Effect of alkyl groups on the cellular hydrolysis of stavudine phosphoramidates.
We examined the effect of cellular metabolism of three alkyl-substituted amino acid ester phosphoramidate derivatives of stavudine in different cell lines. Marked cell-to-cell differences were found in both the rate of hydrolysis and chiral selectivity. This selectivity implies that different enzymes may be involved in the metabolism of these compounds depending on the cell type involved. Notably, both the methyl and ethyl substituted derivatives underwent hydrolysis in presence of various cell lines, whereas the tert-butyl substituted compound was resistant to hydrolysis implying that steric hindrance associated with this group along with electron density may play a key role in the hydrolysis profile of these compounds. Additionally we found this mimicked the hydrolysis profiles obtained for bacterial enzymes. Furthermore, our results suggest that the site of attack of the cellular enzymes is confined to the ester side chain of the molecule. This result is also consistent with our earlier observation using bacterial enzymes as well as using 'd' isomers.
Venkatachalam
T K
TK
Department of Chemistry, Parker Hughes Institute, Roseville, MN 55119, USA.
Sarquis
M
M
Qazi
S
S
Uckun
F M
FM
D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001665:Binding Sites; D019556:COS Cells; D002460:Cell Line; D002522:Chlorocebus aethiops; D004950:Esterases / Q000737:chemistry; D006801:Humans; D006868:Hydrolysis / Q000187:drug effects; D019169:Jurkat Cells; D008049:Lipase / Q000737:chemistry; D051379:Mice; D015394:Molecular Structure; D010447:Peptide Hydrolases / Q000737:chemistry; D010756:Phosphoric Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018119:Stavudine / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
D000577:Amides; D010756:Phosphoric Acids; C011067:phosphoramidic acid; D018119:Stavudine; D004950:Esterases; D008049:Lipase; D010447:Peptide Hydrolases