Structure-activity relationships of β-hydroxyphosphonate nucleoside analogues as cytosolic 5′-nucleotidase II potential inhibitors: Synthesis, in vitro evaluation and molecular modeling studies.

Maïa Meurillon (1) , Zsuzsanna Marton (2) , Audrey Hospital (1) , Lars Petter Jordheim (3) , Jérôme Béjaud (1) , Corinne Lionne (2) , Charles Dumontet (3) , Christian Perigaud (1) , Laurent Chaloin (2) , Suzanne Peyrottes (1)

1 IBMM - Institut des Biomolécules Max Mousseron [Pôle Chimie Balard]
2 IRIM - Institut de Recherche en Infectiologie de Montpellier
3 UNICANCER/CRCL - Centre de Recherche en Cancérologie de Lyon

The cytosolic 5′-nucleotidase II (cN-II) has been proposed as an attractive molecular target for the development of novel drugs circumventing resistance to cytotoxic nucleoside analogues currently used for treating leukemia and other malignant hemopathies. In the present work, synthesis of β-hydroxyphosphonate nucleoside analogues incorporating modifications either on the sugar residue or the nucleobase, and their in vitro evaluation towards the purified enzyme were carried out in order to determine their potency towards the inhibition of cN-II. In addition to the biochemical investigations, molecular modeling studies revealed important structural features for binding affinities towards the target enzyme.

Mots clés: Nucleotides; Enzyme inhibitors; Phosphonate; Leukemia

Domaines: Chimie organique

Maïa Meurillon, Zsuzsanna Marton, Audrey Hospital, Lars Petter Jordheim, Jérôme Béjaud, et al.. Structure-activity relationships of β-hydroxyphosphonate nucleoside analogues as cytosolic 5′-nucleotidase II potential inhibitors: Synthesis, in vitro evaluation and molecular modeling studies.. European Journal of Medicinal Chemistry, 2014, 77 (April 2014), pp.18-37. ⟨10.1016/j.ejmech.2014.02.055⟩. ⟨hal-00956313⟩