Synthesis and biological evaluation of conformationally restricted adenine bicycloribonucleosides

0448379 - ÚOCHB 2016 RIV GB eng J - Journal Article
Hřebabecký, Hubert - Procházková, Eliška - Šála, Michal - Plačková, Pavla - Tloušťová, Eva - Barauskas, O. - Lee, Y. J. - Tian, Y. - Mackman, R. - Nencka, Radim
Synthesis and biological evaluation of conformationally restricted adenine bicycloribonucleosides.
Organic & Biomolecular Chemistry. Roč. 13, č. 35 (2015), s. 9300-9313. ISSN 1477-0520. E-ISSN 1477-0539
R&D Projects: GA ČR GPP207/12/P625; GA ČR GA15-09310S; GA ČR GA13-24880S; GA MV VG20102015046
Institutional support: RVO:61388963
Keywords : nucleic acid analogs * nucleoside triphosphates * sugar ring
Subject RIV: CC - Organic Chemistry
Impact factor: 3.559, year: 2015
http://pubs.rsc.org/en/content/articlepdf/2015/ob/c5ob00987a

We prepared a novel series of conformationally restricted bicyclonucleosides and nucleotides. The synthetic approach employed a ring closing metathesis to provide access to both 6 and 7 membered saturated and unsaturated rings linking the 3' to 5' methylene groups of the sugar. The bicyclonucleosides were also transformed to the corresponding phosphoramidate prodrugs by an innovative one-pot protocol of boronate ester protection, coupling of the phosphoryl chloridate and deprotection of the boronate. A similar strategy was also employed for the synthesis of the corresponding monophosphates as crucial intermediates for the synthesis of selected triphosphates. The biological properties of the nucleosides and monophosphate prodrugs were assessed for antiviral and cytostatic activities in cell based assays whilst the triphosphates were evaluated in enzymatic assays. The lack of significant effects suggests that the linkage of the 3' to 5' via a ring system and the subsequent conformational restriction of the ribose ring to the South conformation are incompatible with the kinases and polymerases that recognize nucleosides and their metabolites.
Permanent Link: http://hdl.handle.net/11104/0250113