Intracellular delivery of nucleoside monophosphates through a reductase-mediated activation process.
On the basis of three different models (namely: ddU, AZT and PMEA), mononucleotide phosphotriester derivatives were designed to be able to liberate the corresponding monophosphate (or phosphonate) inside the cell through a reductase-mediated activation process. It was demonstrated that the use of bis[S-(2-hydroxyethylsulfidyl)-2-thioethyl] esters of ddUMP (11), AZTMP (12) and PMEA (17) resulted in intracellular delivery of the parent monophosphate (or phosphonate). This point was corroborated by observation of an anti-HIV effect of, 11 in various cell lines, for 12 in CEM TK- cells and by the enhanced activity observed for 17. Furthermore, the reported decomposition data in cell extracts fully confirm the validity of this approach and show unambiguously the potential for intracellular reductase-mediated activation of the starting drug.
Puech
F
F
Laboratoire de Chimie Bioorganique, U.R.A. C.N.R.S. n. 488, Université de Montpellier II, Sciences et Techniques du Languedoc, Montpellier, France.
Gosselin
G
G
Lefebvre
I
I
Pompon
A
A
Aubertin
A M
AM
Kirn
A
A
Imbach
J L
JL
D000225:Adenine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D001402:B-Lymphocytes / Q000166:cytology; D002460:Cell Line; D015224:Dideoxynucleosides / Q000378:metabolism / Q000494:pharmacology*; D054306:Dideoxynucleotides; D004952:Esters / Q000138:chemical synthesis / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D063065:Organophosphonates; D010088:Oxidoreductases / Q000378:metabolism*; D011355:Prodrugs / Q000378:metabolism*; D013601:T-Lymphocytes / Q000166:cytology; D013942:Thymine Nucleotides / Q000378:metabolism / Q000494:pharmacology*; D014542:Uridine Monophosphate / Q000031:analogs & derivatives; D015215:Zidovudine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology
D000998:Antiviral Agents; D015224:Dideoxynucleosides; D054306:Dideoxynucleotides; D004952:Esters; D063065:Organophosphonates; D011355:Prodrugs; D013942:Thymine Nucleotides; C083401:2',3'-dideoxyuridine 5'-monophosphate; C057287:3'-azido-3'-deoxythymidine 5'phosphate; D015215:Zidovudine; C053001:adefovir; D014542:Uridine Monophosphate; D010088:Oxidoreductases; D000225:Adenine