title: Chemoenzymatic syntheses and anti-HIV-1 activity of glucose-nucleoside conjugates as prodrugs.
abstract: Phosphodiester linked conjugates of various nucleosides such as d4U, d4T, IdUrd, ddI, ddA, virazole, ara-A, and ara-C containing a glucosyl moiety have been described. These compounds were designed to act as prodrugs, where the corresponding 5'-monophosphates may be generated intracellularly. The synthesis of the glycoconjugates was achieved in good yields by condensation of a glucosyl phosphoramidite 7 with nucleosides in the presence of an activating agent. It was demonstrated that the glucose conjugates improve the water solubility of the nucleoside analogues, for example, up to 31-fold for the ara-A conjugate compared to that of ara-A alone. The new conjugates were tested for their anti-HIV-1 activity in human lymphocytes. These derivatives offer a convenient design for potential prodrug candidates with the possibility of improving the physicochemical properties and therapeutic activity of nucleoside analogues.
authors.affiliation: Departamento de Química Orgánica e Inorgánica and Instituto Universitario de Biotecnología de Asturias, Universidad de Oviedo, 33006-Oviedo (Asturias), Spain.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Rodríguez-Pérez
authors.forename: Susana
authors.initials: S
authors.lastname: Fernández
authors.forename: Yogesh S
authors.initials: YS
authors.lastname: Sanghvi
authors.forename: Mervi
authors.initials: M
authors.lastname: Detorio
authors.forename: Raymond F
authors.initials: RF
authors.lastname: Schinazi
authors.forename: Vicente
authors.initials: V
authors.lastname: Gotor
authors.forename: Miguel
authors.initials: M
authors.lastname: Ferrero
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D005947:Glucose / Q000737:chemistry*; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology; D015497:HIV-1 / Q000254:growth & development; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000821:virology; D009705:Nucleosides / Q000138:chemical synthesis* / Q000494:pharmacology; D010755:Organophosphates / Q000737:chemistry; D009943:Organophosphorus Compounds / Q000737:chemistry*; D011355:Prodrugs / Q000138:chemical synthesis* / Q000494:pharmacology; D012995:Solubility; D013237:Stereoisomerism; D014867:Water
chemical_list: D019380:Anti-HIV Agents; D009705:Nucleosides; D010755:Organophosphates; D009943:Organophosphorus Compounds; D011355:Prodrugs; C434331:phosphoramidite; D014867:Water; D005947:Glucose