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Lipophilic α‐hydroxybenzylphosphonates as prodrugs of 3′‐azido‐2′,3′‐dideoxythymidine (AZT)
Author(s) -
Meier Chris,
Habel Lothar W.,
Balzarini Jan,
De Clercq Eric
Publication year - 1995
Publication title -
liebigs annalen
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 0947-3440
DOI - 10.1002/jlac.1995199512305
Subject(s) - chemistry , prodrug , hydrolysis , phosphonate , moiety , stereochemistry , cleavage (geology) , yield (engineering) , organic chemistry , biochemistry , materials science , geotechnical engineering , fracture (geology) , engineering , metallurgy
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.