Synthesis and biological evaluation of purine derivatives incorporating metal chelating ligands as HIV integrase inhibitors
Synthesis and biological evaluation of purine derivatives incorporating metal chelating ligands as HIV integrase inhibitors
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DOI：
10.1016/j.bmc.2006.04.011
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发表时间：
2006-08-15
影响因子：
3.5
通讯作者：
Vince, Robert
中科院分区：
文献类型：
--
作者：
Li, Xingnan;Vince, Robert
由于其在 HIV 复制中的重要作用且缺乏人类对应物，HIV 整合酶成为开发新型抗艾滋病药物的一个有吸引力的靶标。在最近开发的整合酶抑制剂中，只有α，γ-二酮酸（DKA）化合物被生物学验证为有效的选择性整合酶抑制剂。 DKA 的一般结构包含一个二酮酸部分作为 Mg2+ 螯合药效团，以及一个相邻的芳基以提供选择性。已经对 DKA 进行了大量的构效关系 (SAR) 研究，通常涉及取代羧酸酯基团或芳基。我们的目标是通过在芳基部分中掺入嘌呤环并用其他二价金属 (Me2+) 螯合配体取代不稳定的二酮酸部分来研究 DKA 分子的 SAR。通过钯催化的酰胺化反应合成了一系列酰胺取代的嘌呤衍生物，并评估了它们针对HIV整合酶的生物活性。这些嘌呤衍生物在低微摩尔范围内表现出抗整合酶活性。生物学结果表明，Me2+配体的类型，两点配体吡啶甲酰胺或三点配体8-羟基喹啉-7-甲酰胺，根据对氟苄基的取代位置影响抑制效力。 C-6-,C-8-吡啶二酰胺取代的嘌呤 (32) 在该系列中表现出最佳效力。 (c) 2006 Elsevier Ltd. 保留所有权利。
Because of its essential role in HIV replication and lack of human counterpart, HIV integrase is an attractive target for the development of novel anti-AIDS agents. Among the recently developed integrase inhibitors, only the alpha,gamma-diketo acid (DKA) compounds were biologically validated as potent and selective integrase inhibitors. The general structure of DKAs contains a diketo acid moiety as the Mg2+ chelating pharmacophore, and an adjacent aryl group to provide selectivity. Numerous structure-activity relationship (SAR) studies on DKAs have been conducted, which generally involved substituting the carboxylate group or the aryl group. Our objective was to investigate the SARs of the DKA molecule by incorporating a purine ring in the aryl moiety and replacing the labile diketo acid moiety with other divalent metal (Me2+) chelating ligands. A series of amide substituted purine derivatives were synthesized via palladium-catalyzed amidation reactions, and their biological activities against HIV integrase were evaluated. These purine derivatives showed anti-integrase activity at low micromolar range. The biological results indicated that the type of Me2+ ligands, two-point ligand picolinamide or three-point ligand 8-hydroxy-quinoline-7-carboxamide, affected inhibitory potency depending on the substitution position of the para-fluorobenzyl group. The C-6-,C-8-dipicolinamide substituted purine (32) exhibited the best potency among this series. (c) 2006 Elsevier Ltd. All rights reserved.