Open AccessPhosphoramidates as Potent Prodrugs of anti-HIV Nucleotides: Studies in the Amino Region
Author(s) -
Christopher McGuigan,
Dominique Cahard,
Antonio Salgado,
Erik De Clercq,
Jan Balzarini
Publication year - 1996
Publication title -
antiviral chemistry and chemotherapy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.919
H-Index - 51
eISSN - 2040-2066
pISSN - 0956-3202
DOI - 10.1177/095632029600700106
Subject(s) - phosphoramidate , prodrug , nucleoside , nucleotide , moiety , amino acid , biology , zidovudine , nucleoside analogue , biochemistry , in vitro , stereochemistry , amine gas treating , nucleic acid , chemistry , human immunodeficiency virus (hiv) , organic chemistry , virology , viral disease , gene
Novel phosphoramidate derivatives of the anti-HIV nucleoside analogues AZT and d4T have been prepared by phosphorochloridate chemistry. These materials are designed to act as labile membrane-soluble prodrugs of the bio-active free nucleotides. All compounds were fully characterised by a range of methods and were subjected to evaluation in vitro of their anti-HIV efficacy. A notable feature of the current study was that any attempt to replace the amino acid moiety of the phosphoramidate with a simple amine lead to a marked, virtually total loss of activity. Such simple phenyl alkylamino phosphate derivatives of either d4T or AZT inhibit HIV replication at cytotoxic concentrations and have no detectable antiviral selectivity. This clearly highlights the vital role played by the amino acid in the antiviral efficacy of the blocked phosphoramidates.