Anti-cancer and immunomodulatory evaluation of new nicotinamide derivatives as potential VEGFR-2 inhibitors and apoptosis inducers: in vitro and in silico studies

Abstract

New nicotinamide derivatives 6, 7, 10, and 11 were designed and synthesised based on the essential features of the VEGFR-2 inhibitors. Compound 10 revealed the highest anti-proliferative activities with IC₅₀ values of 15.4 and 9.8 µM against HCT-116 and HepG2, respectively compared to sorafenib (IC₅₀ = 9.30 and 7.40 µM). Compound 7 owned promising cytotoxic activities with IC₅₀ 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 IC₅₀ values. Moreover, compound 7 induced the cell cycle cessation at the cycle at %G2-M and G0-G1phases, and induced apoptosis in the HCT-116. Compounds 7 and 10 reduced the levels of TNF-α 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%). In silico docking, molecular dynamics simulations, ADMET, and toxicity studies were carried out.

Keywords:

• Anticancer
• nicotinamide
• VEGFR-2 inhibition
• cell cycle
• apoptosis
• immunomodulatory

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This research was funded by Princess Nourah Bint Abdulrahman University Researchers Supporting Project number (PNURSP2022R142), Princess Nourah Bint Abdulrahman University, Riyadh, Saudi Arabia.