Effect of change in nucleoside structure on the activation and antiviral activity of phosphoramidate derivatives.
Changing the nucleoside group of a series of phosphoramidate derivatives affects the enzyme mediated hydrolysis rate of the compounds. d4T and AZT-substituted analogs were activated by enzymes such as lipases, esterases, and proteases. On the other hand, 3dT-substituted derivatives were comparatively less prone to hydrolysis under similar experimental conditions. From the experimental results, we propose that the most preferable nucleoside group for enzyme activation is d4T rather than AZT or 3dT. Additionally, we also observed that depending on the enzymes used the chiral selectivity of the enzymes for the phosphorus center of these phosphoramidate derivatives differed, demonstrating the importance of the nucleoside structure for this class of compounds.
Venkatachalam
T K
TK
Department of Chemistry, Parker Hughes Institute, 2699 Patton Road, Roseville, MN 55113, USA.
Samuel
P
P
Qazi
S
S
Uckun
F M
FM
D000577:Amides / Q000737:chemistry* / Q000627:therapeutic use*; D000818:Animals; D019380:Anti-HIV Agents / Q000737:chemistry* / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D054306:Dideoxynucleotides; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000627:therapeutic use; D004950:Esterases / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008049:Lipase / Q000378:metabolism; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism; D008826:Microbial Sensitivity Tests; D008968:Molecular Conformation; D010447:Peptide Hydrolases / Q000378:metabolism; D019800:Phenol / Q000737:chemistry; D010756:Phosphoric Acids / Q000737:chemistry* / Q000627:therapeutic use*; D018119:Stavudine / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013938:Thymidine Monophosphate / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D015215:Zidovudine / Q000031:analogs & derivatives / Q000737:chemistry* / Q000627:therapeutic use*
D000577:Amides; D019380:Anti-HIV Agents; D054306:Dideoxynucleotides; D004791:Enzyme Inhibitors; D010756:Phosphoric Acids; C472384:stampidine; D019800:Phenol; D013938:Thymidine Monophosphate; D015215:Zidovudine; C011067:phosphoramidic acid; D018119:Stavudine; D004950:Esterases; D008049:Lipase; D010447:Peptide Hydrolases