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.
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.
Barral
Karine
K
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.
Priet
Stéphane
S
Sire
Joséphine
J
Neyts
Johan
J
Balzarini
Jan
J
Canard
Bruno
B
Alvarez
Karine
K
D000225:Adenine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001880:Boranes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001896:Boron Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002522:Chlorocebus aethiops; D004267:DNA Viruses / Q000187:drug effects; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D009705:Nucleosides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D063065:Organophosphonates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010710:Phosphates; D012328:RNA Viruses / Q000187:drug effects; D013329:Structure-Activity Relationship; D014709:Vero Cells; D014779:Virus Replication / Q000187:drug effects
C516687:9-(2-(boranophosphonomethoxy)ethyl)adenine; C516688:9-(2-(boranophosphonomethoxy)propyl)adenine; D019380:Anti-HIV Agents; D000998:Antiviral Agents; D001880:Boranes; D001896:Boron Compounds; D009705:Nucleosides; D063065:Organophosphonates; D010710:Phosphates; C510710:boranophosphate; D000225:Adenine