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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• 作者：Min Xie^a ; ^c ; Rena G. Lapidus^b ; Mariola Sadowska^b ; Martin J. Edelman^b ; Ramachandra S. Hosmane^a ; ^&dagger ; ; ^{hosmane@umbc.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Organic synthesis and medicinal chemistry ; Triaminomidazo[4 ; 5-e][1 ; 3]diazepines ; Anti-cancer activity ; Lung ; breast ; prostate and ovarian cancers ; In vitro screening ; Structure&ndash ; activity relationship (SAR) studies ; DDX3 as a potential target
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2016
• 出版时间：15 June 2016
• 年：2016
• 卷：24
• 期：12
• 页码：2595-2602
• 全文大小：598 K

文摘

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 N⁶ and no attachment at N-1, or a combined C-10 at N⁶ and a CH₂Ph at N-1. Any alkyl chain shorter or longer than C-10 at N⁶ with a CH₂Ph attached at N-1, would result in decrease of biological activity.