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

Reda G Yousef; Alaa Elwan; Ibraheem M M Gobaara; Ahmed B M Mehany; Wagdy M Eldehna; Souad A El-Metwally; Bshra A Alsfouk; Eslam B Elkaeed; Ahmed M Metwaly; Ibrahim H Eissa

doi:10.1080/14756366.2022.2110868

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

J Enzyme Inhib Med Chem. 2022 Dec;37(1):2206-2222. doi: 10.1080/14756366.2022.2110868.

Authors

Affiliations

¹ Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, Egypt.
² Zoology Department, Faculty of Science (Boys), Al-Azhar University, Cairo, Egypt.
³ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, Egypt.
⁴ Department of Basic Science, Higher Technological institute, 10th of Ramadan City, Egypt.
⁵ Department of Pharmaceutical Sciences, College of Pharmacy, Princess Nourah Bint Abdulrahman University, Riyadh, Saudi Arabia.
⁶ Department of Pharmaceutical Sciences, College of Pharmacy, AlMaarefa University, Riyadh, Saudi Arabia.
⁷ Pharmacognosy and Medicinal Plants Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, Egypt.
⁸ Biopharmaceutical Products Research Department, Genetic Engineering and Biotechnology Research Institute, City of Scientific Research and Technological Applications (SRTA-City), Alexandria, Egypt.

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; VEGFR-2 inhibition; apoptosis; cell cycle; immunomodulatory; nicotinamide.

MeSH terms

Antineoplastic Agents* / metabolism
Antineoplastic Agents* / pharmacology
Apoptosis
Cell Proliferation
Drug Design
Drug Screening Assays, Antitumor
Molecular Docking Simulation
Molecular Structure
Niacinamide / pharmacology
Protein Kinase Inhibitors / pharmacology
Structure-Activity Relationship
Vascular Endothelial Growth Factor Receptor-2*

Substances

Antineoplastic Agents
Protein Kinase Inhibitors
Niacinamide
Vascular Endothelial Growth Factor Receptor-2

Grants and funding

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