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Nucleic Acids Research, 1995, Vol. 23, No. 21 4434-4442
© 1995

Articles

Synthesis of 2'–modified nucleotides and their incorporation into hammerhead ribozymes

Leonld Beielman, Alexander Karpeisky, Jasenka Matulic-Adamic, Peter Haeberli, David Sweedler and Nassim Usman*

Department of Chemistry and Biochemiostry, Ribozyme Pharmaceuticals Inc., 2950 Wildemess Place, Boulder, CO 80301, USA

*To whom correspondence should be addressed

Received July 5, 1995. Accepted September 19, 1995.

Several 2'-modifled ribonucleoside phosphoramldites have been prepared for structure-activity studies of the hammerhead ribozyme. The aim of these studies was to design and synthesize catalytically active and nuclease-resistant ribozymes. Synthetic schemes for stereosetective synthesis of the R isomer of 2'-deoxy-2'-C-ally1 uridine and cytidine phosphoramidites, based on the Keck allylatlon procedure, were developed. Protection of the 2'-amino group in 2V-deoxy-2'-aminourldine was optimized and a method for the convenient preparation of 5'/O-dimethoxytrltyl- 2'-deoxy-2'-phthalimidourldlne 3'–0(2-cyanoethyl- A/,W-dlisopropylphosphoramidrte) was developed. During the attempted preparation of the 2'–O-f-butyldimethylsilyl- 3'–O-phosphoramldite of arabinouridine a reversed regioselectivity in the sllylatlon reaction,compared with the published procedure, was observed, as well as the unexpected formation of the 2,2'-anhydronucleoslde. A possible mechanism for this cyclization is proposed. The synthesis of 2'-deoxy-2'-methylene and 2'-deoxy-2'-difluoromethylene uridine phosphoramidites is described. Based on a ‘5-ribose' model for essential 2'-hydroxyls In the hammerhead ribozyme these 2'-modrfied monomers were incorporated at positions U4 and/or U7 of the catalytic core. A number of these ribozymes had almost wild-type catalytic activity and improved stability in human serum, compared with an all-RNA molecule.


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