Affiliation:
1. School of Pharmaceutical Sciences Wenzhou Medical University Wenzhou 325035 People's Republic of China
2. Department of Medicinal Chemistry School of Pharmacy Second Military Medical University 325 Guohe Road Shanghai 200433 People's Republic of China
3. Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province School of Medicine Hangzhou City University Hangzhou 310015 Zhejiang Province China
Abstract
AbstractCoumestan represents a biologically relevant structural motif distributed in a number of natural products, and the rapid construction of related derivatives as well as the characterization of targets would accelerate lead compound discovery in medicinal chemistry. In this work, a general and scalable approach to 8,9‐dihydroxycoumestans via two‐electrode constant current electrolysis was developed. The application of a two‐phase (aqueous/organic) system plays a crucial role for success, protecting the sensitive o‐benzoquinone intermediates from over‐oxidation. Based on the structurally diverse products, a primary SAR study on coumestan scaffold was completed, and compound 3 r exhibited potent antiproliferative activities and a robust topoisomerase I (Top1) inhibitory activity. Further mechanism studies demonstrates that compound 3 r was a novel Top1 poison, which might open an avenue for the development of Top1‐targeted antitumor agent.
Funder
National Natural Science Foundation of China
Natural Science Foundation of Zhejiang Province