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Nucleic Acids Research 2004 32(12):3642-3650; doi:10.1093/nar/gkh667
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Published online 9 July 2004

Nucleic Acids Research, Vol. 32 No. 12 © Oxford University Press 2004; all rights reserved

Synthesis and characterization of oligonucleotides containing conformationally constrained bicyclo[3.1.0]hexane pseudosugar analogs

Martin A. Maier, Yongseok Choi1, Hans Gaus, Joseph J. Barchi, Jr1, Victor E. Marquez1,* and Muthiah Manoharan

Isis Pharmaceuticals, Inc., 2292 Faraday Avenue, Carlsbad, CA 92008, USA and 1 Laboratory of Medicinal Chemistry, Center for Cancer Research, NCI-Frederick, NIH, 376 Boyles St, Frederick, MD 21702, USA

* To whom correspondence should be addressed. Tel: +1 301 846 5954 3; Fax: +1 301 846 6033; Email: marquezv{at}dc37a.nci.nih.gov
Correspondence may also be addressed to Muthiah Manoharan at present address: Alnylam Pharmaceuticals, 300 Third Street, Cambridge, MA 02142, USA. Tel: +1 617 551 8319; Fax: +1 617 551 8102; Email: mmanoharan{at}alnylam.com

Received April 8, 2004; Revised May 28, 2004; Accepted June 5, 2004

Oligodeoxyribonucleotides containing pseudorotationally locked sites derived from bicyclo[3.1.0]hexane pseudosugars have been synthesized using adenosine, thymidine and abasic versions of North- and South-methanocarba nucleosides. The reaction conditions for coupling and oxidation steps of oligonucleotide synthesis have been investigated and optimized to allow efficient and facile solid-phase synthesis using phosphoramidite chemistry. Our studies demonstrate that the use of iodine for P(III) to P(V) oxidation leads to strand cleavage at the sites where the pseudosugar is North. In contrast, the same cleavage reaction was not observed in the case of South pseudosugars. Iodine oxidation generates a 5'-phosphate oligonucleotide fragment on the resin and releases the North pseudosugar into the solution. This side reaction, which is responsible for the extremely low yields observed for the incorporation of the North pseudosugar analogs, has been studied in detail and can be easily overcome by replacing iodine with t-butylhydroperoxide as oxidant.


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