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Exploring chromone-2-carboxamide derivatives for triple-negative breast cancer targeting EGFR, FGFR3, and VEGF
Dalia S El-Gamil1, Mohamed Y Zaky2, Patrick M Maximous3
1Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ahram Canadian University, Giza, Egypt.
Abstract:
Chromone-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.
Insights
Novel chromone-2-carboxamide derivatives show potent anticancer activity, particularly against triple-negative breast cancer. Compounds 15 and 17 induce apoptosis and inhibit key growth factors, demonstrating significant antitumor effects in vitro and in vivo.
Area of Science:
- Medicinal Chemistry
- Pharmacology
- Oncology
Background:
- Chromone-based compounds exhibit diverse anticancer properties by targeting various molecular pathways.
- Triple-negative breast cancer (MDA-MB-231) remains a challenging subtype with limited targeted therapies.
Purpose of the Study:
- To synthesize and evaluate novel chromone-2-carboxamide derivatives for their in vitro and in vivo anticancer potential.
- To elucidate the molecular mechanisms underlying the anticancer activity of the most promising compounds.
Main Methods:
- Synthesis of 17 novel chromone-2-carboxamide derivatives.
- In vitro anticancer activity assessment against 15 human cancer cell lines.
- Mechanistic studies including apoptosis induction, cell cycle analysis, protein level assessment (EGFR, FGFR3, VEGF), and molecular docking.
- In vivo antitumor efficacy evaluation in a Solid Ehrlich Carcinoma mouse model.
Main Results:
- Derivatives 15 (N-(2-furylmethylene)) and 17 (α-methylated N-benzyl) showed significant growth inhibition (GI50: 14.8 and 17.1 μM) in MDA-MB-231 cells.
- Compounds 15 and 17 induced apoptosis and suppressed EGFR, FGFR3, and VEGF protein levels.
- Compound 15 caused G0-G1 and G2-M phase cell cycle arrest and demonstrated significant in vivo antitumor activity, reducing tumor weight and volume.
- In vivo studies confirmed repressed angiogenesis and inflammation, supported by biochemical, hematological, and histological analyses.
Conclusions:
- Novel chromone-2-carboxamide derivatives, particularly compounds 15 and 17, possess significant anticancer properties against triple-negative breast cancer.
- These compounds exert their effects through apoptosis induction, cell cycle arrest, and suppression of key growth factor signaling pathways.
- Compound 15 shows promising in vivo efficacy, highlighting its potential as an anticancer agent targeting angiogenesis and inflammation.
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