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

被引:3
|
作者
El-Gamil, Dalia S. [1 ]
Zaky, Mohamed Y. [2 ]
Maximous, Patrick M. [3 ]
Sharaky, Marwa [4 ,5 ]
El-Dessouki, Ahmed M. [6 ]
Riad, Noura M. [7 ]
Shaaban, Saad [8 ,9 ]
Abdel-Halim, Mohammad [3 ]
Al-Karmalawy, Ahmed A. [1 ,10 ]
机构
[1] Ahram Canadian Univ, Fac Pharm, Pharmaceut Chem Dept, Giza 12566, Egypt
[2] Beni Suef Univ, Fac Sci, Zool Dept, Mol Physiol Div, Bani Suwayf, Egypt
[3] German Univ Cairo, Fac Pharm & Biotechnol, Dept Pharmaceut Chem, Cairo, Egypt
[4] Cairo Univ, Natl Canc Inst NCI, Canc Biol Dept, Pharmacol Unit, Cairo, Egypt
[5] Ahram Canadian Univ, Fac Pharm, Biochem Dept, Giza, Egypt
[6] Ahram Canadian Univ, Fac Pharm, Pharmacol & Toxicol Dept, Giza, Egypt
[7] Univ Hertfordshire, Sch Life & Med Sci, Global Acad Fdn, Cairo, Egypt
[8] King Faisal Univ, Coll Sci, Dept Chem, Al Hasa 31982, Saudi Arabia
[9] Mansoura Univ, Dept Chem, Coll Sci, Organ Chem Div, Mansoura, Egypt
[10] Horus Univ Egypt, Fac Pharm, Dept Pharmaceut Chem, New Damietta, Egypt
关键词
anticancer agents; chromone; EGFR; FGFR3; triple-negative breast cancer; VEGF; PEPTIDE COUPLING REAGENTS; CELLS; ACID;
D O I
10.1002/ddr.22228
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
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 alpha-methylated N-benzyl (17) derivatives demonstrated the highest growth inhibition with GI50 values of 14.8 and 17.1 mu M, 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.
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页数:30
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