Comparison of Cytotoxicity of Mononucleoside Phosphotriester Derivatives Bearing Biolabile Phosphate Protecting Groups in Normal Human Bone Marrow Progenitor Cells

The effects of three mononucleoside phosphotriester derivatives of 3′-azido-2′,3′-dideoxythymidine (AZT) which incorporate biolabile phosphate protecting groups, namely S-acetyl-2-thioethyl (MeSATE), S-(2-hydroxyethylsulfidyl)-2-thioethyl (DTE), and pivaloyloxymethyl (POM) were studied and compared to their nucleoside parent in human myeloid colony-forming cells. Moreover, the relative antiviral potency of these three pronucleotides were determined in primary human peripheral blood mononuclear cells infected with human immunodeficiency virus type 1. The results indicate that the SATE and DTE pro-moieties, as well as their degradation products, do not induce additional toxicity. The bis(MeSATE) phosphotriester derivative of AZT emerged as the most selective inhibitor with an in-vitro therapeutic index of the same order of magnitude as observed for AZT. This study has been extended to the corresponding bis(MeSATE) and bis(DTE) phosphotriester derivatives of 2′,3′-dideoxyuridine (ddU).