article · Journal of Enzyme Inhibition and Medicinal Chemistry
Combining indole and 3-hydrazinoindolin-2-one molecular structures offers a rational approach to creating compounds that trigger programmed cell death in cancer cells. Twenty-seven hybrid molecules were synthesised and screened for cytotoxic activity against three human cancer cell lines, namely MCF-7 breast cancer, HepG-2 liver cancer, and HCT-116 colorectal cancer. Structure-activity relationship analyses demonstrated that N-propylindole derivatives showed the highest potency. A lead compound, designated 6n, exhibited notable activity against MCF-7 cells with an IC50 of 1.04 micromolar. This compound reduced the cell population in the G2/M phase and increased early and late apoptosis nineteen-fold. Furthermore, 6n elevated levels of apoptotic markers including caspase-3, caspase-9, cytochrome C, and Bax, while reducing Bcl-2 expression. Additionally, four of the synthesised compounds, including 6n, generated reactive oxygen species in MCF-7 cells by elevating superoxide dismutase and depleting catalase and glutathione peroxidase.
Cancer cells often evade programmed cell death, making the discovery of pro-apoptotic molecules vital for oncology therapeutics. Demonstrating that novel synthetic hybrids can trigger apoptosis, alter critical regulatory proteins, and generate reactive oxygen species in breast cancer cell lines provides valuable molecular insights. These findings assist medicinal chemists in designing more effective chemical scaffolds aimed at overcoming apoptotic resistance in cancer treatment.
This work is relevant to pharmaceutical developers and medicinal chemistry teams seeking early-stage lead compounds for anti-cancer therapeutics. The research represents early-stage, laboratory-based discovery, having been tested strictly in vitro against cultured cancer cell lines. Considerable preclinical development, including in vivo efficacy testing, toxicology profiling, and pharmacokinetic optimisation, will be required before these compounds could advance toward potential clinical trials or therapeutic use.
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On account of their significance as apoptosis inducing agents, merging indole and 3-hydrazinoindolin-2-one scaffolds is a logic tactic for designing pro-apoptotic agents. Consequently, 27 hybrids (6a-r, 9a-f and 11a-c) were synthesised and evaluated for their cytotoxicity against MCF-7, HepG-2 and HCT-116 cancer cell lines. SAR studies unravelled that N-propylindole derivatives were the most active compounds such as 6n (MCF-7; IC<sub>50</sub>=1.04 µM), which displayed a significant decrease of cell population in the G2/M phase and significant increase in the early and late apoptosis by 19-folds in Annexin-V-FTIC assay. Also, 6n increased the expression of caspase-3, caspase-9, cytochrome C and Bax and decreased the expression of Bcl-2. Moreover, compounds 6i, 6j, 6n and 6q generated ROS by significant increase in the level of SOD and depletion of the levels of CAT and GSH-Px in MCF-7.
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DOI: 10.1080/14756366.2017.1421181
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