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

• 29 Molecules were screened for cytotoxicity evaluation.
• In vivo investigations were carried out to examine the activity of the molecule.
• Histopathology images and PCR proved the effectiveness of the molecule.
• Simple synthetic protocols were used to get a promising lead molecule.

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.

This protocol depicts the cytotoxicity and growth inhibitory activity of some indole derivatives, acting against benign prostatic hyperplasia through SIRT1 inhibition, in terms of in vitro and in vivo models.Figure optionsDownload as PowerPoint slide