Synthesis and metabolism of naphthyl substituted phosphoramidate derivatives of stavudine.
The synthesis of naphthylphosphoramidate derivatives of stavudine was achieved using a four-step procedure. The derivatives were subjected to several different enzymes including lipase, esterase, Subtilisin Carlsberg, and Carica papaya, and their hydrolysis rates were determined. Based on the rates of hydrolysis, we were able to differentiate between the chiralities at the phosphorus center of the phosphoramidate compounds. In addition, lipase was found to distinguish between both alpha and beta forms of the compounds. The superior chiral selectivity shown by lipase toward the naphthyl substituted phosphoramidate derivatives is attributed to the restrictive binding pocket of the lipase.
Venkatachalam
T K
TK
Department of Chemistry, Parker Hughes Institute, Roseville, MN 55113, USA.
Qazi
S
S
Uckun
F M
FM
D000577:Amides / Q000737:chemistry* / Q000378:metabolism; D029441:Carica / Q000201:enzymology; D004950:Esterases / Q000737:chemistry; D006868:Hydrolysis; D008049:Lipase / Q000737:chemistry; D015394:Molecular Structure; D009281:Naphthalenes / Q000737:chemistry* / Q000378:metabolism; D010756:Phosphoric Acids / Q000737:chemistry* / Q000378:metabolism; D012697:Serine Endopeptidases / Q000737:chemistry; D018119:Stavudine / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000378:metabolism*; D013237:Stereoisomerism; D013381:Subtilisins / Q000737:chemistry; D013997:Time Factors
D000577:Amides; D009281:Naphthalenes; D010756:Phosphoric Acids; C011067:phosphoramidic acid; D018119:Stavudine; D004950:Esterases; D008049:Lipase; D012697:Serine Endopeptidases; D013381:Subtilisins