|
Inhibition of COX2 at 100 uM by scintillation proximity assay
|
None
|
30.0
%
|
|
Journal : J. Nat. Prod.
Title : Screening of ubiquitous plant constituents for COX-2 inhibition with a scintillation proximity based assay.
Year : 2002
Volume : 65
Issue : 11
First Page : 1517
Last Page : 1521
Authors : Huss U, Ringbom T, Perera P, Bohlin L, Vasänge M.
Abstract : A rapid semi-homogeneous cyclooxygenase-2 (COX-2) enzymatic assay using scintillation proximity assay (SPA) technology was developed, and 49 ubiquitous plant secondary metabolites were screened for inhibition of COX-2-catalyzed prostaglandin E(2) (PGE(2)) biosynthesis. Assay conditions were optimized with respect to reaction time, amount of antibody, radiolabeled PGE(2), and SPA beads, and the kinetic parameter, K(m), was estimated. The assay was validated with two natural triterpenoids, ursolic and oleanolic acid, known to inhibit COX-2, as well as with four synthetic COX inhibitors, NS-398, rofecoxib, indomethacin, and aspirin. Plant metabolites of different biosynthetic origin representing several substance classes, including alkaloids, anthraquinones, flavonoids, phenylpropanes, steroids, and terpenes, were screened for inhibition of COX-2-catalyzed PGE(2) production. Of these 49 plant metabolites, eugenol, pyrogallol, and cinnamaldehyde (with IC(50) values of 129, 144, and 245 microM, respectively) were found to inhibit COX-2. This study showed that a COX-2-catalyzed PGE(2) assay using SPA is suitable for screening natural compounds with respect to COX-2 inhibition.
|
Inhibition of Na+/K+ ATPase
|
None
|
150.0
nM
|
|
Journal : J. Med. Chem.
Title : Identification of a potent, selective, and orally active leukotriene a4 hydrolase inhibitor with anti-inflammatory activity.
Year : 2008
Volume : 51
Issue : 14
First Page : 4150
Last Page : 4169
Authors : Grice CA, Tays KL, Savall BM, Wei J, Butler CR, Axe FU, Bembenek SD, Fourie AM, Dunford PJ, Lundeen K, Coles F, Xue X, Riley JP, Williams KN, Karlsson L, Edwards JP.
Abstract : LTA 4H is a ubiquitously distributed 69 kDa zinc-containing cytosolic enzyme with both hydrolase and aminopeptidase activity. As a hydrolase, LTA 4H stereospecifically catalyzes the transformation of the unstable epoxide LTA 4 to the diol LTB 4, a potent chemoattractant and activator of neutrophils and a chemoattractant of eosinophils, macrophages, mast cells, and T cells. Inhibiting the formation of LTB 4 is expected to be beneficial in the treatment of inflammatory diseases such as inflammatory bowel disease (IBD), asthma, and atherosclerosis. We developed a pharmacophore model using a known inhibitor manually docked into the active site of LTA 4H to identify a subset of compounds for screening. From this work we identified a series of benzoxazole, benzthiazole, and benzimidazole inhibitors. SAR studies resulted in the identification of several potent inhibitors with an appropriate cross-reactivity profile and excellent PK/PD properties. Our efforts focused on further profiling JNJ 27265732, which showed encouraging efficacy in a disease model relevant to IBD.
|
Inhibition of HIV1 RT
|
Human immunodeficiency virus 1
|
200.0
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).
|
Inhibition of Na+K+ATpase from pig cortex
|
Sus scrofa
|
600.0
nM
|
|
Journal : J. Nat. Prod.
Title : Na+-K+-ATPase inhibitors from Lysimachia japonica.
Year : 1984
Volume : 47
Issue : 3
First Page : 530
Last Page : 532
Authors : Shoji N, Umeyama A, Takemoto T, Kobayashi M, Ohizumi Y.
|
Inhibition of pig cerebral cortex Na+/K+ ATPase at 1 mM by colorimetric microplate-based assay
|
Sus scrofa
|
100.0
%
|
|
Journal : J. Nat. Prod.
Title : Cardenolides from Pergularia tomentosa display cytotoxic activity resulting from their potent inhibition of Na+/K+-ATPase.
Year : 2009
Volume : 72
Issue : 6
First Page : 1087
Last Page : 1091
Authors : Piacente S, Masullo M, De Nève N, Dewelle J, Hamed A, Kiss R, Mijatovic T.
Abstract : Two new cardenolide glycosides (1 and 2), along with six known cardenolide glycosides (3-8), have been isolated from the roots of Pergularia tomentosa. In order to investigate their potential anticancer activity, these compounds were tested in an in vitro growth inhibitory assay (a MTT colorimetric assay), including six different human cancer cell lines, and for their ability to inhibit Na(+)/K(+)-ATPase activity, in addition to the morphologic changes induced in human cancer cell lines (using computer-assisted phase-contrast microscopy). The data revealed that these cardenolides displayed marked cytotoxic activity. The results obtained suggest that structural characteristics of the cardenolides studied, with the A/B rings of the steroidal skeleton trans fused and containing a single sugar in a unique "dioxanoid" attachment, confer on them specific cytotoxic properties that are distinct from those displayed by classic cardenolides such as digoxin.
