Synthesis of {[5-(adenin-9-yl)-2-furyl]methoxy}methyl phosphonic acid and evaluations against human adenylate kinases.

Malika Kaci (1) , Jean-Pierre Uttaro (1) , Valérie Lefort (2) , Christophe Mathe (1) , Chahrazade El Amri (2) , Christian Perigaud (1)

1 IBMM - Institut des Biomolécules Max Mousseron [Pôle Chimie Balard]
2 Enzymologie Moléculaire et Fonctionnelle

AMP mimics constitute an important class of therapeutic derivatives to treat diseases where the pool of ATP is involved. A new phosphonate derivative of 9-(5-hydroxymethylfuran-2-yl)adenine was synthesized in a multi-step sequence from commercially available adenosine. Its ability to behave as a substrate of human adenylate kinases 1 and 2 was assessed. The phosphonate was shown to be a moderate but selective substrate of the mitochondrial human AK2, better than well-known antiviral acyclic phosphonates 9-(2-phosphonomethoxyethyl)adenine (PMEA, Adefovir) and (R)-9-(2-phosphonomethoxypropyl)adenine (PMPA, Tenofovir). Putative binding mode within adenylate kinase NMP site revealed by molecular docking in comparison to AMP native substrate allowed to illustrate this selective behavior.

Mots clés: Phosphotransfer; Nucleoside; Phosphonate; Kinase; Adenosine; Analogue/AMP mimics

Domaines: Chimie organique

Malika Kaci, Jean-Pierre Uttaro, Valérie Lefort, Christophe Mathe, Chahrazade El Amri, et al.. Synthesis of {[5-(adenin-9-yl)-2-furyl]methoxy}methyl phosphonic acid and evaluations against human adenylate kinases.. Bioorganic and Medicinal Chemistry Letters, 2014, 24 (17), pp.4227-4230. ⟨10.1016/j.bmcl.2014.07.036⟩. ⟨hal-01061638⟩