title: 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.
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 CH2Ph at N-1. Any alkyl chain shorter or longer than C-10 at N(6) with a CH2Ph attached at N-1, would result in decrease of biological activity.
authors.affiliation: Laboratory for Drug Design & Synthesis, Department of Chemistry & Biochemistry, University of Maryland, Baltimore County, 1000 Hilltop Circle, Baltimore, MD 21250, USA; Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Traylor 338, Baltimore, MD 21205, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Xie
authors.affiliation: Translational Core Laboratory, University of Maryland Marlene & Stewart Greenbaum Cancer Center, 22 South Greene Street, Baltimore, MD 21201, USA.
authors.forename: Rena G
authors.initials: RG
authors.lastname: Lapidus
authors.affiliation: Translational Core Laboratory, University of Maryland Marlene & Stewart Greenbaum Cancer Center, 22 South Greene Street, Baltimore, MD 21201, USA.
authors.forename: Mariola
authors.initials: M
authors.lastname: Sadowska
authors.affiliation: Translational Core Laboratory, University of Maryland Marlene & Stewart Greenbaum Cancer Center, 22 South Greene Street, Baltimore, MD 21201, USA.
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Edelman
authors.affiliation: Laboratory for Drug Design & Synthesis, Department of Chemistry & Biochemistry, University of Maryland, Baltimore County, 1000 Hilltop Circle, Baltimore, MD 21250, USA. Electronic address: hosmane@umbc.edu.
authors.forename: Ramachandra S
authors.initials: RS
authors.lastname: Hosmane
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001381:Azepines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008024:Ligands; D009369:Neoplasms / Q000188:drug therapy; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D001381:Azepines; D007093:Imidazoles; D008024:Ligands
keywords: Anti-cancer activity; DDX3 as a potential target; In vitro screening; Lung, breast, prostate and ovarian cancers; Organic synthesis and medicinal chemistry; Structure–activity relationship (SAR) studies; Triaminomidazo[4,5-e][1,3]diazepines