|
PUBCHEM_BIOASSAY: Luminescence Cell-Based HTS Dose Confirmation to Identify Inhibitors of of 5'UTR Stem-Loop Driven Alpha-Synuclein mRNA Translation in H4 Neuroglioblastoma Cells. (Class of assay: confirmatory) [Related pubchem assays: 1813 (Primary HTS), 1827 (Project Summary)]
|
None
|
64.0
nM
|
|
Title : PubChem BioAssay data set
|
PUBCHEM_BIOASSAY: Luminescence Cell-Based Dose Response HTS to Identify Inhibitors of Luciferase Translation or Activity in H4 Neuroglioblastoma Cells. (Class of assay: confirmatory) [Related pubchem assays: 1813 (Primary HTS), 1827 (Project Summary)]
|
None
|
100.0
nM
|
|
Title : PubChem BioAssay data set
|
PUBCHEM_BIOASSAY: Luminescence Cell-Based Dose Response to Identify Inhibitors of Luciferase Translation or Activity in H4-C Neuroglioblastoma Cells. (Class of assay: confirmatory) [Related pubchem assays: 1813 (Primary HTS), 1827 (Project Summary)]
|
None
|
84.0
nM
|
|
Title : PubChem BioAssay data set
|
PUBCHEM_BIOASSAY: Luminescence-based dose response cell-based high throughput screening assay for inhibitors of kruppel-like factor 5 (KLF5). (Class of assay: confirmatory) [Related pubchem assays: 1700 (Primary screen.), 1834 (Confirmation screen.), 1905 (Counterscreen.), 1858 (Summary AID.)]
|
Homo sapiens
|
164.55
nM
|
|
Title : PubChem BioAssay data set
|
PUBCHEM_BIOASSAY: Luminescence Cell-Based Dose Response to Identify Inhibitors of 5'UTR Stem-Loop Driven Prion Protein mRNA Translation in H4-C Neuroglioblastoma Cells. (Class of assay: confirmatory) [Related pubchem assays: 1827 (Project Summary), 1813 (Primary HTS)]
|
None
|
80.0
nM
|
|
Title : PubChem BioAssay data set
|
PUBCHEM_BIOASSAY: Luminescence Cell-Based Dose Response HTS to Identify Inhibitors of 5'UTR Stem-Loop Driven Prion Protein mRNA Translation in H4 Neuroglioblastoma Cells. (Class of assay: confirmatory) [Related pubchem assays: 1827 (Project Summary), 1813 (Primary HTS)]
|
None
|
100.0
nM
|
|
Title : PubChem BioAssay data set
|
PUBCHEM_BIOASSAY: Luminescence Cell-Based Dose Confirmation HTS to Identify Inhibitors of of 5'UTR Stem-Loop Driven Alpha-Synuclein mRNA Translation in H4 Neuroglioblastoma Cells. (Class of assay: confirmatory) [Related pubchem assays: 1827 (Project Summary), 1813 (Primary HTS)]
|
None
|
100.0
nM
|
|
Title : PubChem BioAssay data set
|
PUBCHEM_BIOASSAY: Late stage assay provider counterscreen results from the probe development effort to identify inhibitors of kruppel-like factor 5 (KLF5): chemiluminescence-based Western blot assay for inhibitors of KLF5 protein levels. (Class of assay: confirmatory) [Related pubchem assays (depositor defined):AID1700, AID1825, AID1834, AID1858, AID1973, AID1975, AID2749, AID2750]
|
Homo sapiens
|
29.73
nM
|
|
Title : PubChem BioAssay data set
|
PUBCHEM_BIOASSAY: Late stage assay provider counterscreen results from the probe development effort to identify inhibitors of kruppel-like factor 5 (KLF5): luminescence-based cell-based dose response assay for cytotoxic compounds using the DLD-1 cell line (Round 1). (Class of assay: confirmatory) [Related pubchem assays (depositor defined):AID1700, AID1825, AID1834, AID1858, AID1973, AID1975, AID2749, AID2750]
|
Homo sapiens
|
46.4
nM
|
|
Title : PubChem BioAssay data set
|
PUBCHEM_BIOASSAY: A Cell-Based Confirmatory Screen for Compounds that Inhibit VEEV, TC-83. (Class of assay: confirmatory) [Related pubchem assays (depositor defined):AID588723]
|
Chlorocebus sabaeus
|
50.0
nM
|
|
Title : PubChem BioAssay data set
|
DRUGMATRIX: ATPase, Na+/K+ enzyme inhibition (substrate: ATP)
|
Sus scrofa
|
678.0
nM
|
|
Title : DrugMatrix in vitro pharmacology data
Authors : Scott S. Auerbach, DrugMatrix¨ and ToxFX¨ Coordinator National Toxicology Program
Abstract : The DrugMatrix Pharmacology data is a subset of the data freely available from the National Toxicology Program. For more details see:https://ntp.niehs.nih.gov/drugmatrix/index.html
|
Cytotoxicity against human T47D cells after 72 hrs by CellTiter-Glo assay
|
Homo sapiens
|
385.0
nM
|
|
Journal : J. Nat. Prod.
Title : Cytotoxic cardiac glycosides and other compounds from Asclepias syriaca.
Year : 2012
Volume : 75
Issue : 3
First Page : 400
Last Page : 407
Authors : Araya JJ, Kindscher K, Timmermann BN.
Abstract : Phytochemical investigation of the dried biomass of Asclepias syriaca afforded five new compounds (1-5), along with 19 known structures. Overall, the secondary metabolites isolated and identified from this plant showed a wide structural diversity including pentacyclic triterpenes, cardiac glycosides, flavonoid glycosides, lignans, a phenylethanoid, and a glycosylated megastigmane. In addition, the isolates were tested against the cancer breast cell line Hs578T, and those showing IC(50) values lower than 50 μM (1 and 6-9) were further investigated in three additional breast cancer cell lines (MCF-7, T47D, and Sk-Br-3) and the normal breast cell line Hs578Bst.
|
Cytotoxicity against human SK-BR-3 cells after 72 hrs by CellTiter-Glo assay
|
Homo sapiens
|
403.0
nM
|
|
Journal : J. Nat. Prod.
