ISSN:
0947-3440
Keywords:
AZT
;
Nucleoside α-hydroxybenzylphosphonates
;
Phosphonate-phosphate rearrangement
;
Prodrugs
;
HIV chemotherapy
;
Chemistry
;
Organic Chemistry
Source:
Wiley InterScience Backfile Collection 1832-2000
Topics:
Chemistry and Pharmacology
Notes:
The α-hydroxybenzylphosphonates 1a-1j of the antiviral drug 3′-azido-2′,3′-dideoxythymidine 5 (AZT) as potential lipophilic prodrugs were readily accessible in 49% to 87% yield via a four-step synthetic pathway introducing the modifications in the aromatic ring system in the last step by making use of intermediate 6. All compounds 1a-1j exhibited higher partition coefficients in 1-octanol/water than AZT (5). In hydrolysis studies at pH 7.5 we observed that precursors to bioactive compounds were delivered by simple hydrolysis of the lipophilic precursors 1a-1j via two different mechanisms: the phosphonate-phosphate rearrangement leading to the benzylphosphotriesters 2 and/or the direct cleavage into the di-AZT phosphonate 6. Both compounds 2 and 6 were further degraded yielding the potentially antiviral active compounds 4 and 8, respectively. The hydrolysis pathway could be controlled by the substitution pattern in the benzylic moiety. Identical hydrolytic behavior of 1 was detected in „biological“ hydrolysis kinetics by using a RPMI culture medium containing 10% heat-inactivated fetal calf serum (FCS). The title compounds 1a-1j exhibited considerable HIV-1 and HIV-2 activity in wild-type CEM/O cells.
Additional Material:
2 Tab.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1002/jlac.1995199512305
