Improved hybridisation potential of oligonucleotides comprising O-methylated anhydrohexitol nucleoside congeners.
The hybridising potential of anhydrohexitol nucleoside analogues (HNAs) is well documented, but tedious synthesis of the monomers hampers their development. In a search for better analogues, the synthesis of two new methylated anhydrohexitol congeners 1 and 2 was accomplished and the physico-chemical properties of their respective oligomers were evaluated. Generally, oligonucleotides (ONs) containing the 3'-O-methyl derivative 1 showed a small increase in thermal stability towards complementary sequences as compared to HNA. Compared to the altritol modification, 3'-O-methylation seems to cause a small decrease in thermal stability of duplexes, especially when targeting RNA. These results suggest the possibility of derivatisation of the 3'-hydroxyl group of altritol-containing congeners without significantly affecting the thermal stability of the duplexes. The methyl glycosidic analogues 2 likewise increased the affinity for RNA in comparison with well-known HNA, while at the same time being economically more favorable monomers. However, homopolymers of 2 displayed self-pairing, but not so homopolymers of 1. Upon incorporation of the hexitols within RNA sequences in an effort to induce a beneficial pre-organised structure, the positive effect of the 3'-O-methyl derivative 1 proved larger than that of 2.
Van Aerschot
A
A
Laboratory of Medicinal Chemistry, Rega Institute for Medical Research, Katholieke Universiteit Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium. arthur.vanaerschot@rega.kuleuven.ac.be
Meldgaard
M
M
Schepers
G
G
Volders
F
F
Rozenski
J
J
Busson
R
R
Herdewijn
P
P
D008745:Methylation; D009693:Nucleic Acid Hybridization / Q000379:methods*; D016376:Oligonucleotides, Antisense / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism*; D011131:Polyribonucleotides / Q000378:metabolism; D012313:RNA / Q000378:metabolism; D020871:RNA Stability; D013402:Sugar Alcohols / Q000378:metabolism*
D016376:Oligonucleotides, Antisense; D011131:Polyribonucleotides; D013402:Sugar Alcohols; C042890:altritol; D012313:RNA