Synthesis and in vitro evaluation of S-acyl-3-thiopropyl prodrugs of Foscarnet.
A new enzyme-labile group called S-acyl-3-thiopropyl group (SATP) has been synthesized from allylic esters of phosphonate. After demonstration of the enzyme-labile character of the SATP in cellular extracts, it has been introduced onto the phosphonate moiety of PFA (Foscarnet) to obtain potential lipophilic prodrugs. To ponder the lipophilicity of the triesters of PFA, esters of monomethylether of polyethyleneglycols and of thioglycerol were introduced on the PFA carboxylate moiety. The SATP groups were introduced in an attempt to deliver PFA after bioactivation inside the cells. The PFA prodrugs were evaluated in vitro for their activity against human immunodeficiency viruses (HIV-1 and HIV-2).
Gagnard
Valérie
V
Laboratoire de Chimie Biomoléculaire, UMR 5032, Université Montpellier II,ENSCM, 8 rue de l'Ecole Normale, 34296, Montpellier Cedex 5, France.
Leydet
Alain
A
Morère
Alain
A
Montero
Jean-Louis
JL
Lefèbvre
Isabelle
I
Gosselin
Gilles
G
Pannecouque
Christophe
C
De Clercq
Erick
E
D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002264:Carboxylic Acids / Q000737:chemistry / Q000378:metabolism; D005069:Evaluation Studies as Topic; D017245:Foscarnet / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D005990:Glycerol / Q000031:analogs & derivatives* / Q000737:chemistry; D015497:HIV-1 / Q000187:drug effects; D015498:HIV-2 / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D063065:Organophosphonates / Q000378:metabolism; D011092:Polyethylene Glycols / Q000737:chemistry; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013438:Sulfhydryl Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D019380:Anti-HIV Agents; D000998:Antiviral Agents; D002264:Carboxylic Acids; D063065:Organophosphonates; D011355:Prodrugs; D013438:Sulfhydryl Compounds; D017245:Foscarnet; D011092:Polyethylene Glycols; C009465:thioglycerol; D005990:Glycerol