Discovery of Novel Polycyclic Heterocyclic Derivatives from Evodiamine for the Potential Treatment of Triple-Negative Breast Cancer.

Evodiamine (Evo) is a quinazolinocarboline alkaloid found in and exhibits moderate antiproliferative activity. Herein, we report using a scaffold-hopping approach to identify a series of novel polycyclic heterocyclic derivatives based on Evo as the topoisomerase I (Top1) inhibitor for the treatment of triple-negative breast cancer (TNBC), which is an aggressive subtype of breast cancer with limited treatment options. The most potent compound inhibited cell growth in a human breast carcinoma cell line (MDA-MB-231) with an IC value of 0.36 μM. Further studies revealed that Top1 was the target of , which directly induced irreversible Top1-DNA covalent complex formation or induced an oxidative DNA lesion through an indirect mechanism mediated by reactive oxygen species. More importantly, studies showed that exhibited potent antitumor activity in a TNBC-patient-derived tumor xenograft model. These results suggest that compound deserves further investigation as a promising candidate for the treatment of TNBC.