Stereochemical influence on lipase-mediated hydrolysis and biological activity of stampidine and other stavudine phosphoramidates.
Stampidine and other halogen substituted stavudine phosphoramidates can be activated by lipase-mediated hydrolysis. The target site for the lipase appears to be the methyl ester group of the L-alanine side chain. Accordingly, the D-amino acid substituted isomers {Rp or Sp}are resistant to lipase-mediated hydrolysis and exhibit substantially less anti-HIV activity. Molecular modeling results indicate that the L-amino acid configured isomers {Rp or Sp} are preferred in the lipase binding pocket.
Venkatachalam
T K
TK
Department of Chemistry, Paradigm Pharmaceuticals, LLC, 2685 Patton Road, St. Paul, MN 55113, USA.
Samuel
P
P
Uckun
F M
FM
D000577:Amides / Q000737:chemistry* / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D054306:Dideoxynucleotides; D006801:Humans; D006868:Hydrolysis; D066298:In Vitro Techniques; D008049:Lipase / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D010756:Phosphoric Acids / Q000737:chemistry* / Q000378:metabolism; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D013056:Spectrophotometry, Ultraviolet; D018119:Stavudine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D013237:Stereoisomerism; D013601:T-Lymphocytes / Q000187:drug effects; D013938:Thymidine Monophosphate / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
D000577:Amides; D054306:Dideoxynucleotides; D010756:Phosphoric Acids; D018894:Reverse Transcriptase Inhibitors; C472384:stampidine; D013938:Thymidine Monophosphate; C011067:phosphoramidic acid; D018119:Stavudine; D008049:Lipase