Synthesis of novel nicotinic acid derivatives of potential antioxidant and anticancer activity

This study comprises the design and synthesis of novel nicotinic acid-based cytotoxic agents with selective inhibitory efficacy against the vascular endothelial growth factor receptor-2 (VEGFR-2). Screening of novel compounds for cytotoxicity was assessed against 60 human cancer cell lines. The two most active compounds, 5b and 5c, and the reference drugs sorafenib and doxorubicin were investigated against HCT-15, PC-3, and CF-295 cancer cell lines. Compound 5c exhibited the highest cytotoxic potential compared to doxorubicin against the HCT-15 and PC-3 tumor cell lines. Moreover, it exhibited higher cytotoxic potential and selectivity toward the HCT-15 cell panel compared with sorafenib. Compound 5c demonstrated promising VEGFR-2 inhibition (concentration needed to inhibit cell viability by 50%, IC50 = 0.068 mu M) and superior VEGFR-2 selectivity over the epidermal growth factor receptor and platelet-derived growth factor receptor-beta enzymes. It also reduced the total and phosphorylated VEGFR-2 and induced apoptosis, as evidenced by a 4.3-fold rise in caspase-3 levels. The antioxidant potential of the new compounds was determined via measuring the superoxide dismutase (SOD) levels, among which compound 5c exhibited an SOD level almost comparable to ascorbic acid. These results suggested that compound 5c exhibited dual cytotoxic and antioxidant activities. Docking of 5c into the VEGFR-2 pocket showed a similar binding mode to sorafenib. Moreover, the ADME (absorption, distribution, metabolism, and excretion) profile of 5c outlined drug-likeness. Finally, The density functional theory calculations displayed an increased binding affinity of 5c to the target enzyme. Novel nicotinic acid-based cytotoxic agents with selective inhibitory efficacy against the vascular endothelial growth factor receptor-2 (VEGFR-2) were designed and synthesized. Compound 5c exhibited higher cytotoxic potential and selectivity toward the HCT-15 cell panel than sorafenib, with promising VEGFR-2 inhibition and good binding affinity to the VEGFR-2 binding site. 5c exhibited dual anticancer and antioxidant activities.image