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Regio- and Stereospecific Synthesis of Oridonin D-Ring Aziridinated Analogues for the Treatment of Triple-Negative Breast Cancer via Mediated Irreversible Covalent Warheads
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2018-03-12 00:00:00 , DOI: 10.1021/acs.jmedchem.7b01514 Ye Ding , Dengfeng Li 1, 2 , Chunyong Ding , Pingyuan Wang , Zhiqing Liu , Eric A. Wold , Na Ye , Haiying Chen , Mark A. White , Qiang Shen 1 , Jia Zhou
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2018-03-12 00:00:00 , DOI: 10.1021/acs.jmedchem.7b01514 Ye Ding , Dengfeng Li 1, 2 , Chunyong Ding , Pingyuan Wang , Zhiqing Liu , Eric A. Wold , Na Ye , Haiying Chen , Mark A. White , Qiang Shen 1 , Jia Zhou
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Covalent drug discovery has undergone a resurgence in recent years due to comprehensive optimization of the structure–activity relationship (SAR) and the structure–reactivity relationship (SRR) for covalent drug candidates. The natural product oridonin maintains an impressive pharmacological profile through its covalent enone warhead on the D-ring and has attracted substantial SAR studies to characterize its potential in the development of new molecular entities for the treatment of various human cancers and inflammation. Herein, for the first time, we report the excessive reactivity of this covalent warhead and mediation of the covalent binding capability through a Rh2(esp)2-catalyzed mild and concise regio- and stereospecific aziridination approach. Importantly, aziridonin 44 (YD0514), with a more-druglike irreversible covalent warhead, has been identified to significantly induce apoptosis and inhibit colony formation against triple-negative breast cancer with enhanced antitumor effects in vitro and in vivo while displaying lower toxicity to normal human mammary epithelial cells in comparison to oridonin.
中文翻译：
区域和立体定向合成的Oridonin D环叠氮iri类似物通过介导的不可逆共价战斗部治疗三阴性乳腺癌。
由于对共价药物候选物的结构-活性关系（SAR）和结构-反应性关系（SRR）进行了全面优化，近年来，共价药物的发现已经复苏。天然产物冬凌草甲素通过其在D环上的共价烯酮弹头保持令人印象深刻的药理作用，并吸引了大量的SAR研究，以表征其在开发用于治疗各种人类癌症和炎症的新分子实体方面的潜力。在本文中，我们首次报道了这种共价战斗部的过度反应性，并通过Rh 2（esp）2催化的温和而简洁的区域和立体定向叠氮化方法介导了共价结合能力。重要的是，阿奇多宁44（YD0514）具有更药性的不可逆共价战斗部，已被证实可显着诱导凋亡并抑制针对三阴性乳腺癌的集落形成，在体内外均具有增强的抗肿瘤作用，同时对正常人乳腺上皮细胞显示出较低的毒性与冬凌草甲素相比。
更新日期：2018-03-12
中文翻译：
区域和立体定向合成的Oridonin D环叠氮iri类似物通过介导的不可逆共价战斗部治疗三阴性乳腺癌。
由于对共价药物候选物的结构-活性关系（SAR）和结构-反应性关系（SRR）进行了全面优化，近年来，共价药物的发现已经复苏。天然产物冬凌草甲素通过其在D环上的共价烯酮弹头保持令人印象深刻的药理作用，并吸引了大量的SAR研究，以表征其在开发用于治疗各种人类癌症和炎症的新分子实体方面的潜力。在本文中，我们首次报道了这种共价战斗部的过度反应性，并通过Rh 2（esp）2催化的温和而简洁的区域和立体定向叠氮化方法介导了共价结合能力。重要的是，阿奇多宁44（YD0514）具有更药性的不可逆共价战斗部，已被证实可显着诱导凋亡并抑制针对三阴性乳腺癌的集落形成，在体内外均具有增强的抗肿瘤作用，同时对正常人乳腺上皮细胞显示出较低的毒性与冬凌草甲素相比。
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