Abstract
Matrine serves as the molecular backbone, targeting the Hsp90 protein N-terminal domain (NTD) and C-terminal domain (CTD), both highly expressed in lung tumor cells. In this study, Matrine Contains Coumarins derivatives were designed and synthesized based on our previously reported compound C. Employing primary structure-activity relationships and docking analysis, a series of derivatives were biologically assessed for their antiproliferative effects against three cancer cell lines: A549, HepG-2, and HeLa cells. Based on the bioactivity results, derivative 5a emerged as the most potent, significantly enhancing antiproliferation against A549, HepG-2, and HeLa cells, with IC50 values of 7.35 ± 0.097, 7.727 ± 0.10, and 8.02 ± 0.065 µM, respectively. Subsequent mechanistic investigations confirmed 5a's ability to inhibit A549 cell proliferation and suppress colony formation and migration. In in vivo studies utilizing a xenograft mouse model inoculated with A549 cells in female Balb/c nude mice, compound 5a displayed superior antitumor activity compared to reference compounds 5-Fluorouracil and Matrine. Notably, the tumor growth inhibition (TGI) values for 5a, 5-Fluorouracil, and Matrine were 72.4%, 64.3%, and 46.8%, respectively.