Synthesis of 3'-C- and 4'-C-branched oligodeoxynucleotides and the development of locked nucleic acid (LNA)

Accounts of Chemical Research

Volumn 32, Issue 4, 1999, Pages 301-310

  Wengel, Jesper ^a  

^a UNIVERSITY OF COPENHAGEN   (Denmark)

Author keywords

[No Author keywords available]

Indexed keywords

BICYCLO COMPOUND; FURAN DERIVATIVE; NUCLEIC ACID; NUCLEOSIDE DERIVATIVE; OLIGODEOXYNUCLEOTIDE DERIVATIVE; OLIGONUCLEOTIDE; PENTOFURANOSE; PHOSPHORAMIDIC ACID DERIVATIVE; UNCLASSIFIED DRUG;

ARTICLE; CHEMICAL REACTION; CHEMICAL STRUCTURE; SYNTHESIS;

EID: 0032909507     PISSN: 00014842     EISSN: None     Source Type: Journal    
DOI: 10.1021/ar980051p     Document Type: Article

References (61)

1. Uhlmann, E.; Peyman, A. Antisense Oligonucleotides: A New Therapeutic Principle. Chem. Rev 1990, 90, 543-84.
2. Beaucage, S. L.; Iyer, R. P. The Synthesis of Modified Oligonucleotides by the Phorphoramidite Approach and Their Applications. Tetrahedron 1993, 49, 6123-94.
3. De Mesmaeker, A.; Häner, R.; Martin, P.; Moser, H. E. Antisense Oligonucleotides. Acc. Chem. Res. 1995, 28, 366-74.
4. Herdewijn, P. Targeting RNA with Conformationally Restricted Oligonucleotides. Liebigs Ann. 1996, 1337-48.
5. Freier, S. M.; Altmann, K.-H. The Ups and Downs of Nucleic Acid Duplex Stability: Structure-Stability Studies on Chemically-Modified DNA:RNA Duplexes. Nucleic Acids Res. 1997, 25, 4429-43.
6. The hybridization between two complementary antiparallel ONs is based on selective Watson-Crick hydrogen bonding between cytosine bases and guanine bases and between adenine bases and thymine bases.
7. m values entails experimentally more reliable data: Lesnik, E. A.; Guinosso, C. J.; Kawasaki, A. M.; Sasmor, H.; Zounes, M.; Cummins, L. L.; Ecker, D. J.; Cook, P. D.; Freier, S. M. Oligodeoxynucleotides Containing 2′-O-Modified Adenosine: Synthesis and Effects on Stability of DNA:RNA Duplexes Biochemistry 1993, 32, 7832-8.
8. Vasseur, J.-J.; Debart, F.; Sanghvi, Y. S.; Cook, P. D. Oligonucleosides: Synthesis of a Novel Methylhydroxylamine-Linked Nucleoside Dimer and Its Incorporation into Antisense Sequences. J. Am. Chem. Soc. 1992, 114, 4006-7.
9. De Mesmaeker, A.; Lesueur, C.; Bévièrre M.-O.; Waldner, A.; Fritch, V.; Wolf, R. M. Amide Backbones with Conformationally Restricted Furanose Rings: Highly Improved Affinity of the Modified Oligonucleotides for Their RNA Complements. Angew. Chem., Int. Ed. Engl. 1996, 35, 2790-4.
10. De Mesmaeker, A.; Lebreton, J.; Jouanno, C.; Fritsch, V.; Wolf, R. M.; Wendeborn, S. Amide-Modified Oligonucleotides with Preorganized Backbone and Furanose Rings: Highly Increased Thermodynamic Stability of the Duplexes Formed with their RNA and DNA Complements. Synlett 1997, 1287-90.
11. Egholm, M.; Buchardt, O.; Christensen, L.; Behrens, C.; Freier, S. M.; Driver, D. A.; Berg, R. H.; Kim, S. K.; Norden, B.; Nielsen, P. E. PNA Hybridizes to Complementary Oligonucleotides Obeying the Watson-Crick Hydrogen-Bonding Rules. Nature 1993, 365, 566-8.
12. Hyrup, B.; Nielsen, P. E. Peptide Nucleic Acids (PNA): Synthesis, Properties and Potential Applications. Bioorg. Med. Chem. 1996, 4, 5-23.
13. Hendrix, C.; Rosemeyer, H.; Verheggen, I.; Seela, F.; Van Aerschot, A.; Herdewijn, P. 1′,5′-Anhydrohexitol Oligonucleotides: Synthesis, Base Pairing and Recognition by Regular Oligodeoxyribonucleotides and Oligoribonucleotides. Chem. Eur. J. 1997, 3, 110-20.
