Oridonin Ring A‑Based Diverse Constructions of Enone Functionality: Identification of Novel Dienone Analogues Effective for Highly Aggressive Breast Cancer by Inducing Apoptosis

Oridonin
(1) has attracted considerable attention
in recent years because of its unique and safe anticancer pharmacological
profile. Nevertheless, it exhibits moderate to poor effects against
highly aggressive cancers including triple-negative and drug-resistant
breast cancer cells. Herein, we report the rational design and synthesis
of novel dienone derivatives with an additional α,β-unsaturated
ketone system diversely installed in the A-ring based on this class
of natural scaffold that features dense functionalities and stereochemistry-rich
frameworks. Efficient and regioselective enone construction strategies
have been established. Meanwhile, a unique 3,7-rearrangement reaction
was identified to furnish an unprecedented dienone scaffold. Intriguingly,
these new analogues have been demonstrated to significantly induce
apoptosis and inhibit colony formation with superior antitumor effects
against aggressive and drug-resistant breast cancer cells in vitro
and in vivo while also exhibiting comparable or lower toxicity to
normal human mammary epithelial cells in comparison with 1.