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.
摘要：
基于色酮的化合物已经建立了细胞毒性，抗增殖,抗转移，以及通过调节不同的分子靶标对各种癌细胞类型的抗血管生成作用。在这里，合成了17种新的色酮-2-甲酰胺衍生物，并评估了它们对15种人癌细胞系的体外抗癌活性。在测试的细胞系中，MDA-MB-231，三阴性乳腺癌细胞系，被发现是最敏感的，其中N-（2-呋喃亚甲基）（15）和α-甲基化N-苄基（17）衍生物表现出最高的生长抑制作用，GI50值为14.8和17.1μM，分别。体外机制研究证实了化合物15和17在诱导细胞凋亡和抑制EGFR中的重要作用。MDA-MB-231癌细胞中的FGFR3和VEGF蛋白水平。此外，化合物15在G0-G1和G2-M期都有细胞周期阻滞。在携带实体埃利希癌的雌性小鼠中进一步研究了化合物15作为抗肿瘤剂的体内功效。值得注意的是,化合物15的给药导致肿瘤重量和体积的显著减少，伴随着生化的改善，血液学,组织学,和免疫组织化学参数验证了血管生成和炎症的抑制作为额外的抗癌机制。此外，化合物15和17在所有三种靶受体的结合位点内的结合相互作用(EGFR，使用分子对接清楚地说明了FGFR3和VEGF）。
