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

Autor: Ayoup MS; 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., Rabee AR; Chemistry Department, Faculty of Science, Alexandria University, P.O. Box 426, Alexandria 21321, Egypt., Abdel-Hamid H; Chemistry Department, Faculty of Science, Alexandria University, P.O. Box 426, Alexandria 21321, Egypt., Amer A; Chemistry Department, Faculty of Science, Alexandria University, P.O. Box 426, Alexandria 21321, Egypt., Abu-Serie MM; 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., Ashraf S; Bio-screening and Preclinical Trial Lab, Biochemistry Department, Faculty of Science, Alexandria University, 21511 Alexandria, Egypt., Ghareeb DA; Bio-screening and Preclinical Trial Lab, Biochemistry Department, Faculty of Science, Alexandria University, 21511 Alexandria, Egypt.; 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., Ibrahim RS; Department of Pharmaceutical Medicinal Chemistry and Drug Design, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo 11754, Egypt., Hawsawi MB; Department of Chemistry, Faculty of Science, Umm Al-Qura University, Al Taif Road, Makkah 24382, Saudi Arabia., Negm A; Department of Chemistry, College of Science, King Faisal University, Al-Ahsa 31982, Saudi Arabia.; Chemistry Department, Faculty of Science, Mansoura University, Mansoura 35516, Egypt., Ismail MMF; Department of Pharmaceutical Medicinal Chemistry and Drug Design, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo 11754, Egypt.
Jazyk: angličtina
Zdroj: ACS omega [ACS Omega] 2024 May 29; Vol. 9 (23), pp. 24643-24653. Date of Electronic Publication: 2024 May 29 (Print Publication: 2024).
DOI: 10.1021/acsomega.4c01075
Abstrakt: 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 (IC 50 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.
Competing Interests: The authors declare no competing financial interest.
(© 2024 The Authors. Published by American Chemical Society.)
Databáze: MEDLINE
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