Oridonin (1 ), a complex ent-kaurane diterpenoid isolated from traditional Chinese herb Rabdosia rubescens, has demonstrated great potential in the treatment of various human cancers due to its unique and safe anticancer pharmacological profile. However, the clinical development of oridonin for cancer therapy has been hampered by its relatively moderate potency, limited aqueous solubility and bioavailability. Up to now, the oridonin-based structural modifications and relevant structure-activity relationship remain sparse likely because of synthetic challenges and its structural complexity. Herein, we report the concise synthesis of a series of novel nitrogen-containing oridonin derivatives with thiazole-fused A-ring through an efficient protecting group-free synthetic strategy. Most of them including compounds 7 , 8 , 9 , 10 , 11 , 13  and 14  exhibited potent antiproliferative effects against breast, pancreatic and prostate cancer cells with low micromolar to nanomolar IC50 values, as well as markedly enhanced aqueous solubility. Moreover, these new analogs obtained by tweaking the natural product have been demonstrated not only to significantly induce apoptosis against estrogen receptor (ER)-negative breast cancer MDA-MB-231 cells, but also drug-resistant ER-positive MCF-7 clones.

Tweaking the natural product: Protecting group-free synthesis of novel nitrogen-enriched oridonin analogs with thiazole-fused A-ring and their potent antiproliferative effects against cancer cells

246th National Meeting (2013)

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