Book of Abstracts: Albany 2005

category image Volume 22
No. 6
June 2005

Synthesis of a ?taller? 2?,5?-linked Ribonucleic Acid: 2?-α-C-hydroxymethyl 2?,5?-linked RNA

Our research group has had a long research interest in the physicochemical and biochemical properties of 2',5'-linked ribonucleic acids (2',5'-RNA) -- a regioisomer of the more commonly occurring RNA (1, 2). 2',5'-Phosphodiester linkages are produced in biological processes such as pre-mRNA splicing (leading to lariat RNAs) and during interferon response (leading to the synthesis of 2',5'-linked adenylic acid). Recent studies have described the remarkable stability of hairpins containing 2', 5'-linked RNA loops (all 2',5'-linked UUCG loop), and hence represent promising motifs for therapeutic applications (3, 4).

In addition, the 2'5'-linked nucleotides are useful structural units in the study of nucleic acid hybridization. The distinct structural features of 2',5'-RNAs is their duplexes (2',5'-RNA:2',5'-RNA) favor A-type conformations with C2' endo sugar puckers, whereas the native RNA duplexes (RNA:RNA) exhibit A-type structures with dominant C3' endo pucker form (5). Molecular modeling studies have indicated that the intra phosphate-phosphate distance in the minor groove of duplexes containing 2'5'-RNA is shorter compared to the RNA duplex (2). This shorter P-P distance may be a factor that destabilizes duplexes containing 2',5'-linked nucleotide residues (2, and refs. therein). This prompted us to incorporate a methylene (-CH2) bridge between the C2' and O2' atoms of 2',5'-RNA, thus obtaining 2'-α-C-hydroxymethyl 2',5'-linked RNA. This modification has been studied previously in the context of the native 3',5'-linked RNA (free 2'-CH2OH) (6, 7). It is expected that this 2'-α-C-hydroxymethyl 2',5'-linkage will reduce intermolecular P-P charge repulsions and benefit duplex and hairpin loop formation. Herein, we describe the synthesis of 2'-α-C-hydroxymethyl-2',5'-linked oligoribonucleotides and their physicochemical properties.

References and Footnotes
  1. Giannaris, P. A. and M. J. Damha. Nucleic Acids Res. 21, 4742-4749 (1993).
  2. Wasner, M. et al. Biochemistry 37, 7478-7486 (1998).
  3. Hannoush, R. N. and M. J. Damha. J. Am. Chem. Soc. 123, 12368-12374 (2001).
  4. Hannoush, R. N. et al. Nucleic Acid Res. 32, 6164-6175 (2004).
  5. Premraj, B. J., S. Raja, and N. Yathindra. Biophys. Chem. 95, 253-272 (2002).
  6. Schmit, C. et al. Bioorg. Med. Chem. Lett. 4:1969-1974 (1994).
  7. Pavey, J. B. J. et al. Tetrahedron Lett. 39, 6967-6970 (1998).

Chang G. Peng1
Rami N. Hannoush1,2
Masad J. Damha1,*

1Department of Chemistry
McGill University
801 Sherbrooke St. West
Montreal, QC, Canada, H3A 2K6
2Current address:
Department of Chemistry and Chemical Biology
Harvard University
12 Oxford Street
Cambridge, MA 02138 (USA)

*Phone: +1-514-398-7522
Fax: +1-514-398-3797
Email: masad.damha@mcgill.ca