Synthesis and anti-HIV activity of cosalane analogues incorporating two dichlorodisalicylmethane pharmacophore fragments.
Synthesis and anti-HIV activity of cosalane analogues incorporating two dichlorodisalicylmethane pharmacophore fragments.
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包含两个二氯二水杨甲烷药效团片段的 cosalane 类似物的合成和抗 HIV 活性。
DOI：
10.1016/s0968-0896(01)00152-3
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发表时间：
2001
影响因子：
3.5
通讯作者：
Cushman,M
中科院分区：
文献类型：
--
作者：
Casimiro-Garcia,A;DeClercq,E;Pannecouque,C;Witvrouw,M;Loftus,TL;Turpin,JA;BuckheitJr,RW;Fanwick,PE;Cushman,M
合成了一系列新的含有二氯二异丙基甲烷药效团两个片段的可莎烷类似物。为了确定药效团片段与类固醇环的连接位置，从而产生最有效的类似物，设计了两种类型的化合物。在第一种类型中，两个药效团片段通过使用适当的接头单元连接在类固醇环的C-3和C-17处。在第二种类型中，两个药效团基团都通过含有酰胺部分的烯基链连接到类固醇的C-3。所有新化合物在细胞培养中显示出对HIV-1 RF、HIV-1 IIIB和HIV-2 ROD的抗病毒活性。发现由两种附着策略产生的化合物的相对效力取决于病毒株以及细胞类型。总体而言，第二药效团的连接没有导致抗HIV活性的大幅增加或大幅损失，因此结果与以下假设一致：两个药效团独立作用，并且一次一个，带正电荷的氨基酸侧链存在于gp 120和CD 4的表面上。
A new series of cosalane analogues incorporating two fragments of the dichlorodisalicylmethane pharmacophore has been synthesized. In order to identify the position for the attachment of the pharmacophore fragments to the steroid ring that results in the most potent analogues, two types of compounds were designed. In the first type, the two pharmacophore fragments were attached at C-3 and C-17 of the steroid ring by using appropriate linker units. In the second type, both pharmacophore groups were connected to C-3 of the steroid through an alkenyl chain containing an amide moiety. All of the new compounds displayed antiviral activity versus HIV-1RF, HIV-1IIIB, and HIV-2RODin cell culture. The relative potencies of the compounds resulting from the two attachment strategies were found to depend on the viral strain as well as the cell type. Overall, the attachment of the second pharmacophore did not result in either a large gain or a large loss in anti-HIV activity, and the results are therefore consistent with the hypothesis that the two pharmacophores act independently, and one at a time, with positively charged amino acid side chains present on the surface of gp120 and CD4.