5′,5′‐di‐O‐nucleosyl‐O′‐benzylphosphotriesters as potential prodrugs of 3′‐azido‐2′,3′‐dideoxythymidine‐5′‐monophosphate

Abstract

AbstractThe synthesis of 5′,5′‐O‐di‐(3′‐azido‐2′,3′‐dideoxythymidinyl)‐O′‐benzylphosphotriesters 1 as potential prodrugs of nucleoside monophosphates is described. The concept is applied to the antiretroviral nucleoside analog 3′‐azido‐2′,3′‐deoxythymidine (AZT) 4. All derivatives 1 were synthesized by reaction of the tetra‐n‐butylammonium salt of di‐AZT‐phosphate 2b with different benzyl bromides or ‐chlorides 9. Compound 2b was obtained by a combination of phosphoamidite/H‐phosphonate chemistry, subsequent oxidation to 2a, and cation exchange. The partition coefficients of 1 in an 1‐octanol/water mixture show that all compounds exhibit a much higher lipophilicity than the parent nucleoside AZT (4). It was also shown, that 1 decomposes spontaneously under mild aqueous basic conditions (phosphate buffer (pH 7.5) and RPMI culture medium containing heat‐deactivated fetal calf serum) releasing selectively the di‐AZT phosphate anion 2. The half‐lives of 1 could be adjusted within a wide range by changing the ring substituents of the benzyl group. Additionally, the mechanism of hydrolysis varies if the substituent is changed from a donor to an acceptor one. The described phosphotriesters 1 exhibit considerable antiviral activity in HIV‐1‐ and HIV‐2‐infected CEM/O cells, whereas no activity was detected in the HIV‐2‐infected thymidine kinase‐deficient CEM cell line. On the other hand, we could not detect any cytotoxicity of the described phosphotriesters. Consequently, compounds 1 should act as prodrugs or depot forms at least of antiviral nucleoside analogs.