article · Journal of Enzyme Inhibition and Medicinal Chemistry
A series of newly synthesised quinoline and isatin derivatives has been developed to target VEGFR-2 kinase activity. Testing against several cancer cell lines, including A549, Caco-2, HepG2, and MDA-MB-231, revealed notable anti-proliferative effects. Specifically, compounds 13 and 14 demonstrated activity against Caco-2 colon cancer cells comparable to the established drug doxorubicin, alongside strong inhibition of the VEGFR-2 enzyme. Evaluation in Vero cells identified compound 7 as having the highest safety and selectivity profile. Compound 7 also restricted cancer cell healing and migration, whilst triggering programmed cell death in Caco-2 cells through the downregulation of Bcl2, Bcl-xl, and Survivin genes, and the upregulation of TGF. Computational docking confirmed these derivatives interact with VEGFR-2 similarly to sorafenib, with molecular dynamics simulations confirming compound 13 remains stable within the enzyme binding pocket over 100 nanoseconds.
Targeting VEGFR-2 is a central strategy in cancer therapy to suppress tumour growth and blood vessel formation. By identifying compounds that match standard chemotherapy performance while limiting harm to non-cancerous cells, this research provides new chemical starting points for developing targeted therapies. Understanding how these molecules bind and trigger cancer cell death helps refine the design of more selective, less toxic anti-cancer treatments.
These findings present early-stage lead compounds for oncology drug discovery programmes targeting VEGFR-2. The primary users would be pharmaceutical research teams and biotechnology companies developing targeted cancer therapies. Because the data relies entirely on in vitro cell assays and computer simulations, the work remains at an early discovery phase and will require extensive preclinical validation, pharmacokinetic profiling, and in vivo animal testing before clinical translation can be considered.
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New quinoline and isatin derivatives having the main characteristics of VEGFR-2 inhibitors was synthesised. The antiproliferative effects of these compounds were estimated against A549, Caco-2, HepG2, and MDA-MB-231. Compounds <b>13</b> and <b>14</b> showed comparable activities with doxorubicin against the Caco-2 cells. These compounds strongly inhibited VEGFR-2 kinase activity. The cytotoxic activities were evaluated against Vero cells. Compound <b>7</b> showed the highest value of safety and selectivity. Cell migration assay displayed the ability of compound <b>7</b> to prevent healing and migration abilities in the cancer cells. Furthermore, compound <b>7</b> induced apoptosis in Caco-2 through the expressive down-regulation of the apoptotic genes, Bcl2, Bcl-xl, and Survivin, and the upregulation of the TGF gene. Molecular docking against VEGFR-2 emerged the interactions of the synthesised compounds in a similar way to sorafenib. Additionally, seven molecular dynamics simulations studies were applied and confirmed the stability of compound <b>13</b> in the active pocket of VEGFR-2 over 100 ns.
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DOI: 10.1080/14756366.2022.2110869
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