Synthesis and antiviral evaluation of 6'-substituted aristeromycins: potential mechanism-based inhibitors of S-adenosylhomocysteine hydrolase

• Published in: Journal of medicinal chemistry 1988-09, Vol.31 (9), p.1798-1804
• Main Authors: Madhavan, G. V. Bindu, McGee, Danny P. C, Rydzewski, Robert M, Boehme, Richard, Martin, John C, Prisbe, Ernest J
• Format: Article
• Language: English
• Subjects: Adenosine - analogs & derivatives; Adenosine - chemical synthesis; Adenosine - pharmacology; Adenosylhomocysteinase; Animals; Antiviral Agents; Carbohydrates. Nucleosides and nucleotides; Chemical Phenomena; Chemistry; Exact sciences and technology; herpes simplex virus 1; herpes simplex virus 2; Hydrolases - antagonists & inhibitors; Nucleosides, nucleotides and oligonucleotides; Organic chemistry; Preparations and properties; Rabbits; Simplexvirus - drug effects; Structure-Activity Relationship; Vaccinia virus - drug effects; Vaccinia virus - physiology; Virus Replication - drug effects
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00117a021

New carbocyclic adenosine analogues substituted at the 6'-position with fluorine, hydroxyl, methylene, or hydroxymethyl have been synthesized as potential mechanism-based inhibitors of S-adenosylhomocysteine (AdoHcy) hydrolase. The synthetic routes began with a functionalized (+/-)-azidocyclopentane 2, which was elaborated to the adenosine analogue, or with functionalized cyclopentane epoxides 11, 20, and 27, which were opened directly with adenine in the presence of base. The 6' alpha-fluoro, 6' beta-fluoro, and 6'-methylene carbocyclic adenosine analogues were potent inhibitors of AdoHcy hydrolase. None of the compounds displayed significant activity against herpes simplex virus type 1 or type 2, but several demonstrated potent inhibition of vaccinia virus replication.