of human protein kinase CK2 inhibitors.
|
Inhibition of human recombinant CK2 expressed in Escherichia coli BL21(DE3) using RRRDDDSDDD as substrate at 10 uM after 15 mins by capillary electrophoretic analysis relative to control
|
Homo sapiens
|
95.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis and biological evaluation of novel substituted pyrrolo[1,2-a]quinoxaline derivatives as inhibitors of the human protein kinase CK2.
Year : 2013
Volume : 65
First Page : 205
Last Page : 222
Authors : Guillon J, Le Borgne M, Rimbault C, Moreau S, Savrimoutou S, Pinaud N, Baratin S, Marchivie M, Roche S, Bollacke A, Pecci A, Alvarez L, Desplat V, Jose J.
Abstract : Herein we describe the synthesis and properties of substituted phenylaminopyrrolo[1,2-a]quinoxaline-carboxylic acid derivatives as a novel class of potent inhibitors of the human protein kinase CK2. A set of 15 compounds was designed and synthesized using convenient and straightforward synthesis protocols. The compounds were tested for inhibition of human protein kinase CK2, which is a potential drug target for many diseases including inflammatory disorders and cancer. New inhibitors with IC50 in the micro- and sub-micromolar range were identified. The most promising compound, the 4-[(3-chlorophenyl)amino]pyrrolo[1,2-a]quinoxaline-3-carboxylic acid 1c inhibited human CK2 with an IC50 of 49 nM. Our findings indicate that pyrrolo[1,2-a]quinoxalines are a promising starting scaffold for further development and optimization of human protein kinase CK2 inhibitors.
|
Inhibition of sodium fluorescein uptake in OATP1B1-transfected CHO cells at an equimolar substrate-inhibitor concentration of 10 uM
|
Cricetulus griseus
|
75.25
%
|
|
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
|
65.47
%
|
|
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 sEH (unknown origin) assessed as substrate PHOME hydrolysis at 25 uM after 1 hr by fluorescence method
|
Homo sapiens
|
40.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Anti-inflammatory components of Euphorbia humifusa Willd.
Year : 2014
Volume : 24
Issue : 8
First Page : 1895
Last Page : 1900
Authors : Luyen BT, Tai BH, Thao NP, Eun KJ, Cha JY, Xin MJ, Lee YM, Kim YH.
Abstract : Two new compounds, euphorbinoside (1) and dehydropicrorhiza acid methyl diester (2), along with 24 known compounds (3-26) were isolated from Euphorbia humifusa Willd. The effects of these compounds on soluble epoxide hydrolase (sEH) inhibitory activity were evaluated. Flavonoid compounds (10-21) exhibited high sEH inhibitory activity. Among them, compounds 12, 13, and 19 greatly inhibited sEH enzymatic activity, with IC50 values as low as 18.05±1.17, 18.64±1.83, and 17.23±0.84 μM, respectively. In addition, the effects of these compounds on lipopolysaccharide (LPS)-induced nitric oxide (NO) and tumor necrosis factor alpha (TNF-α) production by RAW 264.7 cells were investigated. Compounds 3-6, 8, 18, 20-23, and 25-26 inhibited the production of both NO and TNF-α, with IC50 values ranging from 11.1±0.9 to 45.3±1.6 μM and 14.4±0.5 to 44.5±1.2 μM, respectively.
|
Inhibition of human recombinant CK2a1/CK2b holoenzyme expressed in Escherichia coli BL21(DE3) at 10 uM pre-incubated for 10 mins before substrate addition by capillary electrophoresis based assay
|
Homo sapiens
|
95.0
%
|
|
Journal : J. Med. Chem.
Title : Converting potent indeno[1,2-b]indole inhibitors of protein kinase CK2 into selective inhibitors of the breast cancer resistance protein ABCG2.
Year : 2015
Volume : 58
Issue : 1
First Page : 265
Last Page : 277
Authors : Jabor Gozzi G, Bouaziz Z, Winter E, Daflon-Yunes N, Aichele D, Nacereddine A, Marminon C, Valdameri G, Zeinyeh W, Bollacke A, Guillon J, Lacoudre A, Pinaud N, Cadena SM, Jose J, Le Borgne M, Di Pietro A.
