article · Journal of Enzyme Inhibition and Medicinal Chemistry
Researchers designed and synthesised a series of new isatin-based sulphonamide compounds to evaluate their potential as dual inhibitors of vascular endothelial growth factor receptor 2 (VEGFR-2) and carbonic anhydrase enzymes for cancer treatment. Screening across fifty-eight tumour cell lines identified the most effective derivatives. When evaluated against specific carbonic anhydrase isoforms, the compounds showed no inhibitory activity, likely due to steric hindrance from an adjacent methoxy group. However, the molecules demonstrated potent inhibitory effects against VEGFR-2. Subsequent biological testing of two specific compounds, designated 11b and 12b, showed that they disrupted the cancer cell cycle and induced apoptosis. Computational docking and molecular dynamics simulations further characterised how these target molecules achieve stable binding within the VEGFR-2 receptor site.
Cancer therapies often require new molecules capable of blocking specific proteins, such as VEGFR-2, that drive tumour survival and blood vessel growth. Demonstrating that these newly synthesised sulphonamides selectively inhibit VEGFR-2 and trigger cancer cell death provides a clearer structural basis for developing new chemical candidates that could eventually contribute to targeted cancer treatments.
This work represents early-stage research in drug discovery. The compounds could serve as chemical starting points for medicinal chemists and pharmaceutical developers seeking new VEGFR-2 inhibitors. Because the evaluations remain limited to in vitro laboratory assays and computational molecular modelling, extensive preclinical development, including in vivo safety, pharmacokinetic, and efficacy profiling, is required before any potential therapeutic application could emerge.
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In this work, new isatin-based sulphonamides (6a-i, 11a-c, 12a-c) were designed and synthesised as potential dual VEGFR-2 and carbonic anhydrase inhibitors with anticancer activities. Firstly, all target isatins were examined for in vitro antitumor action on NCI-USA panel (58 tumour cell lines). Then, the most potent derivatives were examined for the potential CA inhibitory action towards the physiologically relevant hCA isoforms I, II, and tumour-linked hCA IX isoform, in addition, the VEGFR-2 inhibitory activity was evaluated. The target sulphonamides failed to inhibit the CA isoforms that could be attributable to the steric effect of the neighbouring methoxy group, whereas they displayed potent VEGFR-2 inhibitory effect. Following that, isatins 11b and 12b were tested for their influence on the cell cycle disturbance, and towards the apoptotic potential. Finally, detailed molecular modelling analyses, including docking and molecular dynamics, were carried out to assess the binding mode and stability of target isatins.
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DOI: 10.1080/14756366.2023.2203389
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