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 IC 50 values of 15.4 and 9.8 µM against HCT-116 and HepG2, respectively compared to sorafenib (IC 50 = 9.30 and 7.40 µM). Compound 7 owned promising cytotoxic activities with IC 50 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 50 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.

Identification of new theobromine-based derivatives as potent VEGFR-2 inhibitors: design, semi-synthesis, biological evaluation, and in silico studies

“…The reference molecule, sorafenib, revealed a binding mode similar to the reported results. [22][23][24] It had an energy score of −21.20 kcal mol −1 . It formed one hydrogen bond with Cys917 and three hydrophobic interactions with Leu838, Ala864, and Leu1033 at the hinge region.…”

Design, Synthesis, and Biological Evaluation Studies of Novel Naphthalene-Chalcone Hybrids As Antimicrobial, Anticandidal, Anticancer, and VEGFR-2 Inhibitors

“…The VEGFR-2 binding site is hydrophobic, hence VEGFR-2 inhibitors showed a wide variety of chemical configurations. However, there were significant similarities between the chemical structures of the two well-known inhibitors (sorafenib I and regorafenib II) that are necessary for any inhibitor to correctly engage with the active binding site …”

“…However, there were significant similarities between the chemical structures of the two well-known inhibitors (sorafenib I and regorafenib II) that are necessary for any inhibitor to correctly engage with the active binding site. 12 In light of the above information, 10 new compounds were synthesized within the scope of this study. The naphthalene ring of the compounds was used as the bioisostere of the quinoxaline ring in the structures of the third generation VEGFR inhibitor Lenvatinib and Cabozantinib compounds (Figure 1).…”

“…However, there were significant similarities between the chemical structures of the two well-known inhibitors (sorafenib I and regorafenib II) that are necessary for any inhibitor to correctly engage with the active binding site. 12 …”

Design, synthesis, anti-proliferative evaluation, docking, and MD simulation studies of new thieno[2,3-d]pyrimidines targeting VEGFR-2

“…8 Our laboratory has discovered a plethora of prospective anticancer agents that exhibit inhibitory activity towards VEGFR-2. These agents stem from diverse classes and derivatives, encompassing nicotinamide, [9][10][11] thiazolidine, 12,13 naphthalene, 14 pyridine, 15 quinoline, 16 indole, 17 and isatin. 18 Fig.…”