Abstract : A series of indeno[1,2-b]indole-9,10-dione derivatives were synthesized as human casein kinase II (CK2) inhibitors. The most potent inhibitors contained a N(5)-isopropyl substituent on the C-ring. The same series of compounds was found to also inhibit the breast cancer resistance protein ABCG2 but with totally different structure-activity relationships: a N(5)-phenethyl substituent was critical, and additional hydrophobic substituents at position 7 or 8 of the D-ring or a methoxy at phenethyl position ortho or meta also contributed to inhibition. The best ABCG2 inhibitors, such as 4c, 4h, 4i, 4j, and 4k, behaved as very weak inhibitors of CK2, whereas the most potent CK2 inhibitors, such as 4a, 4p, and 4e, displayed limited interaction with ABCG2. It was therefore possible to convert, through suitable substitutions of the indeno[1,2-b]indole-9,10-dione scaffold, potent CK2 inhibitors into selective ABCG2 inhibitors and vice versa. In addition, some of the best ABCG2 inhibitors, which displayed a very low cytotoxicity, thus giving a high therapeutic ratio, and appeared not to be transported, constitute promising candidates for further investigations.
|
Inhibition of human recombinant CK2a1/CK2b holoenzyme expressed in Escherichia coli BL21(DE3) pre-incubated for 10 mins before substrate addition by capillary electrophoresis based assay
|
Homo sapiens
|
40.0
nM
|
|
Journal : J. Med. Chem.
Title : Converting potent indeno[1,2-b]indole inhibitors of protein kinase CK2 into selective inhibitors of the breast cancer resistance protein ABCG2.
Year : 2015
Volume : 58
Issue : 1
First Page : 265
Last Page : 277
Authors : Jabor Gozzi G, Bouaziz Z, Winter E, Daflon-Yunes N, Aichele D, Nacereddine A, Marminon C, Valdameri G, Zeinyeh W, Bollacke A, Guillon J, Lacoudre A, Pinaud N, Cadena SM, Jose J, Le Borgne M, Di Pietro A.
Abstract : A series of indeno[1,2-b]indole-9,10-dione derivatives were synthesized as human casein kinase II (CK2) inhibitors. The most potent inhibitors contained a N(5)-isopropyl substituent on the C-ring. The same series of compounds was found to also inhibit the breast cancer resistance protein ABCG2 but with totally different structure-activity relationships: a N(5)-phenethyl substituent was critical, and additional hydrophobic substituents at position 7 or 8 of the D-ring or a methoxy at phenethyl position ortho or meta also contributed to inhibition. The best ABCG2 inhibitors, such as 4c, 4h, 4i, 4j, and 4k, behaved as very weak inhibitors of CK2, whereas the most potent CK2 inhibitors, such as 4a, 4p, and 4e, displayed limited interaction with ABCG2. It was therefore possible to convert, through suitable substitutions of the indeno[1,2-b]indole-9,10-dione scaffold, potent CK2 inhibitors into selective ABCG2 inhibitors and vice versa. In addition, some of the best ABCG2 inhibitors, which displayed a very low cytotoxicity, thus giving a high therapeutic ratio, and appeared not to be transported, constitute promising candidates for further investigations.
|
Inhibition of CARM1 in human HeLa cells assessed as reduction of H3R17 methylation at 5 uM after 24 hrs by Western blot analysis relative to control
|
Homo sapiens
|
50.0
%
|
|
Journal : J. Med. Chem.
Title : Selective inhibitors of protein methyltransferases.
Year : 2015
Volume : 58
Issue : 4
First Page : 1596
Last Page : 1629
Authors : Kaniskan HÜ, Konze KD, Jin J.
Abstract : Mounting evidence suggests that protein methyltransferases (PMTs), which catalyze methylation of histone and nonhistone proteins, play a crucial role in diverse biological processes and human diseases. In particular, PMTs have been recognized as major players in regulating gene expression and chromatin state. PMTs are divided into two categories: protein lysine methyltransferases (PKMTs) and protein arginine methyltransferases (PRMTs). There has been a steadily growing interest in these enzymes as potential therapeutic targets and therefore discovery of PMT inhibitors has also been pursued increasingly over the past decade. Here, we present a perspective on selective, small-molecule inhibitors of PMTs with an emphasis on their discovery, characterization, and applicability as chemical tools for deciphering the target PMTs' physiological functions and involvement in human diseases. We highlight the current state of PMT inhibitors and discuss future directions and opportunities for PMT inhibitor discovery.
