D4T-5'-[P-BROMOPHENYL METHOXYALANINYL PHOSPHATE] AS A POTENT AND NONTOXIC ANTI-HUMAN-IMMUNODEFICIENCY-VIRUS AGENT

Three aryl phosphate derivatives of 2',3'-didehydro-2',3'-dideoxythymi dine (d4T) were tested for their anti-human immunodeficiency virus (HI V) activity in peripheral blood mononuclear cells (PBMC) and thymidine kinase (TK)-deficient CEM T cells. Compared to the parent compound d4 T, the lead compound d4T-5'-[p-bromophenyl methoxyalaninylphosphate] w ith a para-bromo substituent in the aryl moiety was 12.6-fold more pot ent in inhibiting p24 production (IC50 values: 44 nM versus 556 nM) an d 41.3-fold more potent in inhibiting the reverse transcriptase (RT) a ctivity (IC50 values: 57 nM versus 2355 nM) in HIV-infected TK-deficie nt CEM cells. None of the compounds exhibited any detectable cytotoxic ity to PBMC or CEM cells at concentrations as high as 10 000 nM. To ou r knowledge, this is the first demonstration that the potency as well as selectivity index of the d4T aryl phosphate derivatives in TK-defic ient cells can be substantially enhanced by introducing a single para- bromo substituent in the phenyl moiety.