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.
Subject(s)
Antineoplastic Agents , Chromones , ErbB Receptors , Molecular Docking Simulation , Receptor, Fibroblast Growth Factor, Type 3 , Triple Negative Breast Neoplasms , Vascular Endothelial Growth Factor A , Humans , ErbB Receptors/antagonists & inhibitors , ErbB Receptors/metabolism , Female , Animals , Triple Negative Breast Neoplasms/drug therapy , Triple Negative Breast Neoplasms/metabolism , Triple Negative Breast Neoplasms/pathology , Vascular Endothelial Growth Factor A/metabolism , Cell Line, Tumor , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Receptor, Fibroblast Growth Factor, Type 3/antagonists & inhibitors , Receptor, Fibroblast Growth Factor, Type 3/metabolism , Mice , Chromones/pharmacology , Chromones/chemical synthesis , Chromones/chemistry , Chromones/therapeutic use , Drug Design , Apoptosis/drug effects , Cell Proliferation/drug effectsABSTRACT
The title compound, C12H9N3O, is an inter-mediate in the synthesis of the muscarinic M2 receptor antagonist AFDX-384. The seven-membered ring adopts a boat conformation and the dihedral angle between the planes of the aromatic rings is 41.51â (9)°. In the crystal, mol-ecules are linked into [001] chains of alternating inversion dimers formed by pairs of N-Hâ¯O hydrogen bonds and pairs of N-Hâ¯N hydrogen bonds. In both cases, R 2 (2)(8) loops are generated.
