Discovery of new VEGFR-2 inhibitors based on bis([1, 2, 4]triazolo)[4,3- a:3',4'- c]quinoxaline derivatives as anticancer agents and apoptosis inducers

Nawaf A Alsaif; Mohammed S Taghour; Mohammed M Alanazi; Ahmad J Obaidullah; Abdulrahman A Al-Mehizia; Manal M Alanazi; Saleh Aldawas; Alaa Elwan; Hazem Elkady

doi:10.1080/14756366.2021.1915303

Discovery of new VEGFR-2 inhibitors based on bis([1, 2, 4]triazolo)[4,3- a:3',4'- c]quinoxaline derivatives as anticancer agents and apoptosis inducers

J Enzyme Inhib Med Chem. 2021 Dec;36(1):1093-1114. doi: 10.1080/14756366.2021.1915303.

Authors

Nawaf A Alsaif¹, Mohammed S Taghour², Mohammed M Alanazi¹, Ahmad J Obaidullah¹, Abdulrahman A Al-Mehizia¹, Manal M Alanazi¹, Saleh Aldawas¹, Alaa Elwan², Hazem Elkady²

Affiliations

¹ Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
² Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, Egypt.

Abstract

Herein, a new wave of bis([1, 2, 4]triazolo)[4,3-a:3',4'-c]quinoxaline derivatives have been successfully designed and synthesised. The synthesised derivatives were biologically investigated for their cytotoxic activities against HepG2 and MCF-7. Also, the tested compounds were further examined in vitro for their VEGFR-2 inhibitory activity. The most promising derivative 23j was further investigated for its apoptotic behaviour in HepG2 cell lines using flow cytometric and western-plot analyses. Additional in-silico studies were performed to predict how the synthesised compounds can bind to VEGFR-2 and to determine the drug-likeness profiling of these derivatives. The results revealed that compounds 23a, 23i, 23j, 23l, and 23n displayed the highest antiproliferative activities against the two cell lines with IC₅₀ values ranging from 6.4 to 19.4 µM. Furthermore, compounds 23a, 23d, 23h, 23i, 23j, 23l, 23 m, and 23n showed the highest VEGFR-2 inhibitory activities with IC₅₀ values ranging from 3.7 to 11.8 nM, comparing to sorafenib (IC₅₀ = 3.12 nM). Moreover, compound 23j arrested the HepG2 cell growth at the G2/M phase and induced apoptosis by 40.12% compared to the control cells (7.07%). As well, such compound showed a significant increase in the level of caspase-3 (1.36-fold), caspase-9 (2.80-fold), and BAX (1.65-fold), and exhibited a significant decrease in Bcl-2 level (2.63-fold).

Keywords: Anticancer; VEGFR-2; apoptosis; bis([1,2,4]triazolo)[4,3-a:3',4'-c]quinoxaline; molecular docking.

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects*
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Discovery*
Drug Screening Assays, Antitumor
Humans
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Quinoxalines / chemical synthesis
Quinoxalines / chemistry
Quinoxalines / pharmacology*
Structure-Activity Relationship
Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors*
Vascular Endothelial Growth Factor Receptor-2 / metabolism

Substances

Antineoplastic Agents
Protein Kinase Inhibitors
Quinoxalines
KDR protein, human
Vascular Endothelial Growth Factor Receptor-2

Grants and funding

The authors extend their appreciation to the Deanship of Scientific Research at King Saud University for funding this work through research group no [RG-1441–364].