title: Selective activity and cellular pharmacology of (1R-1 alpha,2 beta,3 alpha)-9-[2,3-bis(hydroxymethyl)cyclobutyl]guanine in herpesvirus-infected cells.
abstract: The cycloburtane nucleoside analog (1R-1 alpha,2 beta,3 alpha)-9-[2,3-bis(hydroxymethyl)cyclobutyl]guanine [(R)-BHCG or SQ 34,514] was recently synthesized and shown to be the active enantiomer of (+/-)-BHCG (SQ 33,054), a potent inhibitor of several strains of herpesviruses [J. Med. Chem 34:1415-1421 (1991); Antiviral Res. 13:41-52 (1990)]. In plaque reduction assays, (R)-BHCG was about 1000 times more active than its S-enantiomer on herpes simplex virus type I (HSV-1) and over 200 times more active against a thymidine kinase-deficient mutant HSV-1 and human cytomegalovirus (HCMV). We now show that both (R)-BHCG and (S)-BHCG are efficiently phosphorylated to their mono-, di-, and triphosphates by HSV-1-infected cells, in a manner similar to that of acyclovir [Proc. Natl. Acad. Sci. USA 74:5716-5720 (1977)]. The uptake of both enantiomers was greatly increased upon infection; however, (S)-BHCG was taken up to about twice the extent of (R)-BHCG and accumulated primarily as the mono- and diphosphates. (R)-BHCG accumulated primarily as the triphosphate, and accumulation was linear with both time and added drug concentration. The triphosphate had an apparent half-life of about 10 hr. Metabolic studies using HCMV-infected cells showed only a small degree of phosphorylation of (R)-BHCG and none of (S)-BHCG. When cells were labeled with 25 microM (R)-BHCG, the amount of (R)-BHCG triphosphate formed was less than 0.5 pmol/10(6) cells. Interestingly, the ED50 value of (R)-BHCG is about 100-fold higher against HCMV than against HSV-1, and the relative levels of (R)-BHCG triphosphate formed in cells infected by the two viruses are roughly proportional to the antiviral activities.
authors.affiliation: Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543-4000.
authors.forename: G
authors.initials: G
authors.lastname: Yamanaka
authors.forename: A V
authors.initials: AV
authors.lastname: Tuomari
authors.forename: M
authors.initials: M
authors.lastname: Hagen
authors.forename: B
authors.initials: B
authors.lastname: McGeever-Rubin
authors.forename: B
authors.initials: B
authors.lastname: Terry
authors.forename: M
authors.initials: M
authors.lastname: Haffey
authors.forename: G S
authors.initials: GS
authors.lastname: Bisacchi
authors.forename: A K
authors.initials: AK
authors.lastname: Field
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000378:metabolism* / Q000494:pharmacology; D002460:Cell Line; D006147:Guanine / Q000031:analogs & derivatives* / Q000378:metabolism; D006564:Herpesviridae / Q000378:metabolism*; D009705:Nucleosides / Q000494:pharmacology; D010766:Phosphorylation; D013237:Stereoisomerism; D013937:Thymidine Kinase / Q000502:physiology; D014316:Tritium
chemical_list: D000998:Antiviral Agents; D009705:Nucleosides; D014316:Tritium; D006147:Guanine; C063638:lobucavir; D013937:Thymidine Kinase