Stereochemical Structure Activity Relationship Studies (S-SAR) of Tetrahydrolipstatin,ACS Medicinal Chemistry Letters

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Stereochemical Structure Activity Relationship Studies (S-SAR) of Tetrahydrolipstatin
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2018-02-21 00:00:00 , DOI: 10.1021/acsmedchemlett.8b00050
Xiaofan Liu ₁ , Yanping Wang ₁ , Richard I. Duclos ₁ , George A. O’Doherty ₁

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Tetrahydrolipstatin (THL), its enantiomer, and an additional six diastereomers were evaluated as inhibitors of the hydrolysis of p-nitrophenyl butyrate by porcine pancreatic lipase. IC₅₀s were found for all eight stereoisomers ranging from a low of 4.0 nM for THL to a high of 930 nM for the diastereomer with the inverted stereocenters at the 2,3,2′-positions. While the enantiomer of THL was also significantly less active (77 nM) the remaining five stereoisomers retained significant inhibitory activities (IC₅₀s = 8.0 to 20 nM). All eight compounds were also evaluated against three human cancer cell lines (human breast cancers MCF-7 and MDA-MB-231, human large-cell lung carcinoma H460). No appreciable cytotoxicity was observed for THL and its seven diastereomers, as their IC₅₀s in a MTT cytotoxicity assay were all greater than 3 orders of magnitude of camptothecin.

中文翻译：

四氢他汀类固醇的立体化学结构活性关系研究（S-SAR）

评价了四氢lipstatin（THL），其对映异构体和另外六种非对映异构体，它们是猪胰脂肪酶水解对硝基苯基丁酸酯的抑制剂。发现所有八种立体异构体的IC _50值范围从THL的低4.0 nM到非立体异构体的高930 nM的高，其立体中心位于2,3,2'-位置。尽管THL的对映异构体活性也显着降低（77 nM），其余5种立体异构体仍具有显着的抑制活性（IC ₅₀s = 8.0至20 nM）。还对所有三种化合物针对三种人类癌细胞系（人类乳腺癌MCF-7和MDA-MB-231，人类大细胞肺癌H460）进行了评估。对于THL及其7个非对映异构体，未观察到明显的细胞毒性，因为它们在MTT细胞毒性试验中的IC ₅₀均大于喜树碱的3个数量级。

更新日期：2018-02-21

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