Synthesis and in vitro evaluation of S-acyl-3-thiopropyl prodrugs of Foscarnet

• Published in: Bioorganic & medicinal chemistry Vol. 12; no. 6; pp. 1393 - 1402
• Main Authors: Gagnard, Valérie, Leydet, Alain, Morère, Alain, Montero, Jean-Louis, Lefèbvre, Isabelle, Gosselin, Gilles, Pannecouque, Christophe, De Clercq, Erick
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 15.03.2004; Elsevier Science; Elsevier
• Subjects: Anti-HIV Agents - chemical synthesis; Anti-HIV Agents - chemistry; Anti-HIV Agents - pharmacology; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Antiviral Agents - chemical synthesis; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Biological and medical sciences; Calculated logP; Carboxylic Acids - chemistry; Carboxylic Acids - metabolism; Chemical Sciences; Evaluation Studies as Topic; Foscarnet; Foscarnet - analogs & derivatives; Foscarnet - chemical synthesis; Foscarnet - pharmacology; Glycerol - analogs & derivatives; Glycerol - chemistry; HIV-1 - drug effects; HIV-1 and HIV-2; HIV-2 - drug effects; Humans; In Vitro Techniques; Medical sciences; Organic chemistry; Organophosphonates - metabolism; Pharmacology. Drug treatments; Polyethylene Glycols - chemistry; Prodrugs; Prodrugs - chemical synthesis; Prodrugs - chemistry; Prodrugs - pharmacology; S-acyl-3-thiopropyl; Sulfhydryl Compounds - chemical synthesis; Sulfhydryl Compounds - chemistry; Sulfhydryl Compounds - pharmacology; Calculated logP; Foscarnet; S-acyl-3-thiopropyl; Prodrugs; HIV-1 and HIV-2; Organic hydroxysulfide; HIV-1 virus; Enzyme; Transferases; Foscarnet sodium; Retroviridae; Enzyme inhibitor; Lipophily; Organic phosphonate; Prodrug; Lentivirus; In vitro; Phosphorus Organic compounds; HIV-2 virus; Virus; Lipophilic compound; Ester; Nucleotidyltransferases; Structure activity relation; Thioester; Antiviral; Human immunodeficiency virus; Chemical synthesis; Physicochemical properties
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2004.01.017

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). The PFA prodrugs were evaluated in vitro for their activity against human immunodeficiency viruses (HIV-1 and HIV-2).