Design and Synthesis of Quinoxaline Hybrids as Modulators of HIF-1a, VEGF, and p21 for Halting Colorectal Cancer

Mohammed Salah Ayoup; Ahmed R Rabee; Hamida Abdel-Hamid; Adel Amer; Marwa M Abu-Serie; Samah Ashraf; Doaa A Ghareeb; Rabab S Ibrahim; Mohammed B Hawsawi; Amr Negm; Magda M F Ismail

doi:10.1021/acsomega.4c01075

Design and Synthesis of Quinoxaline Hybrids as Modulators of HIF-1a, VEGF, and p21 for Halting Colorectal Cancer

ACS Omega. 2024 May 29;9(23):24643-24653. doi: 10.1021/acsomega.4c01075. eCollection 2024 Jun 11.

Authors

Mohammed Salah Ayoup^{1

2}, Ahmed R Rabee², Hamida Abdel-Hamid², Adel Amer², Marwa M Abu-Serie³, Samah Ashraf⁴, Doaa A Ghareeb^{4

5}, Rabab S Ibrahim⁶, Mohammed B Hawsawi⁷, Amr Negm^{1

8}, Magda M F Ismail⁶

Affiliations

¹ Department of Chemistry, College of Science, King Faisal University, Al-Ahsa 31982, Saudi Arabia.
² Chemistry Department, Faculty of Science, Alexandria University, P.O. Box 426, Alexandria 21321, Egypt.
³ Medical Biotechnology Department, Genetic Engineering and Biotechnology Research Institute, City of Scientific Research and Technological Applications (SRTA-City), New Borg El Arab, Alexandria 21934, Egypt.
⁴ Bio-screening and Preclinical Trial Lab, Biochemistry Department, Faculty of Science, Alexandria University, 21511 Alexandria, Egypt.
⁵ Center of Excellence for Drug Preclinical Studies (CE-DPS), Pharmaceutical and Fermentation Industry Development Center, City of Scientific Research & Technological Applications (SRTA-city), New Borg El Arab, Alexandria 21934, Egypt.
⁶ Department of Pharmaceutical Medicinal Chemistry and Drug Design, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo 11754, Egypt.
⁷ Department of Chemistry, Faculty of Science, Umm Al-Qura University, Al Taif Road, Makkah 24382, Saudi Arabia.
⁸ Chemistry Department, Faculty of Science, Mansoura University, Mansoura 35516, Egypt.

Abstract

A library of 16 3-benzyl-N ¹-substituted quinoxalin-2-ones was synthesized as N ¹-substituted quinoxalines and quinoxaline-triazole hybrids via click reaction. These compounds were tested for their anticancer activity via MTT assay on HCT-116 and normal colonocyte cell lines to assess their cytotoxic potentials and safety profiles. Overall, compounds 6, 9, 14, and 20 were found to be promising anticolorectal cancer agents; they exhibited remarkable cytotoxicity (IC₅₀ 0.05-0.07 μM) against HCT-116 cells within their safe doses (EC100) on normal colon cells. Their pronounced anticancer activities were observed as severe morphological alterations and shrinkage of the treated cancer cells. Besides, qRT-PCR analysis was conducted showing the potential of the promising hits to downregulate HIF-1a, VEGF, and BCL-2 as well as their ability to enhance the expression of proapoptotic genes p21, p53, and BAX in HCT-116 cells. In silico prediction revealed that most of our compounds agree with Lipinski and Veber parameters of rules, in addition to remarkable medicinal chemistry and drug-likeness parameters with no CNS side effects. Interestingly, docking studies of the compounds in the VEGFR-2' active site showed significant affinity toward the essential amino acids, which supported the biological results.