New multifunctional hybrids as modulators of apoptosis markers and topoisomerase II in breast cancer therapy: synthesis, characterization, and in vitro and in silico studies

Abstract

Recently, molecular hybrids of two or more active pharmacophores have shown promise for designing and synthesizing anticancer drugs. Herein, a new multifunctional hybrid (PAHMQ), combining azobenzene and quinoline pharmacophores, and its M(II) complexes (MPAHMQ) have been successfully developed and structurally characterized. The MTT assay revealed CuBHTP as the most efficient and safe breast cancer treatment, with an IC₅₀ of 11.18 ± 0.39 μg mL⁻¹ and a high selectivity index (SI) of 5.63 for cancer MCF-7 cells over healthy MCF10A cells. Moreover, the CuPAHMQ-treated MCF-7 cells experience a dramatic impact with regard to key apoptotic markers, including an increase in P53 and Bax expression, with a decrease in Bcl-2 expression levels compared to the untreated MCF-7 cells. Additionally, CuPAHMQ effectively halted the growth and division of MCF-7 cells by inducing cell cycle arrest in the crucial G1 and S phases, ultimately inhibiting both Topo II activity and cell proliferation. Molecular docking investigations validated the CuPAHMQ complex's groove binding and topoisomerase II binding, establishing it as a potent anticancer drug.