Identification and characterization of novel indole based small molecules as anticancer agents through SIRT1 inhibition
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2013
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Abstract
In our pursuit to develop new potential anticancer leads, we designed a combination of structural units of indole and substituted triazole; and a library of 1-{1-methyl-2-[4-phenyl-5-(propan-2-ylsulfanyl)-4H-1,2,4-triazol-3- yl]-1H-indol-3-yl}methanamine derivatives was synthesized and characterized. Cytotoxic evaluations of these molecules over a panel of three human cancer cell lines were carried out. Few molecules exhibited potent growth inhibitory action against the treated cancer cell lines at lower micro molar concentration. An in vitro assay investigation of these active compounds using recombinant human SIRT1 enzyme showed that one of the compounds (IT-14) inhibited the deacetylation activity of the enzyme. The in vivo study of IT-14 exemplified its promising action by reducing the prostate weight to the body weight ratio in prostate hyperplasia animal models. A remarkable decrease in the disruption of histoarchitecture of the prostate tissues isolated from IT-14 treated animal compared to that of the positive control was observed. The molecular interactions with SIRT1 enzyme were also supported by molecular docking simulations. Hence this compound can act as a lead molecule to treat prostatic hyperplasia. © 2013 Elsevier Masson SAS. All rights reserved.
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1 [1 methyl 2 [4 phenyl 5 (propan 2 ylsulfanyl) 4h 1,2,4 triazol 3 yl] 1h indol 3 yl]methamine derivative, 2 [5 (isopropylthio) 4 phenyl 4h 1,2,4 triazol 3 yl] 1 methyl 3 (morpholinomethyl) 1h indole, 2 [5 (isopropylthio) 4 phenyl 4h 1,2,4 triazol 3 yl] 1 methyl 3 [(2 methylpiperidin 1 yl)methyl] 1h indole, 2 [5 (isopropylthio) 4 phenyl 4h 1,2,4 triazol 3 yl] 1 methyl 3 [(3 methylpiperidin 1 yl)methyl] 1h indole, 2 [5 (isopropylthio) 4 phenyl 4h 1,2,4 triazol 3 yl] 1 methyl 3 [(4 methylpiperidin 1 yl)methyl] 1h indole, 2 [5 (isopropylthio) 4 phenyl 4h 1,2,4 triazol 3 yl] 1 methyl 3 [[4 (pyrrolidin 1 yl)piperidine 1 yl]methyl] 1h indole, 3 [(2,6 dimethylmorpholino)methyl] 2 [5 (isopropylthio) 4 phenyl 4h 1,2,4 triazol 3 yl] 1 methyl 1h indole, 5 fluoro 2 [5 (isopropylthio) 4 phenyl 4h 1,2,4 triazol 3 yl] 1 methyl 3 (morpholinomethyl) 1h indole, 5 fluoro 2 [5 (isopropylthio) 4 phenyl 4h 1,2,4 triazol 3 yl] 1 methyl 3 [(3 methylpiperidine 1 yl)methyl] 1h indole, antineoplastic agent, cyclopropyl n[[2 [5 (isopropylthio) 4 phenyl 4h 1,2,4 triazol 3 yl] 1 methyl 1 1h indol 3 yl]methyl]methanamine, cyclopropyl n[[5 fluoro 2 [5 (isopropylthio) 4 phenyl 4h 1,2,4 triazol 3 yl] 1 methyl 1h indol 3 yl]methyl]methanamine, indole