Synthesis and antiviral properties of (+/-)-5'-noraristeromycin and related purine carbocyclic nucleosides. A new lead for anti-human cytomegalovirus agent design.
(+/-)-5'-Noraristeromycin (3) has been prepared in three steps beginning with the 2,3-O-isopropylidene derivative of (+/-)-(1 alpha, 2 beta, 3 beta, 4 alpha)-4-amino-1,2,3-cyclopentanetriol (7). Also prepared from the same starting material were the related hypoxanthine (4), guanine (5), and 2,6-diaminopurine (6) analogues. Compounds 3-6 were evaluated for antiviral activity against a large number of viruses with marked activity being observed for 3 towards vaccinia virus, human cytomegalovirus, vesicular stomatitis virus, parainfluenza (type 3) virus, measles virus, respiratory syncytial virus, reovirus (type 1), and the arenaviruses Junin and Tacaribe. None of the compounds showed cytotoxicity to the host cell monolayers used in the antiviral studies. Both 3 and 6 have been found to be inhibitors of S-adenosyl-L-homocysteine hydrolase (AdoHcy hydrolase), which likely accounts for their antiviral activity. Inhibition of AdoHcy hydrolase represents a new approach to human cytomegalovirus drug design that should be pursued. Also, the activity of 3 should be further scrutinized for the treatment of pox-, rhabdo-, paramyxo-, reo-, and arenavirus infections.
Patil
S D
SD
Department of Chemistry, University of South Florida, Tampa 33620-5250.
Schneller
S W
SW
Hosoya
M
M
Snoeck
R
R
Andrei
G
G
Balzarini
J
J
De Clercq
E
E
D000241:Adenosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D043383:Adenosylhomocysteinase; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D003587:Cytomegalovirus / Q000187:drug effects*; D015195:Drug Design; D006801:Humans; D006867:Hydrolases / Q000037:antagonists & inhibitors; D011684:Purine Nucleosides / Q000138:chemical synthesis* / Q000494:pharmacology; D013237:Stereoisomerism
D000998:Antiviral Agents; D011684:Purine Nucleosides; C076829:5'-noraristeromycin; D006867:Hydrolases; D043383:Adenosylhomocysteinase; D000241:Adenosine