|
PubChem BioAssay. High Throughput Screen to Identify Inhibitors Targeting HIV-1 Vif-dependent Degradation of Human APOBEC3G:#A time-resolved fluorescence resonance energy transfer (TR-FRET) assay for HIV-1 Vif-APOBEC3G interaction. (Class of assay: confirmatory)
|
None
|
450.0
nM
|
|
Title : PubChem BioAssay data set
|
Inhibition of human recombinant DNA polymerase iota expressed in Baculovirus expression system using TAMRA/BHQ-2-labeled primer/template measured at 2 to 6 mins by reporter-strand displacement assay
|
Homo sapiens
|
62.0
nM
|
|
Journal : J Med Chem
Title : Targeting the Translesion Synthesis Pathway for the Development of Anti-Cancer Chemotherapeutics.
Year : 2016
Volume : 59
Issue : 20
First Page : 9321
Last Page : 9336
Authors : Korzhnev DM, Hadden MK.
Abstract : Human cells possess tightly controlled mechanisms to rescue DNA replication following DNA damage caused by environmental and endogenous carcinogens using a set of low-fidelity translesion synthesis (TLS) DNA polymerases. These polymerases can copy over replication blocking DNA lesions while temporarily leaving them unrepaired, preventing cell death at the expense of increasing mutation rates and contributing to the onset and progression of cancer. In addition, TLS has been implicated as a major cellular mechanism promoting acquired resistance to genotoxic chemotherapy. Owing to its central role in mutagenesis and cell survival after DNA damage, inhibition of the TLS pathway has emerged as a potential target for the development of anticancer agents. This review will recap our current understanding of the structure and regulation of DNA polymerase complexes that mediate TLS and describe how this knowledge is beginning to translate into the development of small molecule TLS inhibitors.
|
Inhibition of human recombinant DNA polymerase eta expressed in Baculovirus expression system using TAMRA/BHQ-2-labeled primer/template measured at 2 to 6 mins by reporter-strand displacement assay
|
Homo sapiens
|
62.0
nM
|
|
Journal : J Med Chem
Title : Targeting the Translesion Synthesis Pathway for the Development of Anti-Cancer Chemotherapeutics.
Year : 2016
Volume : 59
Issue : 20
First Page : 9321
Last Page : 9336
Authors : Korzhnev DM, Hadden MK.
Abstract : Human cells possess tightly controlled mechanisms to rescue DNA replication following DNA damage caused by environmental and endogenous carcinogens using a set of low-fidelity translesion synthesis (TLS) DNA polymerases. These polymerases can copy over replication blocking DNA lesions while temporarily leaving them unrepaired, preventing cell death at the expense of increasing mutation rates and contributing to the onset and progression of cancer. In addition, TLS has been implicated as a major cellular mechanism promoting acquired resistance to genotoxic chemotherapy. Owing to its central role in mutagenesis and cell survival after DNA damage, inhibition of the TLS pathway has emerged as a potential target for the development of anticancer agents. This review will recap our current understanding of the structure and regulation of DNA polymerase complexes that mediate TLS and describe how this knowledge is beginning to translate into the development of small molecule TLS inhibitors.
|
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
|
94.0
%
|
|
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.
|
Inhibition of rat liver CK2 using RRRADDSDDDDD as substrate after 10 mins in presence of [gamma-33P]-ATP
|
Rattus norvegicus
|
40.0
nM
|
|
Title : Use of dibenzofuranone derivatives to inhibit kinases
Year : 2013
|
Inhibition of ELAV3 (unknown origin)-artificial ARE complex formation after 30 mins in the presence of biotin-labeled RNA probe by chemiluminescence nucleic acid detection method
|
Homo sapiens
|
600.0
nM
|
|
Journal : J Med Chem
Title : Compounds Interfering with Embryonic Lethal Abnormal Vision (ELAV) Protein-RNA Complexes: An Avenue for Discovering New Drugs.
Year : 2017
Volume : 60
Issue : 20
First Page : 8257
Last Page : 8267
Authors : Nasti R, Rossi D, Amadio M, Pascale A, Unver MY, Hirsch AKH, Collina S.
