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  3. New nicotinamide derivatives as potential anticancer agents targeting VEGFR-2: design, synthesis, in vitro, and in silico studies

New nicotinamide derivatives as potential anticancer agents targeting VEGFR-2: design, synthesis, in vitro, and in silico studies

  • J Biomol Struct Dyn. 2023 Dec 15:1-18. doi: 10.1080/07391102.2023.2294170.
Reda G Yousef 1,  Ibrahim H Eissa 1,  Hazem Elkady 1,  Wagdy M Eldehna 2,  Ahmed B M Mehany 3,  Ahmed Nabeeh 4,  Ibrahim M Ibrahim 5,  Alaa Elwan 1,  Mohamed Ayman El-Zahabi 1
Affiliations

Affiliations

  • 1 Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, Egypt.
  • 2 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, Egypt.
  • 3 Zoology Department, Faculty of Science (Boys), Al-Azhar University, Cairo, Egypt.
  • 4 Zoology Department, Faculty of Science, Mansoura University, Mansoura, Egypt.
  • 5 Biophysics Department, Faculty of Science, Cairo University, Cairo, Egypt.
PMID: 38100580 DOI: 10.1080/07391102.2023.2294170
Abstract

Herin, new nicotinamide candidates were designed and synthesized as VEGFR-2 inhibitors. In vitro antiproliferative activities were assessed against MCF-7, HepG-2 and HCT-116 Cancer cell lines. The top cytotoxic members 15a, 15b, 16, 18a, and 18b were estimated against their selected target (VEGFR-2). Further mechanistic tests were studied for the most potent cytotoxic candidate 18a, these studies revealed the ability of compound 18a to hinder the progression of HCT-116 cells at S and Pre-G1phases besides boosting early and late Apoptosis. Also compound 18a was found to significantly decrease the levels immunomodulatory proteins TNF-α and IL-6 while showing a four-fold rise in an apoptotic marker Caspase-3 when compared to control cells. The therapeutic index of the designed derivatives was evaluated by computational ADMET and toxicity calculations as well as their potentiality to occupy the VEGFR-2 active site was signposted by molecular docking assessments. Finally, molecular dynamic simulation studies of compound 18a-VEGFR-2 complex indicated the high steadiness of compound 18a in the VEGFR-2 active site. This study presents compound 18a as a lead candidate that can be optimized to get a strong VEGFR-2 inhibitor.Communicated by Ramaswamy H. Sarma.

Keywords

MD simulation; Nicotinamides; VEGFR-2; anticancer; apoptosis; docking studies.

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