Exploring chromone‐2‐carboxamide derivatives for triple‐negative breast cancer targeting EGFR, FGFR3, and VEGF pathways: Design, synthesis, and preclinical insights

Author:

El‐Gamil Dalia S.1,Zaky Mohamed Y.2,Maximous Patrick M.3ORCID,Sharaky Marwa45,El‐Dessouki Ahmed M.6,Riad Noura M.7,Shaaban Saad89,Abdel‐Halim Mohammad3ORCID,Al‐Karmalawy Ahmed A.110ORCID

Affiliation:

1. Pharmaceutical Chemistry Department Faculty of Pharmacy, Ahram Canadian University Giza Egypt

2. Zoology Department, Molecular Physiology Division, Faculty of Science Beni‐Suef University Beni Suef Egypt

3. Department of Pharmaceutical Chemistry Faculty of Pharmacy and Biotechnology, German University in Cairo Cairo Egypt

4. Cancer Biology Department Pharmacology Unit, National Cancer Institute (NCI), Cairo University Cairo Egypt

5. Biochemistry Department Faculty of Pharmacy, Ahram Canadian University Giza Egypt

6. Pharmacology and Toxicology Department Faculty of Pharmacy, Ahram Canadian University Giza Egypt

7. Department of Chemistry School of Life and Medical Sciences, New Administrative Capital, University of Hertfordshire hosted by Global Academic Foundation Cairo Egypt

8. Department of Chemistry College of Science, King Faisal University Al‐Ahsa Saudi Arabia

9. Organic Chemistry Division, Department of Chemistry, College of Science Mansoura University Mansoura Egypt

10. Department of Pharmaceutical Chemistry Faculty of Pharmacy, Horus University‐Egypt New Damietta Egypt

Abstract

AbstractChromone‐based compounds have established cytotoxic, antiproliferative, antimetastatic, and antiangiogenic effects on various cancer cell types via modulating different molecular targets. Herein, 17 novel chromone‐2‐carboxamide derivatives were synthesized and evaluated for their in vitro anticancer activity against 15 human cancer cell lines. Among the tested cell lines, MDA‐MB‐231, the triple‐negative breast cancer cell line, was found to be the most sensitive, where the N‐(2‐furylmethylene) (15) and the α‐methylated N‐benzyl (17) derivatives demonstrated the highest growth inhibition with GI50 values of 14.8 and 17.1 μM, respectively. In vitro mechanistic studies confirmed the significant roles of compounds 15 and 17 in the induction of apoptosis and suppression of EGFR, FGFR3, and VEGF protein levels in MDA‐MB‐231 cancer cells. Moreover, compound 15 exerted cell cycle arrest at both the G0‐G1 and G2‐M phases. The in vivo efficacy of compound 15 as an antitumor agent was further investigated in female mice bearing Solid Ehrlich Carcinoma. Notably, administration of compound 15 resulted in a marked decrease in both tumor weight and volume, accompanied by improvements in biochemical, hematological, histological, and immunohistochemical parameters that verified the repression of both angiogenesis and inflammation as additional Anticancer mechanisms. Moreover, the binding interactions of compounds 15 and 17 within the binding sites of all three target receptors (EGFR, FGFR3, and VEGF) were clearly illustrated using molecular docking.

Publisher

Wiley

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