article · Journal of Biomolecular Structure and Dynamics
Researchers have designed and synthesised novel chemical compounds derived from quinoline and isatine to act as antiangiogenic inhibitors targeting the VEGFR-2 protein. In laboratory evaluations, these molecules displayed potent inhibition of VEGFR-2. When assessed across four cancer cell lines and two healthy cell lines, specific molecules demonstrated promising anticancer activity and safety profiles. Compound 12 displayed cytotoxic potency against lung, colon, and breast cancer lines comparable to or surpassing the standard chemotherapy drug doxorubicin, paired with a superior selectivity index against colon cancer cells. In parallel, compound 9 prevented cancer cell migration, arrested the cell cycle at the G2/M phase, and prompted programmed cell death in colon cancer cells by downregulating survival genes. Computational docking, molecular dynamics simulations, and predictive safety profiling further confirmed that these candidates bind reliably to VEGFR-2 and exhibit drug-like characteristics.
Targeting angiogenesis, the process of forming new blood vessels to supply tumours, is a vital strategy in cancer therapy. Developing molecules that inhibit VEGFR-2 while showing high selectivity for cancer cells over healthy tissue could lead to more effective oncology treatments with fewer toxic side effects than conventional chemotherapeutic options such as doxorubicin.
These compounds could serve as early-stage leads for pharmaceutical companies developing targeted small-molecule inhibitors for colon, lung, and breast cancers. The research is currently at an early preclinical stage, bounded by in vitro cell culture experiments and computational simulations. Substantial further research, including in vivo animal efficacy and pharmacokinetic testing, will be required before these compounds can advance towards clinical development.
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A new set of quinoline and isatine derivatives were synthesized as antiangiogenic VEGFR-2 inhibitors. On a biological level, the <i>in vitro</i> ability of the obtained candidates to inhibit VEGFR-2 was found to be strong with IC<sub>50</sub> values in the range of 76.64-175.50 nM. To investigate the cytotoxicity and safety, all compounds were tested against a panel of four cancer cell lines (A549, Caco2, HepG2 and MDA) as well as two normal cell lines (Vero and WI-38). Interestingly, compound <b>12</b> exhibited noticeable cytotoxicity against A549, Caco2 and MDA with IC<sub>50</sub> values of 5.40, 0.58 and 0.94 µM, respectively. These results were better and comparable to that of doxorubicin (0.70, 0.82 and 0.90 µM, respectively) with more than three folds higher selectivity index against the Caco2 cell lines. Compound <b>9</b> prevented the healing of the cancer cells at a low concentration. Also, the compound's potential to induce programmed cell death in Caco-2 was proved through the significant down regulating of the expression of Bcl2, Bcl-xl and Survivin in addition to the slight upregulation of the TGF-β gene. The cell cycle analysis indicated that compound <b>9</b> arrested the Caco-2 cells in the G2/M phase. Interestingly, the molecular docking studies against VEGFR-2 revealed the correct binding of the targeted compounds similar to sorafenib. Furthermore, MD experiments validated the binding of compound <b>12</b> with VEGFR-2 over 100 ns, as well as MM-PBSA analysis that confirmed the precise binding with optimum energy. Finally, ADMET analysis showed the general drug-likeness and confirmed the safety of the tested compounds.Communicated by Ramaswamy H. Sarma.
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DOI: 10.1080/07391102.2022.2164356
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