Synthesis, anticancer activity, and SAR analyses of compounds containing the 5:7-fused 4,6,8-triaminoimidazo[4,5-e][1,3]diazepine ring system.
Synthesis, anticancer activity, and SAR analyses of compounds containing the 5:7-fused 4,6,8-triaminoimidazo[4,5-e][1,3]diazepine ring system.
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DOI：
10.1016/j.bmc.2016.03.015
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发表时间：
2016-06
影响因子：
3.5
通讯作者：
M. Xie;R. Lapidus;M. Sadowska;M. Edelman;R. Hosmane
中科院分区：
文献类型：
--
作者：
M. Xie;R. Lapidus;M. Sadowska;M. Edelman;R. Hosmane
本文介绍了我们对含有4，6，8-三氨基咪唑并[4，5-e][1，3]二氮杂环体系的5：7-稠合杂环(1)的有限构效关系(SAR)研究，该环系的合成和高效的广谱抗癌活性是我们几年前报道的。我们在这项研究中的努力主要集中在杂环N-1和N6-位取代基的司法连接上。我们的结果表明，杂环的N-1位和N6位上的取代基之间存在着某种微妙的相关性。很可能在目标蛋白上有一个共同的疏水结合口袋，该口袋被杂环配体的N-1和N6-位上的取代基占据。这个口袋似乎足够大，既可以容纳N6的C-18烷基链，在N-1没有连接，也可以容纳N6的C-10和N-1的CH2Ph的组合。在N-1位带有CH2Ph的烷基链长于或短于C-10，都会导致生物活性降低。
Described herein are our limited structure–activity relationship (SAR) studies on a 5:7-fused heterocycle (1), containing the 4,6,8-triaminoimidazo[4,5-e][1,3]diazepine ring system, whose synthesis and potent broad-spectrum anticancer activity we reported a few years ago. Our SAR efforts in this study are mainly focused on judicial attachment of substituents at N-1 and N6-positions of the heterocyclic ring. Our results suggest that there is some subtle correlation between the substituents attached at the N-1 position and those attached at the N6-position of the heterocycle. It is likely that there is a common hydrophobic binding pocket on the target protein that is occupied by the substituents attached at the N-1 and N6-positions of the heterocyclic ligand. This pocket appears to be large enough to hold either a C-18 alkyl chain of N6and no attachment at N-1, or a combined C-10 at N6and a CH2Ph at N-1. Any alkyl chain shorter or longer than C-10 at N6with a CH2Ph attached at N-1, would result in decrease of biological activity.