title: D4T-5'-[p-bromophenyl methoxyalaninyl phosphate] as a potent and non-toxic anti-human immunodeficiency virus agent.
abstract: Three aryl phosphate derivatives of 2',3'-didehydro-2',3'-dideoxythymidine (d4T) were tested for their anti-human immunodeficiency virus (HIV) activity in peripheral blood mononuclear cells (PBMC) and thymidine kinase (TK)-deficient CEM T cells. Compared to the parent compound d4T, the lead compound d4T-5'-[p-bromophenyl methoxyalaninylphosphate] with a para-bromo substituent in the aryl moiety was 12.6-fold more potent in inhibiting p24 production (IC50 values: 44 nM versus 556 nM) and 41.3-fold more potent in inhibiting the reverse transcriptase (RT) activity (IC50 values: 57 nM versus 2355 nM) in HIV-infected TK-deficient CEM cells. None of the compounds exhibited any detectable cytotoxicity to PBMC or CEM cells at concentrations as high as 10,000 nM. To our knowledge, this is the first demonstration that the potency as well as selectivity index of the d4T aryl phosphate derivatives in TK-deficient cells can be substantially enhanced by introducing a single para-bromo substituent in the phenyl moiety.
authors.affiliation: Drug Discovery Program, Hughes Institute, St Paul, Minnesota 55113, USA.
authors.forename: R
authors.initials: R
authors.lastname: Vig
authors.forename: T K
authors.initials: TK
authors.lastname: Venkatachalam
authors.forename: F M
authors.initials: FM
authors.lastname: Uckun
mesh_terms: D000409:Alanine / Q000031:analogs & derivatives*; D019380:Anti-HIV Agents / Q000737:chemistry*; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology; D017605:Bromine Compounds / Q000737:chemistry* / Q000494:pharmacology; D002460:Cell Line; D003843:Deoxycytidine Monophosphate / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D054306:Dideoxynucleotides; D016655:HIV Core Protein p24 / Q000378:metabolism; D006801:Humans; D015394:Molecular Structure; D009711:Nucleotides / Q000737:chemistry* / Q000494:pharmacology; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D018119:Stavudine / Q000031:analogs & derivatives*; D013873:Thionucleotides / Q000737:chemistry* / Q000494:pharmacology; D013937:Thymidine Kinase / Q000235:genetics
chemical_list: D019380:Anti-HIV Agents; D000998:Antiviral Agents; D017605:Bromine Compounds; C117033:D4T-5'-(p-bromophenyl methoxyalaninyl phosphate); D054306:Dideoxynucleotides; D016655:HIV Core Protein p24; D009711:Nucleotides; D018894:Reverse Transcriptase Inhibitors; D013873:Thionucleotides; D003843:Deoxycytidine Monophosphate; D018119:Stavudine; D013937:Thymidine Kinase; D000409:Alanine