- Prodrugs of 2',3'-didehydro-3'-deoxythymidine (D4T): Synthesis, antiviral activity, and rapid pharmacokinetic evaluation
-
A series of 5'-derivatives and modified pyrimidine analogues of 2',3'- didehydro-3'-deoxythymidine (d4T, stavudine, 1) were synthesized to determine their potential as oral prodrugs of d4T. Utilizing a screen developed for the rapid evaluation of a variety of prodrugs in mice, it was determined that 5'- acetate 2 provided comparable plasma levels of d4T after oral administration of the prodrug to that when d4T was administered alone. The relative oral bioavailability of methoxy acetate 3 and cyclohexyl carbonate 5 was 79 and 41%, respectively. Dihydropyridine ester 6 did not provide detectable levels of d4T up to 1 h after oral administration of 6. Thiopyrimidines 8 and 9, as well as aminopyrimidine 10 also failed to provide measurable levels of d4T after oral administration. 5'-Derivatives 3, 5, and 6 showed similar activity to that of d4T against HIV and MuLV, as did 5'-benzoyl-4-thio derivative 8. However, the corresponding 4-thio 5'-alcohol 9 was inactive.
- Tortolani,Russell,Whiterock,Hitchcock,Ghazzouli,Martin,Mansuri,Starrett Jr.
-
p. 339 - 343
(2007/10/02)
-
- Improved synthesis of 2',3'-dideoxycytidine (d2C) and its correlated nucleoside analogues
-
2',3'-deoxy and 2',3'-dideoxy-2',3'-didehydrocytidine (d2C and d4C) have been synthesized in good yields from 2'-deoxyuridine via dichlorinated derivatives 7a-b. The same synthetic strategy was used in the synthesis of d2C(Me) and d4C(Me) from thymidine. Following this method the evaluable 3'-chloro-2'-deoxycytidine derivatives 9-12 can be easily obtained.
- De Napoli,Messere,Montesarchio,Piccialli,Santacroce
-
p. 981 - 992
(2007/10/02)
-