Synthesis, anti-human immunodeficiency virus activity and esterase lability of some novel carboxylic ester-modified phosphoramidate derivatives of stavudine (d4T).
We report the design, synthesis and antiviral evaluation of a series of lipophilic, masked phosphoramidate derivatives of the anti-human immunodeficiency virus (HIV) nucleoside analogue d4T, designed to act as membrane-soluble prodrug forms for the free nucleotide. In particular, we report a series of 12 novel compounds with systematic variation in the structure of the carboxylate ester function. In order to rationalize the changes in antiviral action with variation of this moiety we applied our recently developed 31P NMR-based assay for carboxyesterase lability to this series. However, no clear positive correlation emerged, indicating that, at least within this series, factors other than simple esterase lability may be the major determinants of antiviral potency.
McGuigan
C
C
Welsh School of Pharmacy, Cardiff University, UK. mcguigan@cardiff.ac.uk
Sutton
P W
PW
Cahard
D
D
Turner
K
K
O'Leary
G
G
Wang
Y
Y
Gumbleton
M
M
De Clercq
E
E
Balzarini
J
J
D016475:3T3 Cells; D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D043182:Carboxylesterase; D002264:Carboxylic Acids; D002265:Carboxylic Ester Hydrolases / Q000378:metabolism*; D002460:Cell Line; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004951:Esterification; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D015498:HIV-2 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D008214:Lymphocytes / Q000821:virology; D009682:Magnetic Resonance Spectroscopy; D008563:Membrane Lipids / Q000378:metabolism; D051379:Mice; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D012995:Solubility; D018119:Stavudine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013552:Swine; D013937:Thymidine Kinase / Q000172:deficiency / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects
D019380:Anti-HIV Agents; D002264:Carboxylic Acids; D008563:Membrane Lipids; D011355:Prodrugs; D018894:Reverse Transcriptase Inhibitors; D018119:Stavudine; D013937:Thymidine Kinase; D002265:Carboxylic Ester Hydrolases; D043182:Carboxylesterase