Synthesis, in Vitro Antiviral Evaluation, and Stability Studies of Novel α-Borano-Nucleotide Analogues of 9-[2-(Phosphonomethoxy)ethyl]adenine and ( R )-9-[2-(Phosphonomethoxy)propyl]adenine

Karine Barral (1) , Stephane Priet (2) , Joséphine Sire (2) , Johan Neyts (3) , Jan Balzarini (3) , Bruno Canard (1) , Karine Alvarez (1)

1 AFMB - Architecture et fonction des Macromolécules Biologiques - UMR 6098
2 UVE - Faculté de Médecine - Unité des Virus émergents [Marseille]
3 KU Leuven - Catholic University of Leuven - Katholieke Universiteit Leuven

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.

Domains: Chemical Sciences; Chemical Sciences; Medicinal Chemistry

Karine Barral, Stephane Priet, Joséphine Sire, Johan Neyts, Jan Balzarini, et al.. Synthesis, in Vitro Antiviral Evaluation, and Stability Studies of Novel α-Borano-Nucleotide Analogues of 9-[2-(Phosphonomethoxy)ethyl]adenine and ( R )-9-[2-(Phosphonomethoxy)propyl]adenine. Journal of Medicinal Chemistry, 2006, 49 (26), pp.7799-7806. ⟨10.1021/jm060030y⟩. ⟨hal-02061667⟩