title: New bis(SATE) prodrug of AZT 5'-monophosphate: in vitro anti-HIV activity, stability, and potential oral absorption.
abstract: The in vitro anti-HIV activity, stability, and potential for oral absorption of a phosphotriester derivative of AZT (zidovudine; 3'-azido-2',3'-deoxythymidine) bearing a new esterase-labile S-acyl-2-thioethyl (SATE) group as transient phosphate protection are reported. The biolabile protection is characterized by the presence of a hydroxyl function in the acyl chain. In accordance with previously reported data in the bis(SATE) prodrug series, the present results demonstrate that the studied bis(hydroxytBuSATE)phosphotriester exerts its biological effects via intracellular delivery of the 5'-monophosphate of AZT. The hydroxyl function confers a high resistance against esterase hydrolysis, and the studied prodrug is able to cross the Caco-2 cell monolayers in intact form, suggesting that its further development as a possible anti-HIV pronucleotide candidate is warranted.
authors.affiliation: Laboratorium voor Farmacotechnologie en Biofarmacie, O & N, Gasthuisberg, K.U. Leuven, B-3000 Leuven, Belgium.
authors.forename: M
authors.initials: M
authors.lastname: Shafiee
authors.forename: S
authors.initials: S
authors.lastname: Deferme
authors.forename: A L
authors.initials: AL
authors.lastname: Villard
authors.forename: D
authors.initials: D
authors.lastname: Egron
authors.forename: G
authors.initials: G
authors.lastname: Gosselin
authors.forename: J L
authors.initials: JL
authors.lastname: Imbach
authors.forename: T
authors.initials: T
authors.lastname: Lioux
authors.forename: A
authors.initials: A
authors.lastname: Pompon
authors.forename: S
authors.initials: S
authors.lastname: Varray
authors.forename: A M
authors.initials: AM
authors.lastname: Aubertin
authors.forename: G
authors.initials: G
authors.lastname: Van Den Mooter
authors.forename: R
authors.initials: R
authors.lastname: Kinget
authors.forename: C
authors.initials: C
authors.lastname: Périgaud
authors.forename: P
authors.initials: P
authors.lastname: Augustijns
mesh_terms: D000284:Administration, Oral; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D018938:Caco-2 Cells; D002851:Chromatography, High Pressure Liquid; D004355:Drug Stability; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D008826:Microbial Sensitivity Tests; D011355:Prodrugs / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D013057:Spectrum Analysis; D015215:Zidovudine / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D019380:Anti-HIV Agents; D011355:Prodrugs; D018894:Reverse Transcriptase Inhibitors; D015215:Zidovudine