title: Hybrids of [TSAO-T]-[foscarnet]: The first conjugate of foscarnet with a non-nucleoside reverse transcriptase inhibitor through a labile covalent ester bond.
abstract: 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.
authors.affiliation: Instituto de Química Médica (C.S.I.C.), Juan de la Cierva 3, E-28006 Madrid, Spain. iqmsv29@iqm.csic.es
authors.forename: Sonsoles
authors.initials: S
authors.lastname: Velázquez
authors.forename: Esther
authors.initials: E
authors.lastname: Lobatón
authors.forename: Erik
authors.initials: E
authors.lastname: De Clercq
authors.forename: Dianna L
authors.initials: DL
authors.lastname: Koontz
authors.forename: John W
authors.initials: JW
authors.lastname: Mellors
authors.forename: Jan
authors.initials: J
authors.lastname: Balzarini
authors.forename: María-José
authors.initials: MJ
authors.lastname: Camarasa
mesh_terms: D002457:Cell Extracts; D045744:Cell Line, Tumor; D024882:Drug Resistance, Viral; D004355:Drug Stability; D017245:Foscarnet / Q000037:antagonists & inhibitors* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D054303:HIV Reverse Transcriptase / Q000378:metabolism*; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D006868:Hydrolysis; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013936:Thymidine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014529:Uridine / Q000031:analogs & derivatives
chemical_list: D002457:Cell Extracts; D018894:Reverse Transcriptase Inhibitors; D013141:Spiro Compounds; D017245:Foscarnet; D054303:HIV Reverse Transcriptase; D013936:Thymidine; C075132:TSAO-T; D014529:Uridine