Book of Abstracts: Albany 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
Chang G. Peng1
1Department of Chemistry