article · Journal of Enzyme Inhibition and Medicinal Chemistry
Researchers designed and synthesised a novel series of N-alkylindole-isatin conjugates, aiming to develop more efficient isatin-based anti-tumour candidates. Building on previous findings, they modified the indole motif with various alkyl groups. The new compounds demonstrated significantly improved growth inhibitory profiles compared to a known lead compound. Specifically, hybrid 8a, an N-propylindole-5-methylisatin conjugate, showed broad-spectrum anti-proliferative action against cancer cells, inducing cell cycle disturbance and apoptosis. It also effectively inhibited cell cycle regulator CDK2 protein kinase and the anti-apoptotic Bcl-2 protein. Molecular docking studies indicated that the N-propyl group in 8a is crucial for its interactions with these proteins, suggesting it as a promising lead for further anti-tumour drug development.
Developing new compounds with enhanced anti-tumour activity is crucial for improving cancer treatment options. This research identifies a promising lead compound that targets key proteins involved in cancer cell growth and survival, offering a potential pathway for future drug development.
This early-stage research identifies a novel compound, hybrid 8a, with significant anti-tumour potential. It could serve as a lead compound for pharmaceutical companies developing new cancer therapeutics. Further research and optimisation are required to advance it towards clinical application, potentially offering a new treatment option for various cancers.
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As a continuation for our previous work, a novel set of <i>N</i>-alkylindole-isatin conjugates (<b>7</b>, <b>8a-c</b>, <b>9</b> and <b>10a-e</b>) is here designed and synthesised with the prime aim to develop more efficient isatin-based antitumor candidates. Utilising the SAR outputs from the previous study, our design here is based on appending four alkyl groups with different length (ethyl and n-propyl), bulkiness (iso-propyl) and unsaturation (allyl) on <i>N</i>-1 of indole motif, with subsequent conjugation with different <i>N</i>-unsubstituted isatin moieties to furnish the target conjugates. As planned, the adopted strategy achieved a substantial improvement in the growth inhibitory profile for the target conjugates in comparison to the reported lead <b>VI</b>. The best results were obtained with <i>N</i>-propylindole -5-methylisatin hybrid <b>8a</b> which displayed broad spectrum anti-proliferative action with efficient sub-panel GI<sub>50</sub> (MG-MID) range from 1.33 to 4.23 µM, and promising full-panel GI<sub>50</sub> (MG-MID) equals 3.10 µM, at the NCI five-dose assay. Also, hybrid <b>8a</b> was able to provoke cell cycle disturbance and apoptosis in breast T-47D cells as evidenced by the DNA flow cytometry and Annexin V-FITC/PI assays. Furthermore, hybrid <b>8a</b> exhibited good inhibitory action against cell cycle regulator CDK2 protein kinase and the anti-apoptotic Bcl-2 protein (IC<sub>50</sub>= 0.85 ± 0.03 and 0.46 ± 0.02 µM, respectively). Interestingly, molecular docking for hybrid <b>8a</b> in CDK2 and Bcl-2 active sites unveiled that <i>N</i>-propyl group is involved in significant hydrophobic interactions. Taken together, the results suggested conjugate <b>8a</b> as a promising lead for further development and optimisation as an efficient antitumor drug.
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DOI: 10.1080/14756366.2020.1773814
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