Challenging the anticolorectal cancer capacity of quinoxaline-based scaffold via triazole ligation unveiled new efficient dual VEGFR-2/MAO-B inhibitors

Mohammed Salah Ayoup; Ahmed Ammar; Hamida Abdel-Hamid; Adel Amer; Marwa M Abu-Serie; Samah A Nasr; Doaa A Ghareeb; Mohamed Teleb; Gina N Tageldin

doi:10.1016/j.bioorg.2024.107102

Challenging the anticolorectal cancer capacity of quinoxaline-based scaffold via triazole ligation unveiled new efficient dual VEGFR-2/MAO-B inhibitors

Bioorg Chem. 2024 Feb:143:107102. doi: 10.1016/j.bioorg.2024.107102. Epub 2024 Jan 6.

Authors

Mohammed Salah Ayoup¹, Ahmed Ammar², Hamida Abdel-Hamid², Adel Amer³, Marwa M Abu-Serie⁴, Samah A Nasr⁵, Doaa A Ghareeb⁵, Mohamed Teleb⁶, Gina N Tageldin⁷

Affiliations

¹ Department of Chemistry, College of Science, King Faisal University, Al-Ahsa 31982, Saudi Arabia; Chemistry Department, Faculty of Science, Alexandria University, P.O. Box 426, Alexandria 21321, Egypt. Electronic address: mayoup@kfu.edu.sa.
² Chemistry Department, Faculty of Science, Alexandria University, P.O. Box 426, Alexandria 21321, Egypt.
³ Chemistry Department, Faculty of Science, Alexandria University, P.O. Box 426, Alexandria 21321, Egypt; Department of Chemistry, College of Science, Taibah University, Al-Madinah Al-Munawarah, Saudi Arabia. Electronic address: adel.amer@alex-sci.edu.eg.
⁴ Medical Biotechnology Department, Genetic Engineering and Biotechnology Research Institute, City of Scientific Research and Technological Applications (SRTA-City), Egypt.
⁵ Bio-screening and Preclinical Trial Lab, Biochemistry Department, Faculty of Science, Alexandria University, 21511 Alexandria, Egypt.
⁶ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria, 21521, Egypt.
⁷ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria, 21521, Egypt. Electronic address: gina.tageldin@alexu.edu.eg.

PMID: 38211551
DOI: 10.1016/j.bioorg.2024.107102

Abstract

Monoamine oxidases (MAOs) and vascular endothelial growth factor receptor-2 (VEGFR-2) are promoters of colorectal cancer (CRC) and central signaling nodes in epithelial-mesenchymal transition (EMT) induced by activating hypoxia-inducible factors (HIFs). Herein, a novel series of rationally designed triazole-tethered quinoxalines were synthesized and evaluated against HCT-116 CRC cells. The tailored scaffolds combine the pharmacophoric themes of both VEGFR-2 inhibitors and MAO inhibitors. All the synthesized derivatives were screened utilizing the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay for their possible cytotoxic effects on normal human colonocytes, then evaluated for their anticancer activities against HCT-116 cells overexpressing MAOs. The hit derivatives 11 and 14 exhibited IC₅₀ = 18.04 and 7.850 µM, respectively, against HCT-116cells within their EC₁₀₀ doses on normal human colonocytes. Wound healing assay revealed their efficient CRC antimetastatic activities recording HCT-116 cell migration inhibition exceeding 75 %. In vitro enzymatic assays demonstrated that both 11 and 14 efficiently inhibited VEGFR-2 (IC₅₀ = 88.79 and 9.910 nM), MAO-A (IC₅₀ = 0.763 and 629.1 nM) and MAO-B (IC₅₀ = 0.488 and 209.6 nM) with observed MAO-B over MAO-A selectivity (SI = 1.546 and 3.001), respectively. Enzyme kinetics studies were performed for both compounds to identify their mode of MAO-B inhibition. Furthermore, qRT-PCR analysis showed that the hits efficiently downregulated HIF-1α in HCT-116cells by 3.420 and 16.96 folds relative to untreated cells. Docking studies simulated their possible binding modes within the active sites of VEGFR-2 and MAO-B to highlight their essential structural determinants of activities. Finally, they recorded in silico drug-like absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiles as well as ligand efficiency metrics.

Keywords: Colorectal cancer; MAO-B/A selectivity; Quinoxaline; Triazole; VEGFR-2.

MeSH terms

Antineoplastic Agents* / chemistry
Antineoplastic Agents* / pharmacology
Cell Proliferation
Colorectal Neoplasms* / drug therapy
Drug Screening Assays, Antitumor
Humans
Molecular Docking Simulation
Molecular Structure
Monoamine Oxidase / metabolism
Monoamine Oxidase Inhibitors / chemistry
Monoamine Oxidase Inhibitors / pharmacology
Protein Kinase Inhibitors / pharmacology
Quinoxalines / pharmacology
Structure-Activity Relationship
Triazoles / pharmacology
Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors

Substances

Antineoplastic Agents
Monoamine Oxidase
Protein Kinase Inhibitors
Quinoxalines
Triazoles
Vascular Endothelial Growth Factor Receptor-2
Monoamine Oxidase Inhibitors