or-anomeric uridylates, a-rug and U-rUl2, have been synthesized for the first time. These non natural a-oligoribonucleotidee strongly resist to enzymatic degradation and bind to complementary RNA strands.
During the last few years, exogenous oligonucleotides binding specifically to complementary sequences of nucleic acids (RNA or DNA) through base pairing have been widely used In vitro as artifioial regulators for gene expression1'3 . Conceivable chemotherapeutic applications predicated on sequence specific hybridization require antlsense oligonucleotldes that are resistant to In vlvo degradation by nucleases and strongly bind to their target mRNA. Thus a new class of nuclease resistant oligodeoxynucleotides oonsisting exclusively of u-anomeric nucleotide units has been recently developed in our laboratory4. Furthermore it is generally believed that the order of increaeing stability of oligonucleotide.polynucleotide complexes is DNA.DNA < DNA.RNA < RNA. RNA3 . So, we anticipated that hitherto unknown a-anomeric oligoribonucleotides would combine nuclease resistance and improved binding capacity to their complementary strand.
In this communication, we describe for the first time the synthesis on a solid support of a-hexauridylate (a-r&) and a-dodecauridylate (a-rUl2) and report our results related to their stability towards exo-and endonucleases and their binding properties.
a-uridine & was prepared acoordlng to an already published procedure5. The 5'and 2'-hydroxy functions on the rlbose moelty were respectively protected by the 4,4'-dimethoxytrityl group (DMTr)6 and the tert-butyldimethylsilyl group (TBDMS)' (Figure 1). For the 8electlve monosilylation of ribonucleosidecl, we have applied the procedure described by Ogilvie involving nitrate ion catalysed action of 1.1 molar equivelent of tert-butyldimethylsilyl chloride (TBDMS-Cl) in THFS. In contrast to the results observed in the P series, the TBDMS group was shown to be selectively lntroduoed at the J'position of the 5'-dimethoxytrityl-c+uridlne 1. When the reaction was carried out in pyridine in the presence of fmidazoleg, a mixture of 2'-TBDMS and 3'-TBDMS derivatives 3 and 5 was obtained in nearly equal amount. These two isomers were isolated by silica gel column chromatography and oharacterized by high field 'Ii-NMR spectroscopic decoupling experImentslo.