title: Substrate/inhibition studies of bacteriophage T7 RNA polymerase with the 5'-triphosphate derivative of a ring-expanded ('fat') nucleoside possessing potent antiviral and anticancer activities.
abstract: As part of an effort to explore the mechanism of potent, broad spectrum antiviral and anticancer activities of a number of ring-expanded ('fat') nucleosides that we recently reported, a representative 'fat' nucleoside 4,6-diamino-8-imino-8H-1-beta-D-ribofuranosylimidazo[4,5-e][1,3]di azepine (1) was converted to its 5'-triphosphate derivative (2), and biochemically screened for possible inhibition of nucleic acid polymerase activity, employing synthetic DNA templates and the bacteriophage T7 RNA polymerase as a representative polymerase. Our results suggest that 2 is a moderate inhibitor of T7 RNA polymerase, and that the 5'-triphosphate moiety of 2 appears to be essential for inhibition as nucleoside 1 alone failed to inhibit the polymerase reaction.
authors.affiliation: Department of Chemistry and Biochemistry, University of Maryland, Baltimore County, Baltimore 21250, USA.
authors.forename: M
authors.initials: M
authors.lastname: Bretner
authors.forename: T D
authors.initials: TD
authors.lastname: Beckett
authors.forename: R K
authors.initials: RK
authors.lastname: Sood
authors.forename: D M
authors.initials: DM
authors.lastname: Baldisseri
authors.forename: R S
authors.initials: RS
authors.lastname: Hosmane
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001381:Azepines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001483:Base Sequence; D004247:DNA / Q000235:genetics; D012321:DNA-Directed RNA Polymerases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D009705:Nucleosides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D009711:Nucleotides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic / Q000187:drug effects; D014764:Viral Proteins
chemical_list: C405343:4,6-diamino-8-imino--8H-1-ribofuranosylimidazo(4,5-e)(1,3)diazepine-5'-phosphate; C405342:4,6-diamino-8-imino-8H-1-ribofuranosylimidazo(4,5-e)(1,3)diazepine; D000970:Antineoplastic Agents; D000998:Antiviral Agents; D001381:Azepines; D004791:Enzyme Inhibitors; D009705:Nucleosides; D009711:Nucleotides; D014764:Viral Proteins; D004247:DNA; C062210:bacteriophage T7 RNA polymerase; D012321:DNA-Directed RNA Polymerases