Rational Design and Synthesis of Matrine Containing Coumarin Derivatives as Hsp90 (NTD&CTD) Isoform selective Inhibitors for the Treatment of Lung Carcinoma

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 IC ₅₀ 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.