Potential inhibitors of S-adenosylmethionine-dependent methyltransferases. 11. Molecular dissections of neplanocin A as potential inhibitors of S-adenosylhomocysteine hydrolase.
A series of 9-(hydroxyalkenyl)purines (adenines and 3-deazaadenines), which are analogues of neplanocin A, were synthesized. The analogues were tested as inhibitors of bovine liver and murine L929 cell S-adenosyhomocysteine (AdoHcy) hydrolase (EC 3.3.1.1) and as inhibitors of vaccinia virus replication in murine L929 cells. Compounds 1b, 2a, 2b, 4a, 4b, 7, 9a, and 9b showed the best inhibitory effects toward bovine liver AdoHcy hydrolase, with compound 4b being the most potent. The compounds that were shown to be the most potent inhibitors of the bovine liver AdoHcy hydrolase all contained an allylic hydroxyl group in the cis position to the adenine or the 3-deazaadenine rings. It was concluded that the cis arrangement of the allylic hydroxyl groups in these acyclic compounds represented the minimum structural requirement of the trihydroxycyclopentenyl ring of neplanocin A to show inhibitory effects against AdoHcy hydrolase. The antiviral effects of these acyclic analogues were significantly less than neplanocin A; however, there appears to be a correlation between the antiviral activity and the inhibition of AdoHcy hydrolase for compounds 2a, 2b, 4a, 4b, and 7. Analogue 4b, which exhibited the best antiviral activity (IC50 = 70 microM) in this acyclic series, is substantially less potent than neplanocin A (IC50 = 0.08 microM) as an antiviral agent.
Borcherding
D R
DR
Department of Pharmaceutical Chemistry, University of Kansas, Lawrence 66045.
Narayanan
S
S
Hasobe
M
M
McKee
J G
JG
Keller
B T
BT
Borchardt
R T
RT
D000225:Adenine / Q000031:analogs & derivatives*; D000241:Adenosine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology; D043383:Adenosylhomocysteinase; D000818:Animals; D000903:Antibiotics, Antineoplastic; D000998:Antiviral Agents; D002417:Cattle; D002460:Cell Line; D055598:Chemical Phenomena; D002621:Chemistry; D006867:Hydrolases / Q000037:antagonists & inhibitors*; D008099:Liver / Q000201:enzymology; D051379:Mice; D014616:Vaccinia virus / Q000502:physiology; D014779:Virus Replication / Q000187:drug effects
D000903:Antibiotics, Antineoplastic; D000998:Antiviral Agents; C031096:neplanocin A; D006867:Hydrolases; D043383:Adenosylhomocysteinase; D000225:Adenine; D000241:Adenosine