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
Abstract
High Resolution Image Download MS PowerPoint Slide 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.