Novel Nitrogen-Enriched Oridonin Analogues with Thiazole-Fused A-Ring: Protecting Group-Free Synthesis, Enhanced Anticancer Profile, and Improved Aqueous Solubility

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• 作者：Chunyong Ding ; Yusong Zhang ; Haijun Chen ; Zhengduo Yang ; Christopher Wild ; Lili Chu ; Huiling Liu ; Qiang Shen ; Jia Zhou
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：June 27, 2013
• 年：2013
• 卷：56
• 期：12
• 页码：5048-5058
• 全文大小：502K
• 年卷期：v.56,no.12(June 27, 2013)
• ISSN：1520-4804

文摘

Oridonin (1), a complex ent-kaurane diterpenoid isolated from the traditional Chinese herb Isodon rubescens, has demonstrated great potential in the treatment of various human cancers due to its unique and safe anticancer pharmacological profile. Nevertheless, the clinical development of oridonin for cancer therapy has been hampered by its relatively moderate potency, limited aqueous solubility, and poor bioavailability. Herein, we report the concise synthesis of a series of novel nitrogen-enriched oridonin derivatives with thiazole-fused A-ring through an efficient protecting group-free synthetic strategy. Most of them, including compounds 7鈥?b>11, 13, and 14, exhibited potent antiproliferative effects against breast, pancreatic, and prostate cancer cells with low micromolar to submicromolar IC₅₀ values as well as markedly enhanced aqueous solubility. These new analogues obtained by rationally modifying the natural product have been demonstrated not only to significantly induce the apoptosis and suppress growth of triple-negative MDA-MB-231 breast cancer both in vitro and in vivo but also effective against drug-resistant ER-positive MCF-7 clones.