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. Issue 12 (15th June 2016)

• Record Type: Journal Article
• Authors: Xie, Min; Lapidus, Rena G.; Sadowska, Mariola; Edelman, Martin J.; Hosmane, Ramachandra S.
• Is Part Of: Bioorganic & medicinal chemistry. Volume 24:Issue 12(2016)
• Page Start: 2595
• Page End: 2602
• Publication Date: 2016-06-15
• Subjects: 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–activity relationship (SAR) studies -- DDX3 as a potential target; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2016.03.015
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: 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 N 6 -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 N 6 -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 N 6 -positions of the heterocyclic ligand. This pocket appears to be large enough to hold either a C-18 alkyl chain of N 6 and no attachment at N-1, or a combined C-10 at N 6 and a CH2 Ph at N-1. Any alkyl chain shorter or longer than C-10 at N 6 with a CH2 Ph attached at N-1, would result in decrease of biological activity.