Development of 2-oxindolin-3-ylidene-indole-3-carbohydrazide derivatives as novel apoptotic and anti-proliferative agents towards colorectal cancer cells

Abstract

Mitochondrial anti-apoptotic Bcl2 and BclxL proteins, are overexpressed in multiple tumour types, and has been involved in the progression and survival of malignant cells. Therefore, inhibition of such proteins has become a validated and attractive target for anticancer drug discovery. In this manner, the present studies developed a series of novel isatin-indole conjugates (<b>7a-j</b> and <b>9a-e</b>) as potential anticancer Bcl2 and BclxL inhibitors. The progression of the two examined colorectal cancer cell lines was significantly inhibited by all of the prepared compounds with IC₅₀ ranges132-611 nM compared to IC₅₀ = 4.6 µM for <b>5FU</b>, against HT-29 and IC₅₀ ranges 37-468 nM compared to IC₅₀ = 1.5 µM for <b>5FU</b>, against SW-620. Thereafter, compounds <b>7c</b> and <b>7g</b> were selected for further investigations. Interestingly, both compounds exhibited selective cytotoxicity against both cell lines with high safety to normal fibroblast (HFF-1). In addition, both compounds <b>7c</b> and <b>7g</b> induced apoptosis and inhibited Bcl2 and BclxL expression in a dose-dependent manner. Collectively, the high potency and selective cytotoxicity suggested that conjugates <b>7c</b> and <b>7g</b> could be a starting point for further optimisation to develop novel pro-apoptotic and antitumor agents towards colon cancer.