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首页> 外文期刊>Journal of Medicinal Chemistry >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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Novel nitrogen-enriched oridonin analogues with thiazole-fused a-ring: Protecting group-free synthesis, enhanced anticancer profile, and improved aqueous solubility

机译：具有噻唑稠合的A环的新型富氮冬凌草甲肽类似物：无保护基团的合成，增强的抗癌特性和改善的水溶性

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摘要

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 7-11, 13, and 14, exhibited potent antiproliferative effects against breast, pancreatic, and prostate cancer cells with low micromolar to submicromolar IC_(50) 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.
机译：Oridonin（1）是一种从传统中草药Isodon rubescens分离得到的复杂的对-月桂烷二萜类化合物，由于其独特且安全的抗癌药理学特性，已显示出在治疗各种人类癌症中的巨大潜力。然而，冬凌草甲素在癌症治疗中的临床发展因其相对中等的效力，有限的水溶性和较差的生物利用度而受到阻碍。在本文中，我们报告了通过有效的无保护基团合成策略，与噻唑稠合的A环一起合成了一系列新颖的富氮冬凌草甲素。它们中的大多数，包括化合物7-11、13和14，对乳癌，胰腺癌和前列腺癌细胞显示出有效的抗增殖作用，其微摩尔至亚微摩尔的IC_（50）值低，并且水溶性显着增强。已经证明，通过合理修饰天然产物获得的这些新类似物不仅在体内外显着诱导细胞凋亡并抑制三阴性MDA-MB-231乳腺癌的生长，而且还有效抵抗耐药性ER阳性MCF-7克隆。

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