Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving virus or bacteriophage
Patent
1996-11-12
2000-05-23
Harschel, Ardin H.
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving virus or bacteriophage
435 6, 436501, 514 44, 536 221, 536 241, 536 243, 536 2431, 536 2432, 536 2433, 536 253, C12Q 168
Patent
active
060664479
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to modified oligonucleotides comprising at least one nucleotide dimer with a modified backbone, to the modified nucleotide dimers, processes for the preparation of the modified oligonucleotides or the nucleotide dimers, the use of the modified oligonucleotides or the nucleotide dimers and pharmaceutical preparations containing the modified oligonucleotides.
Nucleosides and oligonucleotides have required wide interest as antiviral active ingredients or because of their capability to interact with nucleic acids ("antisense" oligonucleotides) and the biological activity associated therewith, see, for example, Uhlmann, E., Peyman, A., Chemical Reviews 90:543-584 (1990). To provide nucleosides having novel properties or to improve the interaction of antisense oligonucleotides with natural nucleic acids and their stability to nucleases, the sugar radicals of nucleosides (or the nucleotide units in oligonucleotides) or the internucleotide phosphate bond in oligonucleotides have been modified in very different ways, see, for example, Marquez, V. E., Lim. M-I., Medicinal Research Reviews 6:1-40 (1986), Helene, C., Toulme, J. J., Biochimica et Biophysica Acta 1049:99-125 (1990), Englisch, U., Gauss, D. H., Angewandte Chemie 103:629-646 (1991), Matteucci, M.D., Bischofberger, N., Annual Reports in Medicinal Chemistry 26:287-296 (1991) and WO 91/06556.
In WO 92/20823 backbone modified oligonucleotide analogs are disclosed wherein the phosphodiester inter-sugar linkages found in wild type oligomers are replaced with four atom linking groups and identical 2'-substituents. WO 92/05186 discloses modified oligonucleotides wherein the phosphodiester linkages are replaced by a two to four atom long internucleoside linkage wherein at least one of the atoms is nitrogen, oxygen or sulfur and wherein the substituents in 2'-position may be different. Exemplified are linkages wherein the hetero atom is in 3'-position of the sugar and dimers wherein both nucleosides are unsubstituted.
The hybridization characteristics with DNA/RNA and the resistence to nucleases of the so modified oligonucleotides are, however, not satisfying.
Surprisingly it was found that oligonucleotides which are highly resistant to nucleases and capable of strong hybridization to target RNA or DNA can be obtained by incorporating into the oligonucleotides nucleotide dimers wherein only one of the two 2'-positions is substituted or wherein the 2'-positions are substituted differently, and wherein the phosphodiester linkage is formed by a four membered amide or butylene group.
It is an object of the present invention to provide an oligonucleotide of the formula I nucleoside and n is a number from 2 to 200, preferably 2 to 100, more prefered 2 to 50 and most prefered 2 to 20 monomer units, comprising at least one structural unit of two consecutive nucleosides, the structural unit comprising the formula IIa, IIb, IIc or IId ##STR1## wherein R.sub.1 is H, C.sub.1 -C.sub.4 alkyl or C.sub.1 -C.sub.4 alkoxy; R.sub.2 is H; C.sub.1 -C.sub.4 alkyl; phenyl; phenyl substituted with OH, OR'", O(CH.sub.2 CH.sub.2 O).sub.n R'", C.sub.6 -C.sub.10 aryl or C.sub.3 -C.sub.9 heteroaryl; an intercalator; amino-C.sub.1 -C.sub.4 alkyl; C.sub.1 -C.sub.4 alkylamino; ammonium-C.sub.1 -C.sub.4 alkyl; C.sub.1 -C.sub.4 alkylammonium; amino-C.sub.1 -C.sub.4 alkylaminosulfonyl; C.sub.1 -C.sub.4 alkylamino-C.sub.1 -C.sub.4 alkylaminosulfonyl or (CH.sub.3).sub.2 NCH.sub.2 CH.sub.2 ; R.sub.3 is H or C.sub.1 -C.sub.4 alkyl; R.sub.3 'is H; OH; C.sub.1 -C.sub.4 alkyl; O--C.sub.1 -C.sub.4 alkyl; O(CH.sub.2 CH.sub.2 O).sub.n R'"; R'"is C.sub.1 -C.sub.4 alkyl; X is H, OH, O--C.sub.1 -C.sub.4 alkyl, --O--(CH.sub.2 --CH.sub.2 --O).sub.m H or --O--CH.sub.2 --C(OR)H--CH.sub.2 --OH; Y is H, O--C.sub.1 -C.sub.4 alkyl, --O--(CH.sub.2 --CH.sub.2 --O).sub.m H or --O--CH.sub.2 --C(OR)H--CH.sub.2 --OH; R is H or C.sub.1 -C.sub.10 alkyl; m is an integer from 1 to 4; n is an integer from 1 to 4 and B is a purine or pyrimidine radical or an analogue thereof with the proviso that eithe
REFERENCES:
Idziak et al., Tetrahedron Letters, vol. 34, No. 34, pp. 5417-5420, 1993.
Uhlmann, E. et al, Chemical Reviews 90 (1990) pp. 543-584.
Marquez, V. E. et al., Medicinal Research Reviews 6 (1986), pp. 1-40.
Helene, C. et al. Biochimica. et Biophysica Acta 1049 (1990), pp. 99-125.
English, U. et al., Angew. Chemic Int. Ed. Engl. 30 (1991), pp. 613-629.
Matteucci, M.D. et al., Ann. Rep. in Medicinal Chemistry 26 (1991), pp. 287-296.
De Mesmaeker, A. et al., Angew Chem. Int. Ed. Engl. 33 (1994), pp. 226-229.
Pudlo, J.S. et al., Tetrahedron Letters 31 (1990), pp. 3101-3104.
Codington, J.F. et al., J. Org. Chem. 29 (1964), pp. 558-564.
Pieles, U. et al. Nucleic Acids Res. 21 (1993), pp. 3191-3196.
Freier, S.M. et al. Biopolymers 22 (1983), pp. 1107-1131.
Hoke, G.D. et al., Nucleic Acids Res. 19 (1991), pp. 5743-5748.
Greene, B.T. "Protective Groups in Organic Synthesis," Wiley Interscience, New York (1991), pp. 1-142.
Gait, M.J. "Oligonucleitde Synthesis: A Practical Approach," 1RL Press, Oxford (1984).
Bevierre Marc-Olivier
De Mesmaeker Alain
Lebreton Jacques
Lesueur Catherine
Waldner Adrian
Ferraro Gregory D.
Harschel Ardin H.
Novartis Corporation
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