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

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

  • J Med Chem. 2021 Dec 9;64(23):17346-17365. doi: 10.1021/acs.jmedchem.1c01411.
Shengtao Xu 1,  Hong Yao 1,  Yangyi Qiu 1 2,  Manzhen Zhou 1,  Dahong Li 1 3,  Liang Wu 4,  Dong-Hua Yang 5,  Zhe-Sheng Chen 5,  Jinyi Xu 1
Affiliations

Affiliations

  • 1 State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, P. R. China.
  • 2 Department of Applied Biology and Chemical Technology, Hong Kong Polytechnic University, Kowloon, Hong Kong 999077, P. R. China.
  • 3 Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, P. R. China.
  • 4 Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, P. R. China.
  • 5 College of Pharmacy and Health Sciences, St. John's University, 8000 Utopia Parkway, Queens, New York 11439, United States.
PMID: 34844412 DOI: 10.1021/acs.jmedchem.1c01411
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.

Figures