article · Journal of Enzyme Inhibition and Medicinal Chemistry
New nicotinamide derivatives have been designed and synthesised to target vascular endothelial growth factor receptor 2 (VEGFR-2) for cancer therapy. Laboratory testing evaluated compounds 6, 7, 10, and 11, revealing sub-micromolar VEGFR-2 inhibition across the series. Among these, compound 10 showed the strongest anti-proliferative action against HCT-116 colorectal and HepG2 liver cancer cell lines, performing comparably to the reference drug sorafenib. Compound 7 also demonstrated cytotoxic effects across both cell lines, halted the cell cycle at the G2-M and G0-G1 phases, and triggered programmed cell death in HCT-116 cells. In addition, both compounds 7 and 10 exhibited notable immunomodulatory actions by substantially decreasing levels of the inflammatory cytokines TNF-alpha and IL-6, matching the effects of dexamethasone. Computational docking, molecular dynamics, ADMET, and toxicity evaluations further characterised the candidate molecules.
Cancer treatments often require dual strategies that simultaneously curb tumour cell growth and modulate inflammatory pathways. By demonstrating both targeted enzyme inhibition and the suppression of major inflammatory cytokines like TNF-alpha and IL-6, these new nicotinamide compounds offer a multi-targeted approach. This could help guide the future design of dual-action anti-cancer agents that also address inflammatory mechanisms within tumours.
This research represents an early-stage discovery effort within preclinical medicinal chemistry. The findings could interest pharmaceutical drug development teams seeking small-molecule leads that combine VEGFR-2 inhibition with cytokine suppression. However, because the compounds have only been examined through in vitro cell assays and in silico modelling, substantial laboratory optimisation, animal efficacy studies, and safety profiling remain necessary before any clinical development or commercial translation can take place.
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New nicotinamide derivatives <b>6</b>, <b>7</b>, <b>10</b>, and <b>11</b> were designed and synthesised based on the essential features of the VEGFR-2 inhibitors. Compound <b>10</b> revealed the highest anti-proliferative activities with IC<sub>50</sub> values of 15.4 and 9.8 µM against HCT-116 and HepG2, respectively compared to sorafenib (IC<sub>50</sub> = 9.30 and 7.40 µM). Compound <b>7</b> owned promising cytotoxic activities with IC<sub>50</sub> values of 15.7 and 15.5 µM against the same cell lines, respectively. Subsequently, the VEGFR-2 inhibitory activities were assessed for the titled compounds to exhibit VEGFR-2 inhibition with sub-micromolar IC<sub>50</sub> values. Moreover, compound <b>7</b> induced the cell cycle cessation at the cycle at %G2-M and G0-G1phases, and induced apoptosis in the HCT-116. Compounds <b>7</b> and <b>10</b> reduced the levels of TNF-<i>α</i> by 81.6 and 84.5% as well as IL-6 by 88.4 and 60.9%, respectively, compared to dexamethasone (82.4 and 93.1%). <i>In silico</i> docking, molecular dynamics simulations, ADMET, and toxicity studies were carried out.
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DOI: 10.1080/14756366.2022.2110868
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