Hybrids of [TSAO-T]−[Foscarnet]:  The First Conjugate of Foscarnet with a Non-nucleoside Reverse Transcriptase Inhibitor through a Labile Covalent Ester Bond

• Published in: Journal of medicinal chemistry Vol. 47; no. 13; pp. 3418 - 3426
• Main Authors: Velázquez, Sonsoles, Lobatón, Esther, De Clercq, Erik, Koontz, Dianna L, Mellors, John W, Balzarini, Jan
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 17-06-2004
• Subjects: Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Biological and medical sciences; Cell Extracts; Cell Line, Tumor; Drug Resistance, Viral; Drug Stability; Foscarnet - antagonists & inhibitors; Foscarnet - chemical synthesis; Foscarnet - chemistry; Foscarnet - pharmacology; HIV Reverse Transcriptase - metabolism; HIV-1 - drug effects; Humans; Hydrolysis; Medical sciences; Pharmacology. Drug treatments; Reverse Transcriptase Inhibitors - chemical synthesis; Reverse Transcriptase Inhibitors - chemistry; Reverse Transcriptase Inhibitors - pharmacology; Spiro Compounds - chemical synthesis; Spiro Compounds - chemistry; Spiro Compounds - pharmacology; Structure-Activity Relationship; Thymidine - analogs & derivatives; Thymidine - chemical synthesis; Thymidine - chemistry; Thymidine - pharmacology; Silicon Organic compounds; Non nucleoside compound; Organic siloxane; Phosphorus Organic compounds; Structure activity relation; Carboxylic acid; Reverse transcriptase inhibitor; Bicyclic compound; Antiviral; Chemical synthesis; Oxygen sulfur heterocycle; Treatment resistance; Enzyme; Transferases; Foscarnet sodium; Retroviridae; Enzyme inhibitor; Sultone; Organic phosphonate; Lentivirus; In vitro; RNA-directed RNA polymerase; Spiran; Virus; Nucleotidyltransferases; Covalent bond; Pyrimidine derivatives; Human immunodeficiency virus; Conjugated compound
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm031045o

This paper describes the first example of combination of non-nucleoside reverse transcriptase inhibitors such as TSAO derivatives and foscarnet (PFA) in a single molecule through a labile covalent ester bond. The essential criteria in the design of these hybrids [TSAO-T]−[PFA] was to explore if the conjugation of foscarnet with the highly lipophilic TSAO derivative may facilitate the penetration of the conjugates through the cell membrane and if the hybrids escape extracellular hydrolysis and regenerate the parent inhibitors intracellulary. Several [TSAO-T]−[PFA] conjugates proved markedly inhibitory to HIV-1. Some of them also showed potent activity against PFA-resistant HIV-1 strains but fewer had detectable inhibitory activity against TSAO-resistant HIV-1 strains. These results indicated a pivotal role of the TSAO component of the hybrid but not the PFA component in the activity of the conjugates. Moreover, stability studies of the [TSAO-T]−[PFA] conjugates demonstrated that the compounds were stable in PBS whereas some of the conjugates regenerated the parent inhibitors in extracts from CEM cells.