Abstract
Abstract ABSTRACT: Oridonin, a complex ent-kaurane diterpenoid isolated from Chinese traditional herb Rabdosia rubescens (Chinese name "Donglingcao"), has demonstrated great potential in the treatment of various human cancers due to its unique, safe and remarkable anticancer pharmacological profile. Nevertheless, 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 partially because of the challenging synthesis and structural complexity. To develop novel oridonin derivatives with enhanced anticancer potency and solubility, a sizable compound library of oridonin analogs with unique scaffolds is being established in our laboratories through diversity-orientated synthesis. Our successful synthetic strategies include heterocycle-fused ring A construction, and ring A-based α,β-unsaturated enone formation, as well as other stereoselective and regioselective approaches. A number of novel nitrogen-enriched heterocyclic oridonin derivatives and dienone analogs such as CYD0554, CYD0618, CYD0628, CYD0630, CYD0686, and CYD0692 have been identified with potent anti-proliferation effects against breast, pancreatic, and prostate cancer cells with low micromolar to nanomolar IC50 values. Moreover, some of them also exhibit significantly improved aqueous solubility and enhanced anticancer profiles for the treatment of estrogen receptor (ER)-negative including triple-negative breast cancer in comparison with oridonin. Our success in the chemical design, synthesis and biological characterization of these new molecules opens new avenues to develop promising natural product-like drug candidates for cancer therapy. Key Words: Natural products, Oridonin analogs, Diversity-orientated synthesis, Anticancer agents, Drug discovery Citation Format: Chunyong Ding, Yusong Zhang, Haijun Chen, Zhengduo Yang, Lili Chu, Christopher Wild, Mark A. White, Qiang Shen, Jia Zhou. Natural product-inspired drug discovery: Chemistry and biology of oridonin analogs with unique scaffolds and enhanced anticancer profiles . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2267. doi:10.1158/1538-7445.AM2013-2267
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