Synthesis and antiviral evaluation of 6'-substituted aristeromycins: potential mechanism-based inhibitors of S-adenosylhomocysteine hydrolase.
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.
Madhavan
G V
GV
Syntex Research, Palo Alto, California 94304.
McGee
D P
DP
Rydzewski
R M
RM
Boehme
R
R
Martin
J C
JC
Prisbe
E J
EJ
D000241:Adenosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D043383:Adenosylhomocysteinase; D000818:Animals; D000998:Antiviral Agents; D055598:Chemical Phenomena; D002621:Chemistry; D006867:Hydrolases / Q000037:antagonists & inhibitors*; D011817:Rabbits; D018139:Simplexvirus / Q000187:drug effects*; D013329:Structure-Activity Relationship; D014616:Vaccinia virus / Q000187:drug effects* / Q000502:physiology; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; C030034:aristeromycin; D006867:Hydrolases; D043383:Adenosylhomocysteinase; D000241:Adenosine