Lactate cannot substitute for alanine in d4T-based anti-HIV nucleotide prodrugs--despite efficient esterase-mediated hydrolysis.
As part of our on-going effort to deliver masked phosphates of antiviral nucleosides inside living cells we have previously discovered that amino acid-derived phosphoramidates are particularly effective. Here we report that lactate analogues, with a simple change of bridging nitrogen for oxygen, are virtually inactive as antiviral agents and apparently do not achieve intracellular nucleoside phosphate delivery.
McGuigan
C
C
Welsh School of Pharmacy, Cardiff University, UK. mcguigan@cardiff.ac.uk
Cahard
D
D
Ballatore
C
C
Siddiqui
A
A
De Clercq
E
E
Balzarini
J
J
D000409:Alanine; D019380:Anti-HIV Agents / Q000494:pharmacology*; D004950:Esterases / Q000494:pharmacology*; D006868:Hydrolysis; D019344:Lactic Acid; D009711:Nucleotides / Q000494:pharmacology*; D011355:Prodrugs / Q000378:metabolism / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D019380:Anti-HIV Agents; D009711:Nucleotides; D011355:Prodrugs; D019344:Lactic Acid; D004950:Esterases; D000409:Alanine