title: Novel use of a guanosine prodrug approach to convert 2',3'-didehydro-2',3'-dideoxyguanosine into a viable antiviral agent.
abstract: Transient kinetic studies with human immunodeficiency virus (HIV) type 1 reverse transcriptase suggest that nucleotide analogs containing the 2',3'-didehydro-2',3'-dideoxy ribose ring structure present in D4T (stavudine) triphosphate are among the most effective alternative substrates. For unclear reasons, however, the corresponding purine nucleoside, 2',3'-didehydro-2',3'-dideoxyguanosine (D4G), was found to be inactive in cell culture. We have found that the previously reported lack of activity of D4G is primarily due to solution instability, and in this report we describe a novel use of a guanosine prodrug approach to stabilize the nucleoside. D4G was modified at the 6 position of the purine ring to contain a cyclopropylamino group yielding the prodrug, cyclo-D4G. An evaluation of cyclo-D4G revealed that the prodrug possessed anti-HIV activity. In addition, cyclo-D4G had increased stability, lipophilicity, and solubility, as well as decreased toxicity relative to D4G, suggesting that further study is warranted.
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520-8066, USA.
authors.forename: Adrian S
authors.initials: AS
authors.lastname: Ray
authors.forename: Zhenjun
authors.initials: Z
authors.lastname: Yang
authors.forename: Chung K
authors.initials: CK
authors.lastname: Chu
authors.forename: Karen S
authors.initials: KS
authors.lastname: Anderson
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002460:Cell Line; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D015224:Dideoxynucleosides / Q000138:chemical synthesis* / Q000494:pharmacology*; D015195:Drug Design; D004352:Drug Resistance, Microbial; D006151:Guanosine / Q000031:analogs & derivatives; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors*; D006863:Hydrogen-Ion Concentration; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D012995:Solubility
chemical_list: D019380:Anti-HIV Agents; D015224:Dideoxynucleosides; D011355:Prodrugs; D018894:Reverse Transcriptase Inhibitors; C057503:carbovir; D006151:Guanosine; D054303:HIV Reverse Transcriptase