Synthesis, in vitro antiviral evaluation, and stability studies of novel alpha-borano-nucleotide analogues of 9-[2-(phosphonomethoxy)ethyl]adenine and (R)-9-[2-(phosphonomethoxy)propyl]adenine

Karine Barral; Stéphane Priet; Joséphine Sire; Johan Neyts; Jan Balzarini; Bruno Canard; Karine Alvarez

doi:10.1021/jm060030y

Synthesis, in vitro antiviral evaluation, and stability studies of novel alpha-borano-nucleotide analogues of 9-[2-(phosphonomethoxy)ethyl]adenine and (R)-9-[2-(phosphonomethoxy)propyl]adenine

J Med Chem. 2006 Dec 28;49(26):7799-806. doi: 10.1021/jm060030y.

Authors

Karine Barral¹, Stéphane Priet, Joséphine Sire, Johan Neyts, Jan Balzarini, Bruno Canard, Karine Alvarez

Affiliation

¹ Laboratoire d'Architecture et Fonction des Macromolécules Biologiques, UMR CNRS 6098, Universités Aix-Marseille I et II, Parc scientifique de Luminy, 163 av. de Luminy, 13288 Marseille Cedex 9, France.

PMID: 17181162
DOI: 10.1021/jm060030y

Abstract

We describe here the synthesis of 9-[2-(boranophosphonomethoxy)ethyl]adenine (6a) and (R)-9-[2-(boranophosphonomethoxy)propyl]adenine (6b), the first alpha-boranophosphonate nucleosides in which a borane (BH3) group substitutes one nonbridging oxygen atom of the alpha-phosphonate moiety. H-phosphinates 5a and 5b and alpha-boranophosphonates 6a and 6b were evaluated for their in vitro activity against human immunodeficiency virus (HIV) infected cells and against a panel of DNA or RNA viruses. Compounds 5a, 5b, 6a, and 6b exhibited no significant antiviral activity in vitro and cytotoxicity. To measure the chemical and enzymatic stabilities of the target compounds 6a and 6b, kinetic data of decomposition for derivatives 5a, 5b, 6a, 6b, and standard compounds were studied at 37 degrees C in several media. The alpha-boranophosphonates 6a and 6b were metabolized in culture medium into H-phosphinates 5a and 5b, with half-live values of 5.3 h for 6a and 1.3 h for 6b.

Publication types

Evaluation Study
Research Support, Non-U.S. Gov't

MeSH terms

Adenine / analogs & derivatives*
Adenine / chemical synthesis
Adenine / chemistry
Adenine / pharmacology
Animals
Anti-HIV Agents / chemical synthesis*
Anti-HIV Agents / chemistry
Anti-HIV Agents / pharmacology
Antiviral Agents / chemical synthesis
Antiviral Agents / chemistry
Antiviral Agents / pharmacology*
Boranes / chemical synthesis*
Boranes / chemistry
Boranes / pharmacology
Boron Compounds / chemical synthesis*
Boron Compounds / chemistry
Boron Compounds / pharmacology*
Chlorocebus aethiops
DNA Viruses / drug effects
HIV-1 / drug effects
Humans
In Vitro Techniques
Nucleosides / chemical synthesis*
Nucleosides / chemistry
Nucleosides / pharmacology
Organophosphonates / chemical synthesis*
Organophosphonates / chemistry
Organophosphonates / pharmacology
Phosphates
RNA Viruses / drug effects
Structure-Activity Relationship
Vero Cells
Virus Replication / drug effects

Substances

9-(2-(boranophosphonomethoxy)ethyl)adenine
9-(2-(boranophosphonomethoxy)propyl)adenine
Anti-HIV Agents
Antiviral Agents
Boranes
Boron Compounds
Nucleosides
Organophosphonates
Phosphates
boranophosphate
Adenine