Abstract : RNA-binding proteins play a key role in post-transcriptional processes. Among these proteins, embryonic lethal abnormal vision (ELAV) proteins are among the best described. ELAV proteins predominantly act as positive regulators of gene expression, and their dysregulation is involved in several pathologies, such as cancer, inflammation, and neurodegenerative diseases. Only a few structurally unrelated compounds interfering with ELAV protein-mRNA complexes have been identified by applying high-throughput screening approaches. Considering the structural diversity of the compounds discovered so far and the different techniques employed for screening their ability to interfere with ELAV protein-mRNA complexes, drawing conclusions from structure-activity relationships remains a challenge. We performed docking studies to understand the interactions of compounds reported over the past decade to be inhibitors of ELAV proteins and to evaluate the potential of computer-aided drug design to target this family of proteins for further drug discovery.
|
Antibacterial activity against Klebsiella pneumoniae MDR ATCC 70063 (CO-ADD:GN_003); MIC in CAMBH media using NBS plates, by OD(600)
|
Klebsiella pneumoniae
|
25.12
%
|
|
|
Antibacterial activity against Pseudomonas aeruginosa ATCC 27853 (CO-ADD:GN_042); MIC in CAMBH media using NBS plates, by OD(600)
|
Pseudomonas aeruginosa
|
-0.73
%
|
|
|
Antifungal activity against Candida albicans ATCC 90028 (CO-ADD:FG_001); MIC in YNB media using NBS plates, by OD630
|
Candida albicans
|
8.04
%
|
|
|
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
|
-7.36
%
|
|
|
Antibacterial activity against Staphylococcus aureus MRSA ATCC 43300 (CO-ADD:GP_020); MIC in CAMBH media using NBS plates, by Resazurin F(560/590)
|
Staphylococcus aureus subsp. aureus
|
-17.94
%
|
|
|
Antibacterial activity against Acinetobacter baumannii ATCC 19606 (CO-ADD:GN_034); MIC in CAMBH media using NBS plates, by Resazurin F(560/590)
|
Acinetobacter baumannii
|
-6.11
%
|
|
|
Antibacterial activity against Escherichia coli ATCC 25922 (CO-ADD:GN_001); MIC in CAMBH media using NBS plates, by Resazurin F(560/590)
|
Escherichia coli
|
7.74
%
|
|
|
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
|
-5.38
%
|
|
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 CK2alpha (unknown origin)
|
Homo sapiens
|
20.0
nM
|
|
Journal : Eur J Med Chem
Title : Small molecule modulators targeting protein kinase CK1 and CK2.
Year : 2019
Volume : 181
First Page : 111581
Last Page : 111581
Authors : Qiao Y, Chen T, Yang H, Chen Y, Lin H, Qu W, Feng F, Liu W, Guo Q, Liu Z, Sun H.
Abstract : Casein kinase (CK) is a type of conserved serine/threonine protein kinase that phosphorylates many important proteins in body. Researchers found that CK is involved in a variety of signaling pathways, and also plays an important role in inflammation, cancer, and nervous system diseases. Thus, it is considered to be a promising target for the treatment of related diseases. Many CK small molecule inhibitors have been reported so far, and most are ATP competitive inhibitors. However, these CK inhibitors lack the basic properties required for in vivo use, such as selectivity, cell permeability, metabolic stability, correct pharmacokinetic characteristics, and cellular environment. But small molecule inhibitors still have an advantage in drug research due to their controllable pharmacological and pharmacokinetic properties. CX-4945 discovered by Cylene Pharmaceutical is the only one CK2 inhibitor entering into Phase II clinical trials till now. In recent years, significant advances have been made in the design of non-competitive inhibitors of CK and in the application of multi-target inhibition strategies. Here, we review the published CK inhibitors and analyze their structure-activity relationships (SAR). We also summarized the eutectic structure with identified hot spots to provide a reference for future drug discovery.
|
Inhibition of catalytic activity of human recombinant FLAG-tagged ppGalNAcT2 expressed in HEK293T cells and using 5-FAM labelled-EA2 peptide as substrate incubated for 30 mins by HPLC-based enzyme assay
|
Homo sapiens
|
510.0
nM
|
|
Journal : Bioorg Med Chem
Title : Inhibition of polypeptide N-acetyl-α-galactosaminyltransferases is an underlying mechanism of dietary polyphenols preventing colorectal tumorigenesis.
