article · Journal of Enzyme Inhibition and Medicinal Chemistry
Thiazolidine-2,4-dione was molecularly hybridised with 2-oxo-1,2-dihydroquinoline and 2-oxoindoline moieties to generate new hybrid compounds targeted at inhibiting VEGFR-2. When evaluated in laboratory assays against Caco-2, HepG-2, and MDA-MB-231 cancer cell lines, the synthesised derivatives displayed cytotoxic effects. Among these, compound 12a proved the most potent, with half-maximal inhibitory concentration values of 2, 10, and 40 micromolar against Caco-2, HepG-2, and MDA-MB-231 cells, respectively. The derivatives exhibited strong in vitro inhibitory action against the VEGFR-2 enzyme. In parallel tests on non-cancerous Vero cells, all evaluated compounds demonstrated high safety profiles. Further investigation into compound 12a revealed an influence on apoptotic behaviour through changes in the gene expression of Bcl2, Bcl-xl, TGF, and Survivin. Molecular dynamic simulations confirmed high binding affinity and stable dynamic interactions between compound 12a and VEGFR-2.
Cancer therapies often require new molecules capable of selectively halting tumour growth while sparing healthy tissue. By targeting the VEGFR-2 enzyme, these hybrid compounds offer a pathway to block mechanisms essential to tumour progression. Demonstrating potent cancer cell inhibition alongside low toxicity toward non-cancerous cells provides a promising direction for future therapeutic development.
This research provides early-stage lead compounds for oncology drug discovery programmes. Potential users include pharmaceutical companies and biotechnology firms developing targeted anticancer therapeutics against VEGFR-2. The technology sits at an early discovery stage, having undergone in vitro cell screening, enzyme inhibition assays, and computational simulations, meaning extensive preclinical in vivo validation and toxicology studies will be required before clinical development.
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A thiazolidine-2,4-dione nucleus was molecularly hybridised with the effective antitumor moieties; 2-oxo-1,2-dihydroquinoline and 2-oxoindoline to obtain new hybrids with potential activity against VEGFR-2. The cytotoxic effects of the synthesised derivatives against Caco-2, HepG-2, and MDA-MB-231 cell lines were investigated. Compound 12a was found to be the most potent candidate against the investigated cell lines with IC50 values of 2, 10, and 40 µM, respectively. Furthermore, the synthesised derivatives were tested in vitro for their VEGFR-2 inhibitory activity showing strong inhibition. Moreover, an in vitro viability study against Vero non-cancerous cell line was investigated and the results reflected a high safety profile of all tested compounds. Compound 12a was further investigated for its apoptotic behaviour by assessing the gene expression of four genes (Bcl2, Bcl-xl, TGF, and Survivin). Molecular dynamic simulations authenticated the high affinity, accurate binding, and perfect dynamics of compound 12a against VEGFR-2.
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DOI: 10.1080/14756366.2022.2085693
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