title: Structure-based drug design and potent anti-cancer activity of tricyclic 5:7:5-fused diimidazo[4,5-d:4',5'-f][1,3]diazepines.
abstract: Judicial structural modifications of 5:7-fused ring-expanded nucleosides (RENs), based on molecular modeling studies with one of its known targets, human RNA helicase (hDDX3), led to the lead, novel, 5:7-5-fused tricyclic heterocycle (1). The latter exhibited promising broad-spectrum in vitro anti-cancer activity against a number of cancer cell lines screened. This paper describes our systematic, albeit limited, structure-activity relationship (SAR) studies on this lead compound, which produced a number of analogs with broad-spectrum in vitro anti-cancer activities against lung, breast, prostate, and ovarian cancer cell lines, in particular compounds 15i, 15j, 15m and 15n which showed IC(50) values in submicromolar to micromolar range, and are worthy of further explorations. The SAR data also enabled us to propose a tentative SAR model for future SAR efforts for ultimate realization of optimally active and minimally toxic anti-cancer compounds based on the diimidazo[4,5-d:4',5'-f][1,3]diazepine structural skeleton of the lead compound 1.
authors.affiliation: Laboratory for Drug Design & Synthesis, Department of Chemistry & Biochemistry, University of Maryland, Baltimore County, 1000 Hilltop Circle, Baltimore, MD 21250, USA.
authors.forename: Atul
authors.initials: A
authors.lastname: Kondaskar
authors.forename: Shilpi
authors.initials: S
authors.lastname: Kondaskar
authors.forename: James C
authors.initials: JC
authors.lastname: Fishbein
authors.forename: Brandon A
authors.initials: BA
authors.lastname: Carter-Cooper
authors.forename: Rena G
authors.initials: RG
authors.lastname: Lapidus
authors.forename: Mariola
authors.initials: M
authors.lastname: Sadowska
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Edelman
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; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D061986:MCF-7 Cells; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D001381:Azepines