基于天然产物Aphadilactone C结构关键片段的二酰基甘油酰基转移酶1抑制剂的设计与合成

doi:10.6023/cjoc201511037

有机化学 ›› 2016, Vol. 36 ›› Issue (6): 1359-1367.DOI: 10.6023/cjoc201511037 上一篇下一篇

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基于天然产物Aphadilactone C结构关键片段的二酰基甘油酰基转移酶1抑制剂的设计与合成

李丹^a, 尹建朋^b, 李静雅^b, 南发俊^b

a 华东师范大学化学与分子工程学院上海 200062;
b 中国科学院上海药物研究所国家新药筛选中心上海 201203

收稿日期:2015-11-18 修回日期:2016-01-12 发布日期:2016-02-18
通讯作者: 南发俊 E-mail:fjnan@simm.ac.cn
基金资助:
上海市重性精神病重点实验室开放课题(No.13DZ226050014K-10)资助项目.

Design and Synthesis of Diacylglycerol Acyltransferase 1 Inhibitors Based on Aphadilactone C

Li Dan^a, Yin Jianpeng^b, Li Jingya^b, Nan Fajun^b

aCollege of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062;
b The National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203

Received:2015-11-18 Revised:2016-01-12 Published:2016-02-18
Supported by:
Project supported by the Shanghai Key Laboratory of Psychotic Disorders (No. 13DZ226050014K-10).

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1. 基于天然产物Aphadilactone C结构关键片段的二酰基甘油酰基转移酶1抑制剂的设计与合成.PDF(9315KB)

摘要/Abstract

二酰基甘油酰基转移酶(DGAT)作为甘油三酯合成的唯一限速酶, 成为治疗肥胖以及其他代谢综合征的重要靶标. 利用从具有DGAT1抑制活性的天然产物aphadilactone C分子中重要内酯环与进入临床研究的2-((1R,4R)-4-(4-(4-氨基-5-氧亚基-7,8-二氢嘧啶[5,4-f][1,4] 氧氮杂-6(5H)-基)苯基)环己基)乙酸(PF-04620110), 2-((1R,4R)-4-(4-(6-氨甲酰基-3,5-二甲基对二氮杂苯-2-基)苯基)环己基)乙酸(AZD-7687)分子中杂环单元的重新组合, 设计合成了化合物5~8, 以此来验证aphadilactone C中内酯环单元是否与已知DGAT1抑制剂中的环己基乙酸部分相等同. 最终的活性测试结果显示, 化合物5~8并不具有DGAT1的抑制作用. 天然产物aphadilactone C的DGAT抑制机制值得深入研究.

关键词: aphadilactone C, DGAT1, 选择性抑制剂, PF-04620110, AZD-7687

Diacylglycerol acyltransferase (DGAT), the only limited enzyme in the synthesis of triacylglycerol (TAG), is regarded as an important therapeutic target for human obesity and other metabolic syndromes. Compounds 5~8 were designed and synthesized, in which the lactone group of aphadilactone C was introduced into the PF-04620110 and AZD-7687, which have entered into the clinical research, to verify whether the lactone in aphadilactone C played the same role as carboxylic group in PF-04620110 and AZD-7687. The final vitro assay showed that compounds 5~8 have not the inhibition activity to DGAT1. This might suggest that inhibition mechanism of aphadilactone C was not the same as PF-04620110 and AZD-7687.

Key words: aphadilactone C, DGAT1, selective inhibitor, PF-04620110, AZD-7687

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李丹, 尹建朋, 李静雅, 南发俊. 基于天然产物Aphadilactone C结构关键片段的二酰基甘油酰基转移酶1抑制剂的设计与合成[J]. 有机化学, 2016, 36(6): 1359-1367.

Li Dan, Yin Jianpeng, Li Jingya, Nan Fajun. Design and Synthesis of Diacylglycerol Acyltransferase 1 Inhibitors Based on Aphadilactone C[J]. Chin. J. Org. Chem., 2016, 36(6): 1359-1367.

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基于天然产物Aphadilactone C结构关键片段的二酰基甘油酰基转移酶1抑制剂的设计与合成

Design and Synthesis of Diacylglycerol Acyltransferase 1 Inhibitors Based on Aphadilactone C

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