Year : 2019
Volume : 27
Issue : 15
First Page : 3372
Last Page : 3382
Authors : Liu F, Cui Y, Yang F, Xu Z, Da LT, Zhang Y.
Abstract : Ellagitannin-derived ellagic acid (EA) and colonic metabolite urolithins are functional dietary ingredients for cancer prevention, but the underlying mechanism need elucidation. Mucin-type O-glycosylation, initiated by polypeptide N-acetyl-α-galactosaminyltransferases (ppGalNAc-Ts), fine-tunes multiple biological processes and is closely associated with cancer progression. Herein, we aim to explore how specific tannin-based polyphenols affect tumor behavior of colorectal cancer cells (CRC) by modulating O-glycosylation. Utilizing HPLC-based enzyme assay, we find urolithin D (UroD), EA and gallic acid (GA) potently inhibit ppGalNAc-Ts. In particular, UroD inhibits ppGalNAc-T2 through a peptide/protein-competitive manner with nanomolar affinity. Computational simulations combined with site-directed mutagenesis further support the inhibitors' mode of action. Moreover, lectin analysis and metabolic labelling reveal that UroD can reduce cell O-glycans but not N-glycans. Transwell experiments prove that UroD inhibits migration and invasion of CRC cells. Our work proves that specific tannin-based polyphenols can potently inhibit ppGalNAc-Ts activity to reduce cell O-glycosylation and lead to lowering the migration and invasion of CRC cells, suggesting that disturbance of mucin-type O-glycosylation is an important mechanism for the function of dietary polyphenols.
|
Binding affinity of human recombinant FLAG-tagged ppGalNAcT2 expressed in HEK293 cells assessed as dissociation constant by SPR analysis
|
Homo sapiens
|
371.0
nM
|
|
Journal : Bioorg Med Chem
Title : Inhibition of polypeptide N-acetyl-α-galactosaminyltransferases is an underlying mechanism of dietary polyphenols preventing colorectal tumorigenesis.
Year : 2019
Volume : 27
Issue : 15
First Page : 3372
Last Page : 3382
Authors : Liu F, Cui Y, Yang F, Xu Z, Da LT, Zhang Y.
Abstract : Ellagitannin-derived ellagic acid (EA) and colonic metabolite urolithins are functional dietary ingredients for cancer prevention, but the underlying mechanism need elucidation. Mucin-type O-glycosylation, initiated by polypeptide N-acetyl-α-galactosaminyltransferases (ppGalNAc-Ts), fine-tunes multiple biological processes and is closely associated with cancer progression. Herein, we aim to explore how specific tannin-based polyphenols affect tumor behavior of colorectal cancer cells (CRC) by modulating O-glycosylation. Utilizing HPLC-based enzyme assay, we find urolithin D (UroD), EA and gallic acid (GA) potently inhibit ppGalNAc-Ts. In particular, UroD inhibits ppGalNAc-T2 through a peptide/protein-competitive manner with nanomolar affinity. Computational simulations combined with site-directed mutagenesis further support the inhibitors' mode of action. Moreover, lectin analysis and metabolic labelling reveal that UroD can reduce cell O-glycans but not N-glycans. Transwell experiments prove that UroD inhibits migration and invasion of CRC cells. Our work proves that specific tannin-based polyphenols can potently inhibit ppGalNAc-Ts activity to reduce cell O-glycosylation and lead to lowering the migration and invasion of CRC cells, suggesting that disturbance of mucin-type O-glycosylation is an important mechanism for the function of dietary polyphenols.
|
Binding affinity of human recombinant FLAG-tagged ppGalNAcT2 expressed in HEK293 cells assessed as dissociation rate by SPR analysis
|
Homo sapiens
|
8.79
10'-4/s
|
|
Journal : Bioorg Med Chem
Title : Inhibition of polypeptide N-acetyl-α-galactosaminyltransferases is an underlying mechanism of dietary polyphenols preventing colorectal tumorigenesis.
Year : 2019
Volume : 27
Issue : 15
First Page : 3372
Last Page : 3382
Authors : Liu F, Cui Y, Yang F, Xu Z, Da LT, Zhang Y.
