Replacement of the phosphodiester linkage in oligonucleotides by heterocycles: The effect of triazole- and imidazole-modified backbones on DNA/RNA duplex stability

Bioorganic and Medicinal Chemistry Letters

Volumn 7, Issue 12, 1997, Pages 1553-1556

  Von Matt, Peter ^a   Altmann, Karl Heinz ^a  

^a NOVARTIS PHARMA AG   (Switzerland)

Author keywords

[No Author keywords available]

Indexed keywords

IMIDAZOLE DERIVATIVE; OLIGODEOXYRIBONUCLEOTIDE; THYMIDINE DERIVATIVE;

ARTICLE; DRUG SYNTHESIS; IN VITRO STUDY; RNA BINDING; STEREOCHEMISTRY; STRUCTURE ACTIVITY RELATION;

EID: 0030960298     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0960-894X(97)00270-9     Document Type: Article

References (17)

1. (a) Wendeborn, S.; Wolf, R. M.; De Mesmaeker, A. Tetrahedron Lett. 1995, 36, 6879.
2. (b) De Mesmaeker, A.; Lebreton, J.; Waldner, A.; Fritsch, V.; Wolf, R. M. Bioorg. Med. Chem. Lett. 1994, 4, 873.
3. (c) Lebreton, J.; De Mesmaeker, A.; Waldner, A.; Fritsch, V.; Wolf, R. M.; Freier, S. M. Tetrahedron Lett. 1993, 40, 6383.
4. (a) Sanghvi, Y.; Bharadwaj, R.; Debart, F.; De Mesmaeker, A. Synthesis 1994, 1163.
5. (b) Lebreton, J.; Waldner, A.; Fritsch, V.; Wolf, R. M.; De Mesmaeker, A. Tetrahedron Lett. 1994, 35, 5225.
6. Cf. (a) Rothenburg, A. S.; Dauplaise, D. L.; Panzer, H. P. Angew. Chem. Int. Ed. Engl. 1983, 22, 560.
7. (b) Schaumann, E. Houben-Weyl, E8c, Georg Thieme Verlag, Stuttgart, New York, 1994; pp. 1-215.
8. 2O, 84%.
9. Conditions were adapted from: Rotstein, D. M.; Walker, K. A. M. Tetrahedron: Asymmetry 1993, 4, 1521.
10. De Mesmaeker, A.; Lebreton, J.; Waldner, A.; Fritsch, V.; Wolf, R. M.; Freier, S. M. Synlett 1993, 733.
11. 2, cat. DMAP, 94%).
12. For the use of a similar transfer hydrogenation protocol, see: (a) Kende, A. S.; Liu, K.; Jos Brands, K. M. J. Am. Chem. Soc. 1995, 117, 10597.
13. (b) Bieg, T.; Szeja, W. Synthesis, 1985, 76.
14. Gait, M. J. Oligonucleotide Synthesis: A Practical Approach; IRL: Oxford, 1984. For couplings involving modified building blocks, extended reaction times of 10 to 12 minutes were employed.
15. 3 for 16 h at 55 °C. The 5′-O-DMTr-protected oligonucleotide analogs were purified by RP-HPLC (Hyposil RP C-18), and the 5′-O-DMTr group was subsequently removed by treatment with 80% aqueous acetic acid at it. According to capillary gel electrophoresis, the fully deprotected oligonucleotides were at least 95% pure. The expected molecular weights of the modified oligonucleotides were confirmed by MALDI-TOF MS (Pieles, U.; Zürcher, W.; Schär M.; Moser, H. Nucleic Acids Res. 1993, 21, 3191).
16. These difficulties prompted us to synthesize sequence B with only two incorporations of modified dimeric building blocks.
17. Despite surveying variations of the standard coupling protocol (ref 9), we were unable to pinpoint the reasons for these failed coupling reactions.