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

Abstract

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.

• Authors: Maïa Meurillon, Zsuzsanna Marton, Audrey Hospital, Lars Petter Jordheim, Jérôme Béjaud, Corinne Lionne, Charles Dumontet, Christian Périgaud, Laurent Chaloin, Suzanne Peyrottes
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 77 Pg. 18-37 (Apr 22 2014) ISSN: 1768-3254 [Electronic] France
• PMID: 24607586 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Chemical References

• Enzyme Inhibitors
• Nucleosides
• Organophosphonates
• 5'-Nucleotidase
• NT5C2 protein, human

Topics

• 5'-Nucleotidase (antagonists & inhibitors, metabolism)
• Dose-Response Relationship, Drug
• Enzyme Inhibitors (chemical synthesis, chemistry, pharmacology)
• Humans
• Models, Molecular
• Molecular Conformation
• Nucleosides (chemical synthesis, chemistry, pharmacology)
• Organophosphonates (chemical synthesis, chemistry, pharmacology)
• Structure-Activity Relationship