title: Enhancing effects of a mono-bromo substitution at the para position of the phenyl moiety on the metabolism and anti-HIV activity of d4T-phenyl methoxyalaninyl phosphate derivatives.
abstract: d4T-5'-[p-Bromophenyl methoxyalaninyl phosphate] (d4T-pBPMAP), a novel phenyl phosphate derivative of 2',3'-didehydro-2',3'-dideoxythymidine (d4T) that has an enhanced ability to undergo hydrolysis due to the electron withdrawing properties of its single bromo substituent at the para-position of the phenyl moiety, was found to yield substantially more of the key metabolite alaninyl d4T monophosphate (A-d4T-MP) than the unsubstituted d4T-5'-phenyl methoxyalaninyl phosphate or para-methoxy substituted d4T-5'-phenyl methoxyalaninyl phosphate. d4T-pBPMAP was tested for its anti-HIV-1 activity in peripheral blood mononuclear cells (PBMNC) and thymidine kinase (TK)-deficient CEM T-cells. d4T-pBPMAP was 12.6-fold more potent than the parent compound d4T in inhibiting p24 production (IC50 values: 44 nM vs 556 nM) and 41.3-fold more potent than d4T in inhibiting the reverse transcriptase (RT) activity (IC50 values: 57 nM vs 2355 nM) in HIV-1-infected TK-deficient CEM cells. Similarly, d4T-pBPMAP was more potent than the unsubstituted or para-methoxy substituted phenyl methoxyalaninyl phosphate derivatives of d4T. d4T-pBPMAP did not exhibit any detectable cytotoxicity to PBMNC or CEM cells at concentrations as high as 10,000 nM. Notably, d4T-pBPMAP was capable of inhibiting the replication of a zidovudine (ZDV/AZT)-resistant HIV-1 strain as well as HIV-2 in PBMNC at nanomolar concentrations. To our knowledge, this is the first demonstration that the potency of the d4T-aryl-phosphate derivatives can be substantially enhanced by introducing a single para-bromo substituent in the aryl moiety.
authors.affiliation: Department of Chemistry, Hughes Institute, Roseville, MN 55113, USA.
authors.forename: T K
authors.initials: TK
authors.lastname: Venkatachalam
authors.forename: H L
authors.initials: HL
authors.lastname: Tai
authors.forename: R
authors.initials: R
authors.lastname: Vig
authors.forename: C L
authors.initials: CL
authors.lastname: Chen
authors.forename: S T
authors.initials: ST
authors.lastname: Jan
authors.forename: F M
authors.initials: FM
authors.lastname: Uckun
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis*; D006801:Humans; D018119:Stavudine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D013329:Structure-Activity Relationship; D015215:Zidovudine / Q000494:pharmacology
chemical_list: D019380:Anti-HIV Agents; D015215:Zidovudine; D018119:Stavudine