Title : Cytotoxic cardiac glycosides and other compounds from Asclepias syriaca.
Year : 2012
Volume : 75
Issue : 3
First Page : 400
Last Page : 407
Authors : Araya JJ, Kindscher K, Timmermann BN.
Abstract : Phytochemical investigation of the dried biomass of Asclepias syriaca afforded five new compounds (1-5), along with 19 known structures. Overall, the secondary metabolites isolated and identified from this plant showed a wide structural diversity including pentacyclic triterpenes, cardiac glycosides, flavonoid glycosides, lignans, a phenylethanoid, and a glycosylated megastigmane. In addition, the isolates were tested against the cancer breast cell line Hs578T, and those showing IC(50) values lower than 50 μM (1 and 6-9) were further investigated in three additional breast cancer cell lines (MCF-7, T47D, and Sk-Br-3) and the normal breast cell line Hs578Bst.
|
Cytotoxicity against human Hs578T cells after 72 hrs by CellTiter-Glo assay
|
Homo sapiens
|
110.0
nM
|
|
Journal : J. Nat. Prod.
Title : Cytotoxic cardiac glycosides and other compounds from Asclepias syriaca.
Year : 2012
Volume : 75
Issue : 3
First Page : 400
Last Page : 407
Authors : Araya JJ, Kindscher K, Timmermann BN.
Abstract : Phytochemical investigation of the dried biomass of Asclepias syriaca afforded five new compounds (1-5), along with 19 known structures. Overall, the secondary metabolites isolated and identified from this plant showed a wide structural diversity including pentacyclic triterpenes, cardiac glycosides, flavonoid glycosides, lignans, a phenylethanoid, and a glycosylated megastigmane. In addition, the isolates were tested against the cancer breast cell line Hs578T, and those showing IC(50) values lower than 50 μM (1 and 6-9) were further investigated in three additional breast cancer cell lines (MCF-7, T47D, and Sk-Br-3) and the normal breast cell line Hs578Bst.
|
Cytotoxicity against human Hs578Bst cells after 72 hrs by CellTiter-Glo assay
|
Homo sapiens
|
6.0
nM
|
|
Journal : J. Nat. Prod.
Title : Cytotoxic cardiac glycosides and other compounds from Asclepias syriaca.
Year : 2012
Volume : 75
Issue : 3
First Page : 400
Last Page : 407
Authors : Araya JJ, Kindscher K, Timmermann BN.
Abstract : Phytochemical investigation of the dried biomass of Asclepias syriaca afforded five new compounds (1-5), along with 19 known structures. Overall, the secondary metabolites isolated and identified from this plant showed a wide structural diversity including pentacyclic triterpenes, cardiac glycosides, flavonoid glycosides, lignans, a phenylethanoid, and a glycosylated megastigmane. In addition, the isolates were tested against the cancer breast cell line Hs578T, and those showing IC(50) values lower than 50 μM (1 and 6-9) were further investigated in three additional breast cancer cell lines (MCF-7, T47D, and Sk-Br-3) and the normal breast cell line Hs578Bst.
|
Inhibition of electric eel AChE at 2 mg/ml by Ellman's method
|
Electrophorus electricus
|
-3.72
%
|
|
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
|
5.11
%
|
|
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 human liver OATP1B1 expressed in HEK293 Flp-In cells assessed as reduction in E17-betaG uptake at 20 uM by scintillation counting
|
Homo sapiens
|
50.5
%
|
|
Journal : J. Med. Chem.
Title : Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions.
Year : 2012
Volume : 55
Issue : 10
First Page : 4740
Last Page : 4763
Authors : Karlgren M, Vildhede A, Norinder U, Wisniewski JR, Kimoto E, Lai Y, Haglund U, Artursson P.
Abstract : The hepatic organic anion transporting polypeptides (OATPs) influence the pharmacokinetics of several drug classes and are involved in many clinical drug-drug interactions. Predicting potential interactions with OATPs is, therefore, of value. Here, we developed in vitro and in silico models for identification and prediction of specific and general inhibitors of OATP1B1, OATP1B3, and OATP2B1. The maximal transport activity (MTA) of each OATP in human liver was predicted from transport kinetics and protein quantification. We then used MTA to predict the effects of a subset of inhibitors on atorvastatin uptake in vivo. Using a data set of 225 drug-like compounds, 91 OATP inhibitors were identified. In silico models indicated that lipophilicity and polar surface area are key molecular features of OATP inhibition. MTA predictions identified OATP1B1 and OATP1B3 as major determinants of atorvastatin uptake in vivo. The relative contributions to overall hepatic uptake varied with isoform specificities of the inhibitors.
|
Inhibition of human liver OATP1B3 expressed in HEK293 Flp-In cells assessed as reduction in [3H]E17-betaG uptake at 20 uM incubated for 5 mins by scintillation counting
|
Homo sapiens
|
20.5
%
|
|
Journal : J. Med. Chem.
Title : Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions.
Year : 2012
Volume : 55
Issue : 10
First Page : 4740
Last Page : 4763
Authors : Karlgren M, Vildhede A, Norinder U, Wisniewski JR, Kimoto E, Lai Y, Haglund U, Artursson P.
