Design and Synthesis of A-Ring Simplified Pyripyropene A Analogues as Potent and Selective Synthetic SOAT2 Inhibitors
Design and Synthesis of A-Ring Simplified Pyripyropene A Analogues as Potent and Selective Synthetic SOAT2 Inhibitors
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作为有效和选择性合成 SOAT2 抑制剂的 A 环简化 Pyripyropene A 类似物的设计和合成
DOI：
10.1002/cmdc.201700645
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发表时间：
2018
期刊：
影响因子：
3.4
通讯作者：
Nagamitsu Tohru
中科院分区：
文献类型：
--
作者：
Ohtawa Masaki;Arima Shiho;Ichida Naoki;Terayama Tomiaki;Ohno Hironao;Yamazaki Takaya;Ohshiro Taichi;Sato Noriko;Omura Satoshi;Tomoda Hiroshi;Nagamitsu Tohru
目前，从烟曲霉FO-1289的培养液中分离的啶南平A是已知的唯一一种强烈且选择性地抑制同工酶甾醇O-酰基转移酶2（SOAT 2）的化合物。 为了帮助开发新的降胆固醇或抗动脉粥样硬化药物，基于全合成和啶南平A的构效关系研究结果，设计并合成了新的A环简化啶南平A类似物。 在这些类似物中，两个A环简化的啶南平A类似物表现出与天然啶南平A同样有效的SOAT 2抑制活性。 这些新的类似物是最有效和选择性的SOAT 2抑制剂，可用作合成化合物和有吸引力的种子化合物，用于开发治疗血脂异常（包括动脉粥样硬化疾病和脂肪变性）的药物。
Currently, pyripyropene A, which is isolated from the culture broth ofAspergillus fumigatusFO‐1289, is the only compound known to strongly and selectively inhibit the isozyme sterolO‐acyltransferase 2 (SOAT2). To aid in the development of new cholesterol‐lowering or anti‐atherosclerotic agents, new A‐ring simplified pyripyropene A analogues have been designed and synthesized based on total synthesis, and the results of structure–activity relationship studies of pyripyropene A. Among the analogues, two A‐ring simplified pyripyropene A analogues exhibited equally efficient SOAT2 inhibitory activity to that of natural pyripyropene A. These new analogues are the most potent and selective SOAT2 inhibitors to be used as synthetic compounds and attractive seed compounds for the development of drug for dyslipidemia, including atherosclerotic disease and steatosis.