Mekouar K, Mouscadet J F, Desmaële D, Subra F, Leh H, Savouré D, Auclair C, d'Angelo J
Unité de Chimie Organique, URA du CNRS 1843, Centre d'Etudes Pharmaceutiques, Université Paris-Sud, 5 rue J.-B. Clément, 92296 Châtenay-Malabry, France.
J Med Chem. 1998 Jul 16;41(15):2846-57. doi: 10.1021/jm980043e.
On the basis of the fact that several polynucleotidyl transferases, related to HIV integrase, contain in their active site two divalent metal cations, separated by ca. 4 A, new potential HIV integrase inhibitors were designed, in which a quinoline substructure is linked to an aryl nucleus possessing various hydroxy substitution patterns, by means of an ethylenic spacer. Although the most active compounds contain the catechol structure, this group is not essential for the activity, since compound 21 that lacks such a moiety is a potent drug, implicating the presence of a different pharmacophore. The most promising styrylquinolines thus synthesized inhibit HIV-1 integrase in vitro at micromolar or submicromolar concentrations and block HIV replication in CEM cells, with no significant cellular toxicity in a 5-day period assay. These inhibitors are active against integrase core domain-mediated disintegration, suggesting that fragment 50-212 is their actual target. These new styrylquinolines may provide lead compounds for the development of novel antiretroviral agents for AIDS therapeutics, based upon inhibition of HIV integrase. They might also be used in the elucidation of the mechanism of inhibition of this enzyme; e.g., they could serve as candidates for cocrystallization studies with HIV integrase.
基于与HIV整合酶相关的几种多核苷酸转移酶在其活性位点含有两个二价金属阳离子（相隔约4埃）这一事实，设计了新的潜在HIV整合酶抑制剂，其中喹啉亚结构通过乙烯间隔基与具有各种羟基取代模式的芳基核相连。尽管最具活性的化合物含有儿茶酚结构，但该基团对活性并非必不可少，因为缺乏该部分的化合物21是一种强效药物，这意味着存在不同的药效基团。如此合成的最有前景的苯乙烯基喹啉在微摩尔或亚微摩尔浓度下体外抑制HIV-1整合酶，并在CEM细胞中阻断HIV复制，在为期5天的试验中无明显细胞毒性。这些抑制剂对整合酶核心结构域介导的解体有活性，表明片段50 - 212是它们的实际靶点。这些新的苯乙烯基喹啉可能为基于抑制HIV整合酶开发用于艾滋病治疗的新型抗逆转录病毒药物提供先导化合物。它们也可用于阐明该酶的抑制机制；例如，它们可作为与HIV整合酶进行共结晶研究的候选物。
