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2
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8
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9
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新型抗 HIV 活性整合酶抑制剂的合成方法。

Approaches to the synthesis of a novel, anti-HIV active integrase inhibitor.

机构信息

Center for Drug Discovery and College of Pharmacy, University of Georgia, Athens, GA 30602, USA.

出版信息

Org Biomol Chem. 2013 Dec 7;11(45):7852-8. doi: 10.1039/c3ob41728j. Epub 2013 Oct 7.

DOI:10.1039/c3ob41728j
PMID:24100441
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3846259/
Abstract

The novel HIV-1 integrase inhibitor 1, discovered in our laboratory, exhibits potent anti-HIV activity against a diverse set of HIV-1 isolates and also against HIV-2 and SIV. In addition, this compound displays low cellular cytotoxicity and possesses a favorable in vitro drug interaction profile with respect to isozymes of cytochrome P450 (CYP) and uridine 5'-diphospho-glucuronosyltransferase (UGT). However, the total synthesis of this significant HIV integrase inhibitor has not been reported. This contribution describes an optimized, reproducible, multi-step, synthetic route to inhibitor 1. The yield for the separate steps averaged about 80%. The methodologies utilized in the synthesis were, among others, a palladium-catalyzed cross-coupling reaction, a crossed-Claisen condensation, and a hydrazino amide synthesis step. Successful alternative synthetic methodologies for some of the steps are also described.

摘要

新型 HIV-1 整合酶抑制剂 1 由本实验室发现，对多种 HIV-1 分离株以及 HIV-2 和 SIV 均具有强大的抗 HIV 活性。此外，该化合物对细胞的细胞毒性低，并且与细胞色素 P450（CYP）同工酶和尿苷 5′-二磷酸葡糖醛酸基转移酶（UGT）具有有利的体外药物相互作用谱。然而，该重要的 HIV 整合酶抑制剂的全合成尚未见报道。本研究介绍了一种优化的、可重复的、多步骤的合成路线，用于制备抑制剂 1。各步的产率平均约为 80%。合成中使用的方法除其他外，还包括钯催化的交叉偶联反应、交叉-Claisen 缩合和肼酰胺合成步骤。还描述了一些步骤的成功替代合成方法。