Abstract : The hepatic organic anion transporting polypeptides (OATPs) influence the pharmacokinetics of several drug classes and are involved in many clinical drug-drug interactions. Predicting potential interactions with OATPs is, therefore, of value. Here, we developed in vitro and in silico models for identification and prediction of specific and general inhibitors of OATP1B1, OATP1B3, and OATP2B1. The maximal transport activity (MTA) of each OATP in human liver was predicted from transport kinetics and protein quantification. We then used MTA to predict the effects of a subset of inhibitors on atorvastatin uptake in vivo. Using a data set of 225 drug-like compounds, 91 OATP inhibitors were identified. In silico models indicated that lipophilicity and polar surface area are key molecular features of OATP inhibition. MTA predictions identified OATP1B1 and OATP1B3 as major determinants of atorvastatin uptake in vivo. The relative contributions to overall hepatic uptake varied with isoform specificities of the inhibitors.
|
Inhibition of human liver OATP2B1 expressed in HEK293 Flp-In cells assessed as reduction in [3H]E3S uptake at 20 uM incubated for 5 mins by scintillation counting
|
Homo sapiens
|
-24.1
%
|
|
Journal : J. Med. Chem.
Title : Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions.
Year : 2012
Volume : 55
Issue : 10
First Page : 4740
Last Page : 4763
Authors : Karlgren M, Vildhede A, Norinder U, Wisniewski JR, Kimoto E, Lai Y, Haglund U, Artursson P.
Abstract : The hepatic organic anion transporting polypeptides (OATPs) influence the pharmacokinetics of several drug classes and are involved in many clinical drug-drug interactions. Predicting potential interactions with OATPs is, therefore, of value. Here, we developed in vitro and in silico models for identification and prediction of specific and general inhibitors of OATP1B1, OATP1B3, and OATP2B1. The maximal transport activity (MTA) of each OATP in human liver was predicted from transport kinetics and protein quantification. We then used MTA to predict the effects of a subset of inhibitors on atorvastatin uptake in vivo. Using a data set of 225 drug-like compounds, 91 OATP inhibitors were identified. In silico models indicated that lipophilicity and polar surface area are key molecular features of OATP inhibition. MTA predictions identified OATP1B1 and OATP1B3 as major determinants of atorvastatin uptake in vivo. The relative contributions to overall hepatic uptake varied with isoform specificities of the inhibitors.
|
Cytotoxicity against human SK-MEL-28 cells after 3 days by MTT assay
|
Homo sapiens
|
211.0
nM
|
|
Journal : J. Nat. Prod.
Title : Structure-activity relationship analysis of bufadienolide-induced in vitro growth inhibitory effects on mouse and human cancer cells.
Year : 2013
Volume : 76
Issue : 6
First Page : 1078
Last Page : 1084
Authors : Moreno Y Banuls L, Urban E, Gelbcke M, Dufrasne F, Kopp B, Kiss R, Zehl M.
Abstract : The in vitro growth inhibitory effects of 27 bufadienolides and eight degradation products, with two cardenolides (ouabain and digoxin) chosen as reference compounds, were analyzed by means of an MTT colorimetric assay in six human and two mouse cancer cell lines. A structure-activity analysis was then performed to highlight the most important substituents relating to the in vitro growth inhibitory activity of bufadienolides in cancer cells. Thus, the current study revealed that various bufadienolides, including gamabufotalin rhamnoside (1a), bufotalin (2a), and hellebrin (3a), displayed higher growth inhibitory activities for various human cancer cell lines when compared to ouabain and digoxin. Gamabufotalin rhamnoside (1a) was the only compound that displayed growth inhibitory effects of <1 μM in mouse cancer cells that expressed mutated forms of the Na(+),K(+)-ATPase α-1 subunit. In addition, all genins and degradation products displayed weaker (if any) in vitro growth inhibitory effects on cancer cells when compared to their respective glycosylated homologue, with the exception of hellebrigenin (3b), which was as active as hellebrin (3a).
|
Cytotoxicity against human U373 cells after 3 days by MTT assay
|
Homo sapiens
|
77.0
nM
|
|
Journal : J. Nat. Prod.
Title : Structure-activity relationship analysis of bufadienolide-induced in vitro growth inhibitory effects on mouse and human cancer cells.
Year : 2013
Volume : 76
Issue : 6
First Page : 1078
Last Page : 1084
Authors : Moreno Y Banuls L, Urban E, Gelbcke M, Dufrasne F, Kopp B, Kiss R, Zehl M.
Abstract : The in vitro growth inhibitory effects of 27 bufadienolides and eight degradation products, with two cardenolides (ouabain and digoxin) chosen as reference compounds, were analyzed by means of an MTT colorimetric assay in six human and two mouse cancer cell lines. A structure-activity analysis was then performed to highlight the most important substituents relating to the in vitro growth inhibitory activity of bufadienolides in cancer cells. Thus, the current study revealed that various bufadienolides, including gamabufotalin rhamnoside (1a), bufotalin (2a), and hellebrin (3a), displayed higher growth inhibitory activities for various human cancer cell lines when compared to ouabain and digoxin. Gamabufotalin rhamnoside (1a) was the only compound that displayed growth inhibitory effects of <1 μM in mouse cancer cells that expressed mutated forms of the Na(+),K(+)-ATPase α-1 subunit. In addition, all genins and degradation products displayed weaker (if any) in vitro growth inhibitory effects on cancer cells when compared to their respective glycosylated homologue, with the exception of hellebrigenin (3b), which was as active as hellebrin (3a).
|
Cytotoxicity against human A549 cells after 3 days by MTT assay
|
Homo sapiens
|
27.0
nM
|
|
Journal : J. Nat. Prod.
