title: Chemical and biological effects of substitution of the 2-position of ring-expanded ('fat') nucleosides containing the imidazo[4,5-e][1,3]diazepine-4,8-dione ring system: the role of electronic and steric factors on glycosidic bond stability and anti-HCV activity.
abstract: The attempted removal of the aralkyl group of 2-bromo-1-p-methoxybenzyl-6-octylimidazo[4,5-e][1,3]diazepine (ZP-33) with trifluoroacetic acid resulted in replacement of the bromo group with a carbonyl at position-2 in addition to the desired deprotection at the 1-position. 2'-Deoxynucleosides of 2-bromo-substituted-imidazole-4,5-diesters (ZP-35 and ZP-103) were synthesized by direct glycosylation of the corresponding heterocycles. The attempted ring-closure of the above nucleosides resulted in deglycosylation to form the starting heterocycles. The 2-phenyl derivatives of the above nucleosides (ZP-45 and ZP-73) were successfully prepared by Suzuki coupling with the appropriate phenylboronic acids, but the attempted ring-closure with guanidines to form the desired 5,7-fused ring-expanded nucleosides (RENs) resulted once again in the formation of the corresponding heterocyclic aglycons (ZP-64 and ZP-75). The first successful 2-substituted REN (ZP-110) was synthesized by replacing the 2-deoxyribose sugar moiety with a ribosyl group and replacing the bromo group with a p-methoxyphenyl substituent at the 2-position. A number of imidazole riboside diester precursors containing a substituted phenyl group at the 2-position were synthesized in order to prepare analogues of ZP-110. The substituents on the phenyl ring included a variety of electron-donating or electron-withdrawing groups operating through inductive and/or resonance effects. However, the final ring-closure of the diesters with guanidines in order to prepare RENs was successful only in a limited number of cases, including the ones containing a p-fluorophenyl (ZP-121), a m-methoxyphenyl (ZP-122), or an unsubstituted phenyl (NZ-53) at the 2-position. Deglycosylation and incomplete ring-closure of the intermediates were the major problems encountered with most other cases. The stability of glycosidic bonds was found to be dependent on several factors including, but not limited to, the electron-donating inductive effect of the 2-phenyl substituents and the temperature of the reaction medium. The three target RENs ZP-110, ZP-121, and ZP-122 were screened for in vitro anti-HCV activity, employing an HCV RNA replicon assay. While ZP-121 was inactive, the other two compounds showed only weak anti-HCV activity.
authors.affiliation: Laboratory for Drug Design and Synthesis, Department of Chemistry and Biochemistry, University of Maryland, Baltimore County, 1000 Hilltop Circle, Baltimore, MD 21250, USA.
authors.forename: Peng
authors.initials: P
authors.lastname: Zhang
authors.forename: Ning
authors.initials: N
authors.lastname: Zhang
authors.forename: Victor E
authors.initials: VE
authors.lastname: Buckwold
authors.forename: Ramachandra S
authors.initials: RS
authors.lastname: Hosmane
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001381:Azepines / Q000737:chemistry*; D002460:Cell Line; D004583:Electrons; D006027:Glycosides / Q000737:chemistry*; D016174:Hepacivirus / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D007093:Imidazoles / Q000737:chemistry*; D015394:Molecular Structure; D009705:Nucleosides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D001381:Azepines; D006027:Glycosides; D007093:Imidazoles; D009705:Nucleosides; C521786:imidazo(4,5-e)(1,3)diazepine-4,8-dione