Synthesis and biological activity of unsaturated carboacyclic purine nucleoside analogues.
Two new carboacyclic nucleoside analogues, 9-[4-hydroxy-3-(hydroxymethyl)-2-butenyl]adenine (6) and 9-[4-hydroxy-3-(hydroxymethyl)-2-butenyl]guanine (5), modeled on the unsaturated carbocyclic nucleoside analogue neplanocin A (2), have been synthesized and tested for antiviral activity against HSV-2 and, in the case of 6, for activity against influenza and in vitro inhibition of S-adenosylhomocysteine hydrolase. The synthesis was accomplished through the coupling of either adenine or the guanine precursor 2-amino-6-chloropurine (15) to the key intermediate 1-(benzyloxy)-2-[(benzyloxy)methyl]-4-chloro-2-butene (13). Debenzylation of the N-9 adenine adduct gave 6 directly, while the product of the debenzylation of the N-9 adduct of 15 when treated with sodium hydroxide gave the guanine analogue 5. The carboacyclic guanine analogue (5) exhibited significant antiviral activity against HSV-2 (VR = 1.5, MIC50 = 65.6 micrograms/mL), a level of activity that is superior to that of ara-A but inferior to that of acyclovir. The adenine analogue 6 was active against HSV-2 only at a very high dose; it was devoid of antiviral activity against influenza type A2, and it lacked inhibitory activity against S-adenosylhomocysteine hydrolase.
D000241:Adenosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D043383:Adenosylhomocysteinase; D000818:Animals; D002460:Cell Line; D055598:Chemical Phenomena; D002621:Chemistry; D006151:Guanosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D006867:Hydrolases / Q000037:antagonists & inhibitors; D009980:Influenza A virus / Q000187:drug effects*; D009682:Magnetic Resonance Spectroscopy; D018139:Simplexvirus / Q000187:drug effects*
C052345:9-(4-hydroxy-3-(hydroxymethyl)-2-butenyl)adenine; D006151:Guanosine; C052344:9-(4-hydroxy-3-hydroxymethyl-2-butenyl)guanine; D006867:Hydrolases; D043383:Adenosylhomocysteinase; D000241:Adenosine