Title : Structure-activity relationship analysis of bufadienolide-induced in vitro growth inhibitory effects on mouse and human cancer cells.
Year : 2013
Volume : 76
Issue : 6
First Page : 1078
Last Page : 1084
Authors : Moreno Y Banuls L, Urban E, Gelbcke M, Dufrasne F, Kopp B, Kiss R, Zehl M.
Abstract : The in vitro growth inhibitory effects of 27 bufadienolides and eight degradation products, with two cardenolides (ouabain and digoxin) chosen as reference compounds, were analyzed by means of an MTT colorimetric assay in six human and two mouse cancer cell lines. A structure-activity analysis was then performed to highlight the most important substituents relating to the in vitro growth inhibitory activity of bufadienolides in cancer cells. Thus, the current study revealed that various bufadienolides, including gamabufotalin rhamnoside (1a), bufotalin (2a), and hellebrin (3a), displayed higher growth inhibitory activities for various human cancer cell lines when compared to ouabain and digoxin. Gamabufotalin rhamnoside (1a) was the only compound that displayed growth inhibitory effects of <1 μM in mouse cancer cells that expressed mutated forms of the Na(+),K(+)-ATPase α-1 subunit. In addition, all genins and degradation products displayed weaker (if any) in vitro growth inhibitory effects on cancer cells when compared to their respective glycosylated homologue, with the exception of hellebrigenin (3b), which was as active as hellebrin (3a).
|
Cytotoxicity against human PC3 cells after 3 days by MTT assay
|
Homo sapiens
|
43.0
nM
|
|
Journal : J. Nat. Prod.
Title : Structure-activity relationship analysis of bufadienolide-induced in vitro growth inhibitory effects on mouse and human cancer cells.
Year : 2013
Volume : 76
Issue : 6
First Page : 1078
Last Page : 1084
Authors : Moreno Y Banuls L, Urban E, Gelbcke M, Dufrasne F, Kopp B, Kiss R, Zehl M.
Abstract : The in vitro growth inhibitory effects of 27 bufadienolides and eight degradation products, with two cardenolides (ouabain and digoxin) chosen as reference compounds, were analyzed by means of an MTT colorimetric assay in six human and two mouse cancer cell lines. A structure-activity analysis was then performed to highlight the most important substituents relating to the in vitro growth inhibitory activity of bufadienolides in cancer cells. Thus, the current study revealed that various bufadienolides, including gamabufotalin rhamnoside (1a), bufotalin (2a), and hellebrin (3a), displayed higher growth inhibitory activities for various human cancer cell lines when compared to ouabain and digoxin. Gamabufotalin rhamnoside (1a) was the only compound that displayed growth inhibitory effects of <1 μM in mouse cancer cells that expressed mutated forms of the Na(+),K(+)-ATPase α-1 subunit. In addition, all genins and degradation products displayed weaker (if any) in vitro growth inhibitory effects on cancer cells when compared to their respective glycosylated homologue, with the exception of hellebrigenin (3b), which was as active as hellebrin (3a).
|
Cytotoxicity against human MCF7 cells after 3 days by MTT assay
|
Homo sapiens
|
133.0
nM
|
|
Journal : J. Nat. Prod.
Title : Structure-activity relationship analysis of bufadienolide-induced in vitro growth inhibitory effects on mouse and human cancer cells.
Year : 2013
Volume : 76
Issue : 6
First Page : 1078
Last Page : 1084
Authors : Moreno Y Banuls L, Urban E, Gelbcke M, Dufrasne F, Kopp B, Kiss R, Zehl M.
Abstract : The in vitro growth inhibitory effects of 27 bufadienolides and eight degradation products, with two cardenolides (ouabain and digoxin) chosen as reference compounds, were analyzed by means of an MTT colorimetric assay in six human and two mouse cancer cell lines. A structure-activity analysis was then performed to highlight the most important substituents relating to the in vitro growth inhibitory activity of bufadienolides in cancer cells. Thus, the current study revealed that various bufadienolides, including gamabufotalin rhamnoside (1a), bufotalin (2a), and hellebrin (3a), displayed higher growth inhibitory activities for various human cancer cell lines when compared to ouabain and digoxin. Gamabufotalin rhamnoside (1a) was the only compound that displayed growth inhibitory effects of <1 μM in mouse cancer cells that expressed mutated forms of the Na(+),K(+)-ATPase α-1 subunit. In addition, all genins and degradation products displayed weaker (if any) in vitro growth inhibitory effects on cancer cells when compared to their respective glycosylated homologue, with the exception of hellebrigenin (3b), which was as active as hellebrin (3a).
|
Cytotoxicity against human Hs683 cells after 3 days by MTT assay
|
Homo sapiens
|
28.0
nM
|
|
Journal : J. Nat. Prod.
Title : Structure-activity relationship analysis of bufadienolide-induced in vitro growth inhibitory effects on mouse and human cancer cells.
Year : 2013
Volume : 76
Issue : 6
First Page : 1078
Last Page : 1084
Authors : Moreno Y Banuls L, Urban E, Gelbcke M, Dufrasne F, Kopp B, Kiss R, Zehl M.
