Zouhiri F, Mouscadet J F, Mekouar K, Desmaële D, Savouré D, Leh H, Subra F, Le Bret M, Auclair C, d'Angelo J
Unité de Chimie Organique, UPRES-A du CNRS 8076, Centre d'Etudes Pharmaceutiques, Université Paris-Sud, 5 rue J.-B. Clément, 92296 Châtenay-Malabry, France.
J Med Chem. 2000 Apr 20;43(8):1533-40. doi: 10.1021/jm990467o.
Our prior studies showed that polyhydroxylated styrylquinolines are potent HIV-1 integrase (IN) inhibitors that block the replication of HIV-1 in cell culture at nontoxic concentrations. To explore the mechanism of action of these inhibitors, various novel styrylquinoline derivatives were synthesized and tested against HIV-1 IN and in cell-based assays. Regarding the in vitro experiments, the structural requirements for biological activity are a carboxyl group at C-7, a hydroxyl group at C-8 in the quinoline subunit, and an ancillary phenyl ring. However the in vitro inhibitory profile tolerates deep alterations of this ring, e.g. by the introduction of various substituents or its replacement by heteroatomic nuclei. Regarding the ex vivo assays, the structural requirements for activity are more stringent than for in vitro inhibition. Thus, in addition to an o-hydroxy acid group in the quinoline, the presence of one ortho pair of substituents at C-3' and C-4', particularly two hydroxyl groups, in the ancillary phenyl ring is imperatively required for inhibitory potency. Starting from literature data and the SARs developed in this work, a putative binding mode of styrylquinoline inhibitors to HIV-1 IN was derived.
我们之前的研究表明，多羟基化苯乙烯基喹啉是有效的HIV-1整合酶（IN）抑制剂，能够在无毒浓度下阻断HIV-1在细胞培养中的复制。为了探究这些抑制剂的作用机制，合成了各种新型苯乙烯基喹啉衍生物，并针对HIV-1 IN进行了测试以及基于细胞的分析。关于体外实验，生物活性的结构要求是喹啉亚基的C-7位有一个羧基、C-8位有一个羟基以及一个辅助苯环。然而，体外抑制谱能够容忍该环的深度改变，例如通过引入各种取代基或用杂原子环取代它。关于体外实验，活性的结构要求比体外抑制更为严格。因此，除了喹啉中的邻羟基酸基团外，辅助苯环中C-3'和C-4'位存在一对邻位取代基，特别是两个羟基，对于抑制效力来说是必不可少的。从文献数据和本研究中得出的构效关系出发，推导了苯乙烯基喹啉抑制剂与HIV-1 IN的假定结合模式。
