title: Analogs of iso-azepinomycin as potential transition-state analog inhibitors of guanase: synthesis, biochemical screening, and structure-activity correlations of various selectively substituted imidazo[4,5-e][1,4]diazepines.
abstract: Guanase is an important enzyme of the purine salvage pathway of nucleic acid metabolism and its inhibition has beneficial implications in viral, bacterial, and cancer therapy. The work described herein is based on a hypothesis that azepinomycin, a heterocyclic natural product and a purported transition state analog inhibitor of guanase, does not represent the true transition state of the enzyme-catalyzed reaction as closely as does iso-azepinomycin, wherein the 6-hydroxy group of azepinomycin has been translocated to the 5-position. Based on this hypothesis, and assuming that iso-azepinomycin would bind to guanase at the same active site as azepinomycin, several analogs of iso-azepinomycin were designed and successfully synthesized in order to gain a preliminary understanding of the hydrophobic and hydrophilic sites surrounding the guanase binding site of the ligand. Specifically, the analogs were designed to explore the hydrophobic pockets, if any, in the vicinity of N1, N3, and N4 nitrogen atoms as well as O(5) oxygen atom of iso-azepinomycin. Biochemical inhibition studies of these analogs were performed using a mammalian guanase. Our results indicate that (1) increasing the hydrophobicity near O(5) results in a negative effect, (2) translocating the hydrophobicity from N3 to N1 also results in decreased inhibition, (3) increasing the hydrophobicity near N3 or N4 produces significant enhancement of inhibition, (4) increasing the hydrophobicity at either N3 or N4 with a simultaneous increase in hydrophobicity at O(5) considerably diminishes any gain in inhibition made by solely enhancing hydrophobicity at N3 or N4, and (5) finally, increasing the hydrophilic character near N3 has also a deleterious effect on inhibition. The most potent compound in the series has a Ki value of 8.0±1.5μM against rabbit liver guanase.
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: Saritha
authors.initials: S
authors.lastname: Tantravedi
authors.forename: Saibal
authors.initials: S
authors.lastname: Chakraborty
authors.forename: Niti H
authors.initials: NH
authors.lastname: Shah
authors.forename: James C
authors.initials: JC
authors.lastname: Fishbein
authors.forename: Ramachandra S
authors.initials: RS
authors.lastname: Hosmane
mesh_terms: D000818:Animals; D001381:Azepines / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D006148:Guanine Deaminase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007093:Imidazoles / Q000737:chemistry*; D007536:Isomerism; D007700:Kinetics; D008099:Liver / Q000201:enzymology; D011485:Protein Binding; D011817:Rabbits; D013329:Structure-Activity Relationship
chemical_list: D001381:Azepines; D004791:Enzyme Inhibitors; D007093:Imidazoles; C029899:imidazole; C054358:azepinomycin; D006148:Guanine Deaminase
keywords: Biochemical inhibition studies; Imidazo[4,5-e][1,4]diazepines; Inhibitors of guanase; Organic synthesis and medicinal chemistry; Structure–activity relationship (SAR) studies; iso-Azepinomycin analogs
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