Beschreibung:
<jats:title>Abstract</jats:title><jats:p>The α‐hydroxybenzylphosphonates <jats:bold>1a–1j</jats:bold> of the antiviral drug 3′‐azido‐2′,3′‐dideoxythymidine <jats:bold>5</jats:bold> (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 <jats:bold>6.</jats:bold> All compounds <jats:bold>1a–1j</jats:bold> exhibited higher partition coefficients in 1‐octanol/water than AZT <jats:bold>(5)</jats:bold>. In hydrolysis studies at pH 7.5 we observed that precursors to bioactive compounds were delivered by simple hydrolysis of the lipophilic precursors <jats:bold>1a–1j</jats:bold> via two different mechanisms: the phosphonate‐phosphate rearrangement leading to the benzylphosphotriesters <jats:bold>2</jats:bold> and/or the direct cleavage into the di‐AZT phosphonate <jats:bold>6.</jats:bold> Both compounds <jats:bold>2</jats:bold> and <jats:bold>6</jats:bold> were further degraded yielding the potentially antiviral active compounds <jats:bold>4</jats:bold> and <jats:bold>8</jats:bold>, respectively. The hydrolysis pathway could be controlled by the substitution pattern in the benzylic moiety. Identical hydrolytic behavior of <jats:bold>1</jats:bold> was detected in „biological”︁ hydrolysis kinetics by using a RPMI culture medium containing 10% heat‐inactivated fetal calf serum (FCS). The title compounds <jats:bold>1a–1j</jats:bold> exhibited considerable HIV‐1 and HIV‐2 activity in wild‐type CEM/O cells.</jats:p>