Norbornane-based nucleoside and nucleotide analogues locked in North conformation

  • Bioorg Med Chem. 2015 Jan 1;23(1):184-91. doi: 10.1016/j.bmc.2014.11.011.
Milan Dejmek  1 ,  Michal Šála  1 ,  Hubert Hřebabecký  1 ,  Martin Dračínský  1 ,  Eliška Procházková  1 ,  Dominika Chalupská  1 ,  Martin Klíma  1 ,  Pavla Plačková  1 ,  Miroslav Hájek  1 ,  Graciela Andrei  2 ,  Lieve Naesens  2 ,  Pieter Leyssen  2 ,  Johan Neyts  2 ,  Jan Balzarini  2 ,  Evzen Boura  1 ,  Radim Nencka  1
Affiliations
  • 1. Gilead Sciences & IOCB Research Centre, Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i., 166 10 Prague 6, Czech Republic.
  • 2. Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, BE-3000 Leuven, Belgium.
PMID: 25435471 DOI: 10.1016/j.bmc.2014.11.011
Abstract

We report on the synthesis of novel conformationally locked nucleoside and nucleotide derivatives, which are structurally closely related to clinically used antivirals such as didanosine and abacavir. As a suitable conformationally rigid substitute of the sugar/pseudosugar ring allowing a permanent stabilization of the nucleoside in North conformation we employed bicyclo[2.2.1]heptane (norbornane) substituted in the bridgehead position with a hydroxymethyl group and in the C-3 position with a nucleobase. Prepared nucleoside derivatives were also converted into appropriate phosphoramidate prodrugs (ProTides) in order to increase delivery of the compounds in the cells. All target compounds were evaluated in a broad Antiviral and cytostatic assay panel.

Keywords
Antiviral; Carbocyclic nucleosides; Norbornane; PI4KIIα; Purines.