Comparison of the antiviral activity of hydrophobic amino acid phosphoramidate monoesters of 2'3'-dideoxyadenosine (DDA) and 3'-azido-3'-deoxythymidine (AZT).
A series of hydrophobic, water soluble and non-toxic amino acid phosphoramidate monoesters of dideoxyadenosine (ddA) and 3'-azido-3'-deoxythymidine were shown to inhibit the replication of HIV-1 in human peripheral blood mononuclear cells (PBMC) from two donors. The tryptophan methyl ester phosphoramidates of AZT and ddA were equally potent (EC50S = 0.3-0.4 microM), while the phenyl methyl ester of ddA was 40- to 100- fold more potent than the AZT derivatives. The alaninyl methyl ester of AZT was found to be 70- fold more potent than the ddA derivative. The methyl amide derivatives were found to be 5-20 fold less active than the methyl esters for the ddA series, while for AZT the derivatives were found to be of similar potency or 60- to 166- fold more potent than the methylesters.
Chang
S L
SL
Department of Medicinal Chemistry, University of Minnesota, Minneapolis 55455, USA.
Griesgraber
G
G
Wagner
C R
CR
D000577:Amides / Q000737:chemistry*; D000596:Amino Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002478:Cells, Cultured; D002855:Chromatography, Thin Layer; D016048:Dideoxyadenosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D009682:Magnetic Resonance Spectroscopy; D010756:Phosphoric Acids / Q000737:chemistry*; D016339:Spectrometry, Mass, Fast Atom Bombardment; D015215:Zidovudine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*
D000577:Amides; D000596:Amino Acids; D000998:Antiviral Agents; D010756:Phosphoric Acids; D015215:Zidovudine; D016048:Dideoxyadenosine; C011067:phosphoramidic acid