Abstract : The in vitro growth inhibitory effects of 27 bufadienolides and eight degradation products, with two cardenolides (ouabain and digoxin) chosen as reference compounds, were analyzed by means of an MTT colorimetric assay in six human and two mouse cancer cell lines. A structure-activity analysis was then performed to highlight the most important substituents relating to the in vitro growth inhibitory activity of bufadienolides in cancer cells. Thus, the current study revealed that various bufadienolides, including gamabufotalin rhamnoside (1a), bufotalin (2a), and hellebrin (3a), displayed higher growth inhibitory activities for various human cancer cell lines when compared to ouabain and digoxin. Gamabufotalin rhamnoside (1a) was the only compound that displayed growth inhibitory effects of <1 μM in mouse cancer cells that expressed mutated forms of the Na(+),K(+)-ATPase α-1 subunit. In addition, all genins and degradation products displayed weaker (if any) in vitro growth inhibitory effects on cancer cells when compared to their respective glycosylated homologue, with the exception of hellebrigenin (3b), which was as active as hellebrin (3a).
|
Inhibition of sodium fluorescein uptake in OATP1B1-transfected CHO cells at an equimolar substrate-inhibitor concentration of 10 uM
|
Cricetulus griseus
|
108.07
%
|
|
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
|
98.13
%
|
|
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 guinea pig kidney Na+-K+ dependent ATPase after 10 to 20 mins
|
Cavia porcellus
|
500.0
nM
|
|
Journal : J. Med. Chem.
Title : Trichloroacetamidines, a new class of positive inotropic agents.
Year : 1978
Volume : 21
Issue : 12
First Page : 1283
Last Page : 1290
Authors : Saari WS, Freedman MB, Huff JR, King SW, Raab AW, Bergstrand SJ, Engelhardt EL.
Abstract : A series of trichloroacetamidine derivatives, obtained by addition of amines to trichloroacetonitrile, was evaluated for positive inotropic activity on isolated cat heart papillary muscles. Increased contractility, not antagonized by beta-adrenergic blockade with sotalol or reserpine pretreatment, was observed in this assay with a variety of N-substituted trichloroacetamidine derivatives. More extensive pharmacological studies with the 3-indolylmethyl analogue 2 showed that this amidine in dogs, 5 mg/kg iv, produced a positive inotropic effect more pronounced than that of ouabain, 50 microgram/kg iv. Several of the trichloroacetamidines were found to be inhibitors of guinea pig kidney and calf heart Na-K-dependent ATPase and to have specificity for these enzymes different from that of ouabain. Bacterial mutagenic activity was observed with three members, 2,3, and 12, of the series.
|
Inhibition of calf heart Na+-K+ dependent ATPase after 10 to 20 mins
|
Bos taurus
|
500.0
nM
|
|
Journal : J. Med. Chem.
Title : Trichloroacetamidines, a new class of positive inotropic agents.
Year : 1978
Volume : 21
Issue : 12
First Page : 1283
Last Page : 1290
Authors : Saari WS, Freedman MB, Huff JR, King SW, Raab AW, Bergstrand SJ, Engelhardt EL.
Abstract : A series of trichloroacetamidine derivatives, obtained by addition of amines to trichloroacetonitrile, was evaluated for positive inotropic activity on isolated cat heart papillary muscles. Increased contractility, not antagonized by beta-adrenergic blockade with sotalol or reserpine pretreatment, was observed in this assay with a variety of N-substituted trichloroacetamidine derivatives. More extensive pharmacological studies with the 3-indolylmethyl analogue 2 showed that this amidine in dogs, 5 mg/kg iv, produced a positive inotropic effect more pronounced than that of ouabain, 50 microgram/kg iv. Several of the trichloroacetamidines were found to be inhibitors of guinea pig kidney and calf heart Na-K-dependent ATPase and to have specificity for these enzymes different from that of ouabain. Bacterial mutagenic activity was observed with three members, 2,3, and 12, of the series.
|
Inhibition of calf heart Na+-K+ dependent ATPase preincubated for 30 mins measured after 10 to 20 mins
|
Bos taurus
|
200.0
nM
|
|
Journal : J. Med. Chem.
Title : Trichloroacetamidines, a new class of positive inotropic agents.
Year : 1978
Volume : 21
Issue : 12
First Page : 1283
Last Page : 1290
Authors : Saari WS, Freedman MB, Huff JR, King SW, Raab AW, Bergstrand SJ, Engelhardt EL.
Abstract : A series of trichloroacetamidine derivatives, obtained by addition of amines to trichloroacetonitrile, was evaluated for positive inotropic activity on isolated cat heart papillary muscles. Increased contractility, not antagonized by beta-adrenergic blockade with sotalol or reserpine pretreatment, was observed in this assay with a variety of N-substituted trichloroacetamidine derivatives. More extensive pharmacological studies with the 3-indolylmethyl analogue 2 showed that this amidine in dogs, 5 mg/kg iv, produced a positive inotropic effect more pronounced than that of ouabain, 50 microgram/kg iv. Several of the trichloroacetamidines were found to be inhibitors of guinea pig kidney and calf heart Na-K-dependent ATPase and to have specificity for these enzymes different from that of ouabain. Bacterial mutagenic activity was observed with three members, 2,3, and 12, of the series.
|
Inhibition of rat brain sodium/potassium-transporting ATPase in presence of Mg2+ and Na+
|
Rattus norvegicus
|
500.0
nM
|
|
Journal : J. Med. Chem.
Title : Cardenolide analogues. 2. 22-Methylenecard-14-enolides.
Year : 1977
Volume : 20
Issue : 6
First Page : 841
Last Page : 844
Authors : Fullerton DS, Gilman TM, Pankaskie MC, Ahmed K, From AH, Duax WL, Rohrer DC.
