Identification and characterization of novel indole based small molecules as anticancer agents through SIRT1 inhibition

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• 作者：Naveen Panathur ; Udayakumar Dalimba ; Pulla Venkat Koushik ; Mallika Alvala ; Perumal Yogeeswari ; Dharmarajan Sriram ; Vijith Kumar
• 关键词：Indole ; Leukemia ; Breast cancer ; Prostate hyperplasia ; Human SIRT1
• 刊名：European Journal of Medicinal Chemistry
• 出版年：November, 2013
• 年：2013
• 卷：69
• 期：Complete
• 页码：125-138
• 全文大小：2437 K

文摘

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聽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聽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.