The cyclohexene ring system as a furanose mimic: synthesis and antiviral activity of both enantiomers of cyclohexenylguanine.
Both enantiomers of cyclohexenylguanine were synthesized in a stereospecific way starting from the same starting material: R-(-)-carvone. Both compounds showed potent and selective anti-herpesvirus activity (HSV-1, HSV-2, VZV, CMV). The binding of both cyclohexene nucleosides in the active site of HSV-1 thymidine kinase was investigated, and a model for the binding of both enantiomers is proposed. The amino acids involved in binding of the optical antipodes are the same, but the interaction energy of both enantiomers is slightly different. This may be attributed to the interaction of the secondary hydroxyl function of the nucleoside analogues with Glu-225. Structural analysis has demonstrated the flexibility of the cyclohexenyl system, and this may be considered as an important conformational characteristic explaining the potent antiviral activity.
Wang
J
J
Laboratories of Medicinal Chemistry and of Virology and Chemotherapy, Rega Institute for Medical Research, Minderbroedersstraat 10, B-3000 Leuven, Belgium.
Froeyen
M
M
Hendrix
C
C
Andrei
G
G
Snoeck
R
R
De Clercq
E
E
Herdewijn
P
P
D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D003510:Cyclohexanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D003587:Cytomegalovirus / Q000187:drug effects; D018259:Herpesvirus 1, Human / Q000187:drug effects; D018258:Herpesvirus 2, Human / Q000187:drug effects; D014645:Herpesvirus 3, Human / Q000187:drug effects; D006801:Humans; D008958:Models, Molecular; D018716:Molecular Mimicry; D011684:Purine Nucleosides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000998:Antiviral Agents; D003510:Cyclohexanes; D011684:Purine Nucleosides