Abstract : Ellagitannin-derived ellagic acid (EA) and colonic metabolite urolithins are functional dietary ingredients for cancer prevention, but the underlying mechanism need elucidation. Mucin-type O-glycosylation, initiated by polypeptide N-acetyl-α-galactosaminyltransferases (ppGalNAc-Ts), fine-tunes multiple biological processes and is closely associated with cancer progression. Herein, we aim to explore how specific tannin-based polyphenols affect tumor behavior of colorectal cancer cells (CRC) by modulating O-glycosylation. Utilizing HPLC-based enzyme assay, we find urolithin D (UroD), EA and gallic acid (GA) potently inhibit ppGalNAc-Ts. In particular, UroD inhibits ppGalNAc-T2 through a peptide/protein-competitive manner with nanomolar affinity. Computational simulations combined with site-directed mutagenesis further support the inhibitors' mode of action. Moreover, lectin analysis and metabolic labelling reveal that UroD can reduce cell O-glycans but not N-glycans. Transwell experiments prove that UroD inhibits migration and invasion of CRC cells. Our work proves that specific tannin-based polyphenols can potently inhibit ppGalNAc-Ts activity to reduce cell O-glycosylation and lead to lowering the migration and invasion of CRC cells, suggesting that disturbance of mucin-type O-glycosylation is an important mechanism for the function of dietary polyphenols.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
9.451
%
|
|
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
|
0.25
%
|
|
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
|
0.25
%
|
|
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.
|
Inhibition of mouse CD73
|
Mus musculus
|
40.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery of natural product ellagic acid as a potent CD73 and CD39 dual inhibitor.
Year : 2021
Volume : 34
First Page : 127758
Last Page : 127758
Authors : Wang Y,Wang C,Zhu Y,Zhang Y,Chen B,Wu Y,Yao J,Miao Z
Abstract : The ATP-adenosine pathway has been recently identified as an attractive immune-oncology target and several drug candidates have been entered clinic trials. Inspired by the report of the first small-molecule CD73inhibitor AB680, we describe the discovery of natural product ellagic acid as a dual CD73 and CD39 inhibitor with an IC value of 1.85 ± 0.21 μM and 0.50 ± 0.22 μM, respectively. The result of cytotoxicity assays indicated that ellagic acid is a valuable lead compound with low cytotoxicity effect for immune therapy.
|
Inhibition of mouse CD39
|
Mus musculus
|
500.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery of natural product ellagic acid as a potent CD73 and CD39 dual inhibitor.
Year : 2021
Volume : 34
First Page : 127758
Last Page : 127758
Authors : Wang Y,Wang C,Zhu Y,Zhang Y,Chen B,Wu Y,Yao J,Miao Z
Abstract : The ATP-adenosine pathway has been recently identified as an attractive immune-oncology target and several drug candidates have been entered clinic trials. Inspired by the report of the first small-molecule CD73inhibitor AB680, we describe the discovery of natural product ellagic acid as a dual CD73 and CD39 inhibitor with an IC value of 1.85 ± 0.21 μM and 0.50 ± 0.22 μM, respectively. The result of cytotoxicity assays indicated that ellagic acid is a valuable lead compound with low cytotoxicity effect for immune therapy.
|
Inhibition of N-terminus hexa-histidine tagged-SARS-coV guanine-N7 methyltransferase expressed in Escherichia coli using GpppAUAU RNA as substrate incubated for 30 mins by liquid scintillation counting method
|
Severe acute respiratory syndrome-related coronavirus
|
19.0
nM
|
|
Journal : Bioorg Med Chem
Title : Druggable targets from coronaviruses for designing new antiviral drugs.
Year : 2020
Volume : 28
Issue : 22.0
First Page : 115745
Last Page : 115745
Authors : Silva LR,da Silva Santos-Júnior PF,de Andrade Brandão J,Anderson L,Bassi ÊJ,Xavier de Araújo-Júnior J,Cardoso SH,da Silva-Júnior EF
Abstract : Severe respiratory infections were highlighted in the SARS-CoV outbreak in 2002, as well as MERS-CoV, in 2012. Recently, the novel CoV (COVID-19) has led to severe respiratory damage to humans and deaths in Asia, Europe, and Americas, which allowed the WHO to declare the pandemic state. Notwithstanding all impacts caused by Coronaviruses, it is evident that the development of new antiviral agents is an unmet need. In this review, we provide a complete compilation of all potential antiviral agents targeting macromolecular structures from these Coronaviruses (Coronaviridae), providing a medicinal chemistry viewpoint that could be useful for designing new therapeutic agents.
