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

Abstract

Evodiamine (Evo) is a quinazolinocarboline alkaloid found in Evodia rutaecarpa 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 7f inhibited cell growth in a human breast carcinoma cell line (MDA-MB-231) with an IC50 value of 0.36 μM. Further studies revealed that Top1 was the target of 7f, 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, in vivo studies showed that 7f exhibited potent antitumor activity in a TNBC-patient-derived tumor xenograft model. These results suggest that compound 7f deserves further investigation as a promising candidate for the treatment of TNBC.

A novel prognostic signature and potential therapeutic drugs based on tumor immune microenvironment characterization in breast cancer

“…Isoevodiamine, also known as Evodiamine, is a chemical compound extracted from the fruit Evodiae fructus [ 37 ]. Accumulating evidence has unraveled the anti-tumor effect of Evodiamine both in vitro and in vivo by inhibiting proliferation, repressing metastasis, and inducing apoptosis in various tumor types [ [38] , [39] , [40] ]. To note, Evodiamine inhibited the proliferation of BC cell lines in a concentration-dependent manner, while induced apoptosis via up-regulation of caspase 7 activation [ 41 ].…”

Design of Evodiamine–Glucose Conjugates with Improved In Vivo Antitumor Activity

“…Evodiamine, an indolequinone alkaloid derived from Chinese herbal medicine Evodia rutaecarpa , represents a promising antitumor lead compound. − Previously, a number of evodiamine derivatives were designed, − and we identified 3-fluoro-10-hydroxylevodiamine (compound 2 in Figure B) with excellent in vitro antitumor activity . However, compound 2 possesses poor water solubility and limited in vivo antitumor activity, which has hampered further development in clinical treatment.…”

Evodiamine Exhibits Anti-Bladder Cancer Activity by Suppression of Glutathione Peroxidase 4 and Induction of Ferroptosis

“…Evodiamine (EVO), one of the quinazoline alkaloids, is an essential isolated from the seeds of Evodia rutaecarpa (Wu-Zhu-Yu) [ 10 ]. It has been demonstrated to exhibit anti-cancer activities in non-small-cell lung cancer, hepatocellular carcinoma (HCC), leukemia, and breast cancer [ 11 , 12 , 13 , 14 , 15 ]. However, the literature discussing the anti-cancer effect of EVO in bladder UC is currently limited [ 15 , 16 ].…”