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.

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