Abstract : 22-Methylene-3beta-hydroxy-5beta,20(S)-card-14-enolide (11) and 22-methylene-3beta-hydroxy-5beta,20(R)-card-14-enolide (12) were synthesized from digitoxin (1). Attempts to prepare the 14beta-hydroxy-22-methylene analogues were unsuccessful. The 20(R) isomer (12) was found in Na+, K+-ATPase inhibition studies to be twice as active as 14-dehydrogitoxigenin (17). The 20(S) isomer (11) was significantly less active than 17. The hydrolysis of steroid 3beta-tert-butyldimethysilyl ethers was also found to be much more difficult than with nonsteroids.
|
Inhibition of rat brain sodium/potassium-transporting ATPase after 10 mins in presence of Mg2+ and Na+
|
Rattus norvegicus
|
40.0
nM
|
|
Journal : J. Med. Chem.
Title : Cardenolide analogues. 2. 22-Methylenecard-14-enolides.
Year : 1977
Volume : 20
Issue : 6
First Page : 841
Last Page : 844
Authors : Fullerton DS, Gilman TM, Pankaskie MC, Ahmed K, From AH, Duax WL, Rohrer DC.
Abstract : 22-Methylene-3beta-hydroxy-5beta,20(S)-card-14-enolide (11) and 22-methylene-3beta-hydroxy-5beta,20(R)-card-14-enolide (12) were synthesized from digitoxin (1). Attempts to prepare the 14beta-hydroxy-22-methylene analogues were unsuccessful. The 20(R) isomer (12) was found in Na+, K+-ATPase inhibition studies to be twice as active as 14-dehydrogitoxigenin (17). The 20(S) isomer (11) was significantly less active than 17. The hydrolysis of steroid 3beta-tert-butyldimethysilyl ethers was also found to be much more difficult than with nonsteroids.
|
Inhibition of Na+/K+ -ATPase in human intrauterine growth restriction placental membrane using 3-O-methylfluorescein phosphate by fluorometric method in presence of Kcl
|
Homo sapiens
|
3.4
ug.mL-1
|
|
Journal : J. Nat. Prod.
Title : Meroterpenoids from a Tropical Dysidea sp. Sponge.
Year : 2015
Volume : 78
Issue : 11
First Page : 2814
Last Page : 2821
Authors : Kim CK, Woo JK, Kim SH, Cho E, Lee YJ, Lee HS, Sim CJ, Oh DC, Oh KB, Shin J.
Abstract : Six new meroterpenoids (1-6), along with arenarol (7), a known rearranged drimane sesquiterpene hydroquinone, were isolated from a Dysidea sp. sponge collected from the Federated States of Micronesia. On the basis of the results of combined spectroscopic analysis, compound 1 was determined to be the cyclic ether derivative of 7, whereas 2 and 3 were assigned as the corresponding sesquiterpene quinones containing taurine-derived substituents. Compounds 4-6 possess a novel tetracyclic skeleton formed by a direct linkage between the quinone and sesquiterpene moieties. The configurations of these new compounds were assigned on the basis of combined NOESY and ECD analysis. These compounds exhibited cytotoxic and antimicrobial activities and weak inhibition against Na(+)/K(+)-ATPase.
|
Inhibition of recombinant rat Na+/K+-ATPase alpha2/beta1 expressed in baculovirus infected insect Sf9 cell membranes using [gamma-32P]ATP as substrate preincubated for 20 mins followed by substrate addition measured after 30 mins by liquid scintillation counting
|
Rattus norvegicus
|
170.0
nM
|
|
Journal : J Med Chem
Title : Design, Synthesis, and in Vitro and in Vivo Evaluation of Ouabain Analogues as Potent and Selective Na,K-ATPase α4 Isoform Inhibitors for Male Contraception.
Year : 2018
Volume : 61
Issue : 5
First Page : 1800
Last Page : 1820
Authors : Syeda SS, Sánchez G, Hong KH, Hawkinson JE, Georg GI, Blanco G.
Abstract : Na,K-ATPase α4 is a testis-specific plasma membrane Na+ and K+ transporter expressed in sperm flagellum. Deletion of Na,K-ATPase α4 in male mice results in complete infertility, making it an attractive target for male contraception. Na,K-ATPase α4 is characterized by a high affinity for the cardiac glycoside ouabain. With the goal of discovering selective inhibitors of the Na,K-ATPase α4 and of sperm function, ouabain derivatives were modified at the glycone (C3) and the lactone (C17) domains. Ouabagenin analogue 25, carrying a benzyltriazole moiety at C17, is a picomolar inhibitor of Na,K-ATPase α4, with an outstanding α4 isoform selectivity profile. Moreover, compound 25 decreased sperm motility in vitro and in vivo and affected sperm membrane potential, intracellular Ca2+, pH, and hypermotility. These results proved that the new ouabagenin triazole analogue is an effective and selective inhibitor of Na,K-ATPase α4 and sperm function.
|
Inhibition of recombinant rat Na+/K+-ATPase alpha3/beta1 expressed in baculovirus infected insect Sf9 cell membranes using [gamma-32P]ATP as substrate preincubated for 20 mins followed by substrate addition measured after 30 mins by liquid scintillation counting
|
Rattus norvegicus
|
31.0
nM
|
|
Journal : J Med Chem
Title : Design, Synthesis, and in Vitro and in Vivo Evaluation of Ouabain Analogues as Potent and Selective Na,K-ATPase α4 Isoform Inhibitors for Male Contraception.
Year : 2018
Volume : 61
Issue : 5
First Page : 1800
Last Page : 1820
Authors : Syeda SS, Sánchez G, Hong KH, Hawkinson JE, Georg GI, Blanco G.
