In vitro and in vivo evaluation of 6-azido-2',3'-dideoxy-2'-fluoro-beta-D-arabinofuranosylpurine and N6-methyl-2',3'-dideoxy-2'-fluoro-beta-D-arabinofuranosyladenine as prodrugs of the anti-HIV nucleosides 2'-F-ara-ddA and 2'-F-ara-ddI.
In an effort to improve the pharmacokinetic properties and tissue distribution of 2'-F-ara-ddI, two lipophilic prodrugs, 6-azido-2'-3'-dideoxy-2'-fluoro-beta-D- arabinofuranosylpurine (FAAddP, 4) and N6-methyl-2'-3'-dideoxy-2'-fluoro-beta-D-arabinofuranosyladenine (FMAddA, 5), were synthesized and their biotransformation was investigated in vitro and in vivo, in mice. Compounds 4 and 5 were synthesized via the intermediate 2. For the in vitro studies, FAAddP and FMAddA were incubated in mouse serum, liver homogenate, and brain homogenate. FAAddP was metabolized in liver homogenate by the reduction of the azido to the amino moiety followed by deamination, yielding 2'-F-ara-ddI. The conversion of FAAddP to 2'-F-ara-ddA was mediated by microsomal P-450 NADPH reductase system, as shown by the liver microsomal assay. FAAddP was also converted to 2'-F-ara-ddI at a slower rate in the brain than in the liver. FMAddA, however, was stable in brain homogenate and was slowly metabolized in the liver homogenate. Metabolic conversion of FMAddA in vitro was stimulated by the addition of adenosine deaminase. In the in vivo metabolism study, FAAddP underwent reduction to 2'-F-ara-ddA followed by deamination to 2'-F-ara-ddI. FMAddA did not result in increased brain delivery of 2'-F-ara-ddI in vivo, probably due to the slow conversion as observed in the in vitro studies. However, there was an increase in the half-life of 2'-F-ara-ddI produced from FMAddA. This report is the first example in the design of prodrugs using the azido group for adenine- and hypoxanthine-containing nucleosides. This interesting and novel approach can be extended to other antiviral and anticancer nucleosides.
Koudriakova
T
T
Department of Medicinal Chemistry and Pharmaceutics, College of Pharmacy, University of Georgia, Athens 30602-2352, USA.
Manouilov
K K
KK
Shanmuganathan
K
K
Kotra
L P
LP
Boudinot
F D
FD
Cretton-Scott
E
E
Sommadossi
J P
JP
Schinazi
R F
RF
Chu
C K
CK
D000818:Animals; D019380:Anti-HIV Agents / Q000494:pharmacology*; D001386:Azides / Q000737:chemistry / Q000493:pharmacokinetics*; D001711:Biotransformation; D016049:Didanosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D016048:Dideoxyadenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D005260:Female; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D011355:Prodrugs / Q000737:chemistry / Q000493:pharmacokinetics*; D013056:Spectrophotometry, Ultraviolet; D014740:Vidarabine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics
C102323:6-azido-2',3'-dideoxy-2'-fluoro-beta-arabinofuranosylpurine; D019380:Anti-HIV Agents; D001386:Azides; D011355:Prodrugs; C102322:N(6)-methyl-2',3'-dideoxy-2'-fluoro-beta-arabinofuranosyladenine; C083218:2'-fluoro-2',3'-dideoxyinosine; C073072:lodenosine; D016048:Dideoxyadenosine; D014740:Vidarabine; D016049:Didanosine