title: 4'-modified analogues of aristeromycin and neplanocin A: synthesis and inhibitory activity toward S-adenosyl-L-homocysteine hydrolase.
abstract: The carbocyclic adenosine analogues aristeromycin and neplanocin A both display significant S-adenosyl-L-homocysteine (AdoHcy) hydrolase inhibitory activity and broad-spectrum antiviral effects. Since phosphorylation of the 4'-hydroxymethyl substituent has been implicated with the cytotoxicity of these compounds, various analogues modified at this position were synthesized utilizing a key cyclopentenone intermediate 3 which can be derived from several members of the natural chiral pool. Cyclopentenone 3 underwent a highly stereoselective conjugate addition with organocuprate reagents, and the 1,4-adducts so formed were then readily elaborated to the corresponding 4'-modified aristeromycin analogues. Alternatively, quenching the enolate intermediate of the organocuprate conjugate addition with methanesulfinyl chloride followed by pyrolytic syn elimination resulted in the formation of 4'-modified neplanocin A intermediates. Three of the final compounds (1b, 1c, and 1e) displayed inhibitory activity toward AdoHcy hydrolase in the nanomolar range.
authors.affiliation: Department of Medicinal Chemistry, University of Kansas, Lawrence 66045.
authors.forename: M S
authors.initials: MS
authors.lastname: Wolfe
authors.forename: Y
authors.initials: Y
authors.lastname: Lee
authors.forename: W J
authors.initials: WJ
authors.lastname: Bartlett
authors.forename: D R
authors.initials: DR
authors.lastname: Borcherding
authors.forename: R T
authors.initials: RT
authors.lastname: Borchardt
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D043383:Adenosylhomocysteinase; D000818:Animals; D002417:Cattle; D006867:Hydrolases / Q000037:antagonists & inhibitors*; D008099:Liver / Q000201:enzymology; D010766:Phosphorylation
chemical_list: C030034:aristeromycin; C031096:neplanocin A; D006867:Hydrolases; D043383:Adenosylhomocysteinase; D000241:Adenosine