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. 2001 Oct 15;29(20):4187-94.
doi: 10.1093/nar/29.20.4187.

Improved hybridisation potential of oligonucleotides comprising O-methylated anhydrohexitol nucleoside congeners

A Van Aerschot  1 , M Meldgaard, G Schepers, F Volders, J Rozenski, R Busson, P Herdewijn
Affiliations

Improved hybridisation potential of oligonucleotides comprising O-methylated anhydrohexitol nucleoside congeners

A Van Aerschot et al. Nucleic Acids Res. .

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.

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Figures

Figure 1
Figure 1
Stability of duplexes comprising homopolymeric hexitol sequences and their RNA complement (rA)13. Open symbols: circle, (hU)13–RN; inverted triangle, (1)13–RNA; triangle, (dT)13–RNA. Filled symbols: circle, (2)13–RNA; inverted triangle, (hT)13–RNA; triangle, (hT)13–(hT)13.
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Scheme 1. Synthesis of the 3′-O-methylated altritol congener 1. (a) 3.2 equiv. uracil, 3 equiv. NaH, DMF, 120°C, 24 h (86%) (17); (b) 3 equiv. NaH, 5 equiv. CH3I, THF, 7 h, 0°C (50%); (c) 90% aqueous TFA (71%); (d) 1.2 equiv. MMTrCl, pyridine (89%); (e) DIEA, CH2Cl2, (iPr)2N(OCE)PCl (90%).
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Scheme 1. Synthesis of the 3′-O-methylated altritol congener 1. (a) 3.2 equiv. uracil, 3 equiv. NaH, DMF, 120°C, 24 h (86%) (17); (b) 3 equiv. NaH, 5 equiv. CH3I, THF, 7 h, 0°C (50%); (c) 90% aqueous TFA (71%); (d) 1.2 equiv. MMTrCl, pyridine (89%); (e) DIEA, CH2Cl2, (iPr)2N(OCE)PCl (90%).
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Scheme 2. Synthesis of the methylpyranoside building block 2. (a) C6H5CHO, ZnCl2, 72 h (66%); (b) 6 equiv. CH3C6H5SO2Cl, pyridine, 72 h, 60°C (78%); (c) NaOMe, MeOH, CH2Cl2 (79%) (19,20); (d) 3 equiv. thymine, 2.8 equiv. NaH, DMF, 96 h, 120°C (71%); (e) 2 equiv. CSCl2, 7 equiv. DMAP, CH2Cl2 at –40°C followed by 4 equiv. 2,4-Cl2C6H3OH at room temperature for 1 h; (f) 1.5 equiv. Bu3SnH, AIBN, toluene 80°C (85% over two steps); (g) 10% TFA-MeOH, 3 h (45%); alternatively H2, Pd/C in MeOH-HOAc 98:2 for 18 h (90%); (h) DMTrCl, pyridine (85%); (i) DIEA, CH2Cl2, (iPr)2N(OCE)PCl (67%).
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