Abstract 2668: Regio- and stereospecific synthesis of oridonin D-ring aziridinated analogues for the treatment of triple-negative breast cancer via mediated irreversible covalent warheads

Abstract

Abstract The covalent drugs dramatically resurge in recent years due to the comprehensive optimization of the structure-activity relationship (SAR) and structure-reactivity relationship (SRR). Natural product oridonin with an impressive pharmacological profile through its covalent enone warhead on the D-ring has attracted substantial SAR studies to appreciate its potential in the development of new molecular entities for the treatment of various human cancers and inflammation. Herein, for the first time we report the excessive reactivity of this covalent warhead and mediation of the covalent binding capability through a Rh2(esp)2-catalyzed mild and concise regio- and stereospecific aziridination approach. Intriguingly, new analogue YD0514 with a more drug-like irreversible covalent warhead has been identified to significantly induce apoptosis and inhibit colony formation against triple-negative breast cancer with comparable to enhanced antitumor effects in vitro and in vivo, while displaying lower toxicity to normal human mammary epithelial cells in comparison with oridonin. Citation Format: Ye Ding, Dengfeng Li, Chunyong Ding, Zhiqing Liu, Eric A. Wold, Na Ye, Haiying Chen, Mark A. White, Qiang Shen, Jia Zhou. Regio- and stereospecific synthesis of oridonin D-ring aziridinated analogues for the treatment of triple-negative breast cancer via mediated irreversible covalent warheads [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2668.