Studies on 2',3'-dideoxy-2',3'-didehydropyrimidine nucleosides. II. N4-benzoyl-2',3'-dideoxy-2',3'-didehydrocytidine as a prodrug of 2',3'-dideoxy-2',3'-didehydrocytidine (DDCN).

Abstract

N4-Benzoyl-2',3'-dideoxy-2',3'-didehydrocytidine (Bz-DDCN) was synthesized as a novel prodrug of 2',3'-dideoxy-2',3'-didehydrocytidine (DDCN), which is a reverse transcriptase inhibitor and is considered to be a potential anti-acquired immunodeficiency syndrome agent. Chemical and enzymatic regeneration of DDCN from the prodrug has been investigated in both in vitro and in vivo experiments. Bz-DDCN regenerated DDCN under basic conditions (greater than pH 8), while cleavage of the N-glycosidic linkage and production of N4-benzoylcytosine were observed under acidic conditions (less than pH 6). DDCN was enzymatically regenerated from the prodrug in the presence of several enzyme preparations, including human plasma. DDCN and Bz-DDCN were intravenously administered to mice and the plasma concentrations of DDCN and the prodrug were measured. Though DDCN levels following direct DDCN administration decreased exponentially with a half-life of 14.5 min, the plasma levels of DDCN following the prodrug administration were sustained above 2 microM for over 3 h.

• Authors: T Kawaguchi, K Ishikawa, T Seki, K Juni, S Fukushima, M Nakano
• Journal: Chemical & pharmaceutical bulletin (Chem Pharm Bull (Tokyo)) Vol. 37 Issue 9 Pg. 2547-9 (Sep 1989) ISSN: 0009-2363 [Print] Japan
• PMID: 2557984 (Publication Type: Journal Article)

Chemical References

• Prodrugs
• N(4)-benzoyl-2',3'-dideoxy-2',3'-didehydrocytidine
• Zalcitabine
• 2',3'-dideoxycytidinene

Topics

• Animals
• Chemical Phenomena
• Chemistry
• Male
• Mice
• Mice, Inbred Strains
• Prodrugs
• Zalcitabine (analogs & derivatives, chemical synthesis, pharmacokinetics)