H2S-releasing oridonin derivatives with improved antitumor activity by inhibiting the PI3K/AKT pathway

Activating programmed cell death by delivering hydrogen sulfide (H₂S) has emerged as a promising strategy for tumor therapy. Oridonin serves as a lead compound for drug development due to its unique scaffold and wide-ranging biological effects, especially its antitumor properties. Based on the previous structure–activity relationship studies, 33 novel 1-O/14-O H₂S-releasing oridonin derivatives were synthesized. Particularly, 11a exhibited the most potent antiproliferative activity, effectively inhibiting colony formation, migration and invasion in both MCF-7 and MIA-PaCa-2 cells. It also inhibited the PI3K/AKT pathway to regulate the expression of Bax and Bcl-2, thereby initiating the Caspase cascade to activate mitochondrial mediated apoptosis. Furthermore, 11a suppressed tumor growth in breast cancer syngeneic models with no apparent toxicity.