Regio- and Stereospecific Synthesis of Oridonin D‑Ring Aziridinated Analogues for the Treatment of Triple-Negative Breast Cancer via Mediated Irreversible Covalent Warheads

Covalent drug discovery
has undergone a resurgence in recent years
due to comprehensive optimization of the structure–activity
relationship (SAR) and the structure–reactivity relationship
(SRR) for covalent drug candidates. The natural product oridonin maintains
an impressive pharmacological profile through its covalent enone warhead
on the D-ring and has attracted substantial SAR studies to characterize
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. Importantly, aziridonin 44 (YD0514),
with a more-druglike irreversible covalent warhead, has been identified
to significantly induce apoptosis and inhibit colony formation against
triple-negative breast cancer with enhanced antitumor effects in vitro
and in vivo while displaying lower toxicity to normal human mammary
epithelial cells in comparison to oridonin.