derivative, n[[2 [5 (isopropylthio) 4 phenyl 4h 1,2,4 triazol 3 yl] 1 methyl 1h indol 3 yl] 1 methyl 1h indol 3 yl]methyl] 2 (pyrrolidin 1 yl)ethan 1 amine, n[[2 [5 (isopropylthio) 4 phenyl 4h 1,2,4 triazol 3 yl] 1 methyl 1h indol 3 yl]methly] 3 morpholinopropan 1 amine, n[[2 [5 (isopropylthio) 4 phenyl 4h 1,2,4 triazol 3 yl] 1 methyl 1h indol 3 yl]methyl(4 methoxyphenyl)methanamine, n[[2 [5 (isopropylthio) 4 phenyl 4h 1,2,4 triazol 3 yl] 1 methyl 1h indol 3 yl]methyl] 2 methoxyethan 1 amine, n[[2 [5 (isopropylthio) 4 phenyl 4h 1,2,4 triazol 3 yl] 1 methyl 1h indol 3 yl]methyl] 2 morpholinoethan 1 amine, n[[2 [5 (isopropylthio) 4 phenyl 4h 1,2,4 triazol 3 yl] 1 methyl 1h indol 3 yl]methyl](3 methoxyphenyl)methanamine, n[[2 [5 (isopropylthio) 4 phenyl 4h 1,2,4 triazol 3 yl] 1 methyl 1h indol 3 yl]methyl]cyclopropanamine, n[[2 [5 (isopropythio) 4 phenyl 4h 1,2,4 triazol 3 yl] 1 methyl 1h indol 3 yl]methyl] 3,4,5 trimethoxybenzenamine, n[[5 fluoro 2 [5 (isopropylthio) 4 phenyl 4h 1,2,4 triazol 3 yl] 1 methyl 1h indol 3 yl]methyl] 2 9pyrrolidin 1 yl)ethan 1 amine, n[[5 fluoro 2 [5 (isopropylthio) 4 phenyl 4h 1,2,4 triazol 3 yl] 1 methyl 1h indol 3 yl]methyl] 2 methoxyethan 1 amine, n[[5 fluoro 2 [5 (isopropylthio) 4 phenyl 4h 1,2,4 triazol 3 yl] 1 methyl 1h indol 3 yl]methyl] 2 morpholinoethan 1 amine, n[[5 fluoro 2 [5 (isopropylthio) 4 phenyl 4h 1,2,4 triazol 3 yl] 1 methyl 1h indol 3 yl]methyl] 3 morpholinopropan 1 amine, n[[5 fluoro 2 [5 (isopropylthio) 4 phenyl 4h 1,2,4 triazol 3 yl] 1 methyl 1h indol 3 yl]methyl] 3,4,5 trimethoxybenzenamine, n[[5 fluoro 2 [5 (isopropylthio) 4 phenyl 4h 1,2,4 triazol 3 yl] 1 methyl 1h indol 3 yl]methyl](3 methoxyphenyl)methanamine, n[[5 fluoro 2 [5 (isopropylthio) 4 phenyl 4h 1,2,4 triazol 3 yl] 1 methyl 1h indol 3 yl]methyl](4 methoxyphenyl)methanamine, n[[5 fluoro 2 [5 (isopropylthio) 4 phenyl 4h 1,2,4 triazol 3 yl] 1 methyl 1h indol 3 yl]methyl]cyclopropanamine, unclassified drug, unindexed drug, animal experiment, animal model, antineoplastic activity, article, body weight, cancer cell culture, cancer inhibition, controlled study, cytotoxicity, deacetylation, drug synthesis, human, human cell, in vitro study, in vivo study, male, molecular docking, molecular interaction, nonhuman, prostate hypertrophy, prostate weight, rat, Breast cancer, Human SIRT1, Indole, Leukemia, Prostate hyperplasia, Animals, Antineoplastic Agents, Cell Line, Tumor, Cell Proliferation, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, HEK293 Cells, Histone Deacetylase Inhibitors, Humans, Hyperplasia, Indoles, K562 Cells, Male, Models, Molecular, Molecular Structure, Rats, Rats, Wistar, Sirtuin 1, Small Molecule Libraries, Structure-Activity Relationship, Testosterone
Citation
European Journal of Medicinal Chemistry, 2013, 69, , pp. 125-138