ABSTRACT
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.
Subject(s)
Nucleic Acid Hybridization/methods , Oligonucleotides, Antisense/chemistry , Oligonucleotides, Antisense/metabolism , Sugar Alcohols/metabolism , Methylation , Oligonucleotides, Antisense/chemical synthesis , Polyribonucleotides/metabolism , RNA/metabolism , RNA StabilityABSTRACT
1,5-Anhydrohexitol nucleoside congeners with alkoxy substituents, were prepared, resulting in a further improvement of their RNA affinity and antisense potential.
Subject(s)
Nucleosides/chemical synthesis , RNA/metabolism , Sugar Alcohols/chemistry , Kinetics , Nucleosides/metabolism , Oligonucleotides, Antisense/chemical synthesis , Oligonucleotides, Antisense/metabolism , RNA/chemistry , Structure-Activity Relationship , Sugar Alcohols/chemical synthesis , Sugar Alcohols/metabolismABSTRACT
In this study, 6-methyl-2'-deoxyuridine, an artificial nucleoside, was labeled with 11C in the methyl position. Tissue distribution of 6-methyl[11C]-2'-deoxyuridine was investigated in normal Wistar rats and compared to the behavior of the natural nucleoside [methyl-11C]thymidine. High renal clearance, up to at least 20% of the injected activity, was noticed during the 20 min period following injection. Tissue distribution as determined by dynamic PET studies of both 11C-labeled nucleosides was significantly different for most of the organs.
