Design, synthesis and biological evaluation of novel guanidine-containing matrine derivatives as Topo I/II dual target inhibitors

Topoisomerase inhibitors are a key focus in the development of antitumor agents. In this work, using matrine as a lead compound, a series of novel derivatives were designed and synthesized as potential dual inhibitors of Topoisomerase I and II (Topo I/II). Among these compounds, A6 and A10 exhibited significant cytotoxicity against MCF-7 cells, with IC₅₀ values of 0.6 μM and 0.7 μM, respectively, comparable to those of the positive controls (CPT, VP-16). Given their superior cytotoxicity and dual Topo I/II inhibitory activity, these two compounds were selected for further pharmacological evaluation. Mechanistic investigations demonstrated that A6 and A10 effectively suppressed the proliferation, invasion, and migration of MCF-7 cells in vitro by inducing DNA damage and activating the mitochondrial apoptotic pathway. Collectively, these findings underscore the potential of A6 and A10 as novel dual Topo I/II inhibitors for Cancer therapy.