Abstract : Na,K-ATPase α4 is a testis-specific plasma membrane Na+ and K+ transporter expressed in sperm flagellum. Deletion of Na,K-ATPase α4 in male mice results in complete infertility, making it an attractive target for male contraception. Na,K-ATPase α4 is characterized by a high affinity for the cardiac glycoside ouabain. With the goal of discovering selective inhibitors of the Na,K-ATPase α4 and of sperm function, ouabain derivatives were modified at the glycone (C3) and the lactone (C17) domains. Ouabagenin analogue 25, carrying a benzyltriazole moiety at C17, is a picomolar inhibitor of Na,K-ATPase α4, with an outstanding α4 isoform selectivity profile. Moreover, compound 25 decreased sperm motility in vitro and in vivo and affected sperm membrane potential, intracellular Ca2+, pH, and hypermotility. These results proved that the new ouabagenin triazole analogue is an effective and selective inhibitor of Na,K-ATPase α4 and sperm function.
|
Inhibition of recombinant rat Na+/K+-ATPase alpha4/beta1 expressed in baculovirus infected insect Sf9 cell membranes using [gamma-32P]ATP as substrate preincubated for 10 mins followed by substrate addition measured after 30 mins in presence of Na+, K+ and Mg2+ by liquid scintillation counting
|
Rattus norvegicus
|
4.3
nM
|
|
Journal : J Med Chem
Title : Design, Synthesis, and in Vitro and in Vivo Evaluation of Ouabain Analogues as Potent and Selective Na,K-ATPase α4 Isoform Inhibitors for Male Contraception.
Year : 2018
Volume : 61
Issue : 5
First Page : 1800
Last Page : 1820
Authors : Syeda SS, Sánchez G, Hong KH, Hawkinson JE, Georg GI, Blanco G.
Abstract : Na,K-ATPase α4 is a testis-specific plasma membrane Na+ and K+ transporter expressed in sperm flagellum. Deletion of Na,K-ATPase α4 in male mice results in complete infertility, making it an attractive target for male contraception. Na,K-ATPase α4 is characterized by a high affinity for the cardiac glycoside ouabain. With the goal of discovering selective inhibitors of the Na,K-ATPase α4 and of sperm function, ouabain derivatives were modified at the glycone (C3) and the lactone (C17) domains. Ouabagenin analogue 25, carrying a benzyltriazole moiety at C17, is a picomolar inhibitor of Na,K-ATPase α4, with an outstanding α4 isoform selectivity profile. Moreover, compound 25 decreased sperm motility in vitro and in vivo and affected sperm membrane potential, intracellular Ca2+, pH, and hypermotility. These results proved that the new ouabagenin triazole analogue is an effective and selective inhibitor of Na,K-ATPase α4 and sperm function.
|
Inhibition of recombinant rat Na+/K+-ATPase alpha4/beta3 expressed in baculovirus infected Sf9 cell membranes using [gamma-32P]ATP as substrate preincubated for 20 mins followed by substrate addition measured after 30 mins by liquid scintillation counting
|
Rattus norvegicus
|
1.8
nM
|
|
Journal : J Med Chem
Title : Design, Synthesis, and in Vitro and in Vivo Evaluation of Ouabain Analogues as Potent and Selective Na,K-ATPase α4 Isoform Inhibitors for Male Contraception.
Year : 2018
Volume : 61
Issue : 5
First Page : 1800
Last Page : 1820
Authors : Syeda SS, Sánchez G, Hong KH, Hawkinson JE, Georg GI, Blanco G.
Abstract : Na,K-ATPase α4 is a testis-specific plasma membrane Na+ and K+ transporter expressed in sperm flagellum. Deletion of Na,K-ATPase α4 in male mice results in complete infertility, making it an attractive target for male contraception. Na,K-ATPase α4 is characterized by a high affinity for the cardiac glycoside ouabain. With the goal of discovering selective inhibitors of the Na,K-ATPase α4 and of sperm function, ouabain derivatives were modified at the glycone (C3) and the lactone (C17) domains. Ouabagenin analogue 25, carrying a benzyltriazole moiety at C17, is a picomolar inhibitor of Na,K-ATPase α4, with an outstanding α4 isoform selectivity profile. Moreover, compound 25 decreased sperm motility in vitro and in vivo and affected sperm membrane potential, intracellular Ca2+, pH, and hypermotility. These results proved that the new ouabagenin triazole analogue is an effective and selective inhibitor of Na,K-ATPase α4 and sperm function.
|
Antiviral activity against SARS-CoV-2 (viral titer) measured by plaque assay in Vero cells at MOI 0.0125 after 24 hr
|
Chlorocebus sabaeus
|
97.0
nM
|
|
Title : Identification of antiviral drug candidates against SARS-CoV-2 from FDA-approved drugs
Year : 2020
Authors : Sangeun Jeon, Meehyun Ko, Jihye Lee, Inhee Choi, Soo Young Byun, Soonju Park, David Shum, Seungtaek Kim
Abstract : COVID-19 is an emerging infectious disease and was recently declared as a pandemic by WHO. Currently, there is no vaccine or therapeutic available for this disease. Drug repositioning represents the only feasible option to address this global challenge and a panel of 48 FDA- approved drugs that have been pre-selected by an assay of SARS-CoV was screened to identify potential antiviral drug candidates against SARS-CoV-2 infection. We found a total of 24 drugs which exhibited antiviral efficacy (0.1 μM < IC50 < 10 μM) against SARS-CoV-2. In particular, two FDA-approved drugs - niclosamide and ciclesonide – were notable in some respects. These drugs will be tested in an appropriate animal model for their antiviral activities. In near future, these already FDA-approved drugs could be further developed following clinical trials in order to provide additional therapeutic options for patients with COVID-19.
