article · Journal of Enzyme Inhibition and Medicinal Chemistry
This research developed a series of novel isatin-indole conjugates to target mitochondrial anti-apoptotic Bcl2 and BclxL proteins, which are often overexpressed in various tumours and contribute to cancer cell survival. The synthesised compounds were tested against two colorectal cancer cell lines, HT-29 and SW-620, and all demonstrated significant inhibition of cancer cell progression at nanomolar concentrations, outperforming the standard drug 5FU. Two specific compounds, 7c and 7g, were further investigated and showed selective toxicity towards cancer cells with high safety for normal fibroblast cells. These compounds also induced apoptosis and reduced Bcl2 and BclxL protein expression in a dose-dependent manner, suggesting their potential as starting points for new colon cancer treatments.
Overexpressed Bcl2 and BclxL proteins help cancer cells survive and progress, making them key targets for new therapies. This research offers potential new chemical compounds that effectively inhibit these proteins and selectively kill colorectal cancer cells, paving the way for novel drug development in cancer treatment.
This early-stage research presents novel chemical compounds, 7c and 7g, as potential candidates for developing new pro-apoptotic and anti-tumour agents specifically for colorectal cancer. These compounds target Bcl2 and BclxL proteins, offering a pathway for new drug discovery. Further optimisation and development would be required to advance these findings towards clinical applications.
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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 IC<sub>50</sub> ranges132-611 nM compared to IC<sub>50</sub> = 4.6 µM for <b>5FU</b>, against HT-29 and IC<sub>50</sub> ranges 37-468 nM compared to IC<sub>50</sub> = 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.
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DOI: 10.1080/14756366.2020.1862100
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