14. Hendrix, C.; Rosemeyer, H.; De Bouvere, B.; Van Aerschot, A.; Seela, F.; Herdewijn, P. 1′,5′-Anhydrohexitol Oligonucleotides: Hybridization and Strand Displacement with Oligoribonucleotides, Interaction with RNase H and HIV Reverse Transcriptase Chem. Eur. J. 1997, 3, 1513-20.
15. Schultz, D. G.; Gryaznov, S. M. Oligo-2′-fluoro-2′-deoxynucleotide N3′-P5′ Phosphoramidates: Synthesis and Properties. Nucleic Acids Res. 1996, 24, 2966-73.
16. Other groups have chosen a similar strategy. See, e.g., ref 5.
17. Lesnik, E. A.; Freier, S. M. Relative Thermodynamic Stability of DNA, RNA and DNA:RNA Hybrid Duplexes: Relationship with Base Composition and Structure. Biochemistry 1995, 34, 10807-15.
18. Saenger, W. Principles of Nucleic Acid Structure, Springer Advanced Texts in Chemistry, Springer-Verlag: New York, 1984; pp 1-556.
19. Marquez, V. E.; Ezzitouni, A.; Russ, P.; Siddiqui, M. A.; Ford, H., Jr.; Feldman, R. J.; Mitsuya, H.; George, C.; Barchi, J. J., Jr. HIV-1 Reverse Transcriptase Can Discriminate between Two Conformationally Locked Carbocyclic AZT Triphosphate Analogues. J. Am. Chem. Soc. 1998, 120, 2780-9.
20. In ref 19, an overview of conformational aspects of nucleosides is presented.
21. Chou, S.-H.; Flynn, P.; Reid, B. High-Resolution NMR Study of a Synthetic DNA-RNA Hybrid Dodecamer Containing the Consensus Pribnow Promotor Sequence: d(CGTTATAATGCG):r(CGCAUUAUAACG). Biochemistry 1989, 28, 2435-43.
22. Jørgensen, P. N.; Stein, P. C.; Wengel, J. Synthesis of 3′-C-(Hydroxymethyl)thymidine: Introduction of a Novel Class of Deoxynucleosides and Oligodeoxynucleotides. J. Am. Chem. Soc. 1994, 116, 2231-2.
23. Jørgensen, P. N.; Svendsen, M. L.; Scheuer-Larsen, C.; Wengel, J. Incorporation of 3′-C-(Hydroxymethyl)thymidine into Novel Oligodeoxynucleotide Analogues. Tetrahedron 1995, 51, 2155-64.
24. Caruthers, M. H. Chemical Synthesis of DNA and DNA Analogues. Acc. Chem. Res. 1991, 24, 278-84.
25. We have generally obtained low stepwise coupling yields (0-60%) for amidites derived from tertiary hydroxyl groups. The coupling yield of amidite 4 has been recently increased to > 80% by exchanging the standard iodine/water/pyridine oxidation with tert-butyl hydroperoride mediated oxidation: Scheuer-Larsen, C.; Dahl, B. M.; Wengel, J.; Dahl, O. Phosphoramidites Derived from Tertiary Alcohols. Why do They Sometime Couple with Low Efficiency? Tetrahedron Lett. 1998, 39, 8361-4.
26. Wang, G.; Middelton, P. J.; He, L.; Stoisavljevic, V.; Seifert, W. E. Synthesis and Evaluation of Oligodeoxynucleotides Containing 3′-C-Aminomethyl- and 3′-C-Methylthymidine. Nucleosides Nucleotides 1997, 16, 445-54.
27. Pfundheller, H. M.; Jørgensen, P. N.; Sørensen, U. S.; Sharma, S. K.; Grimstrup, M.; Ströch, C.; Nielsen, P.; Viswanadham, G.; Olsen, C. E.; Wengel, J. Synthesis of Novel 3′-C-Branched 2′-Deoxynucleosides. Incorporation of 3′-C-(3-Hydroxypropyl)thymidine into Oligodeoxynucleotides. J. Chem. Soc., Perkin Trans. 1 1998, 1409-21.
28. (a) Jung, P. M. J.; Burger, A.; Biellmann, J.-F. Rapid and Efficient Stereocontrolled Synthesis of C-3′-Ethynyl Ribo and Xylonucleosides by Organocerium Additions to 3′-Ketonucleosides. Tetrahedron Lett. 1995, 36, 1031-4.
29. (b) Jung, P. M. J.; Burger, A.; Biellmann, J.-F. Diastereofacial Selective Addition of Ethynylcerium Reagent and Barton-McCombie Reaction as the Key Steps for the Synthesis of C-3′-Ethynylribonucleosides and of C-3′-Ethynyl-2′-deoxynucleosides. J. Org. Chem. 1997, 62, 8309-14.
30. Nielsen, P.; Larsen, K.; Wengel, J. Stereoselective Synthesis of 3′-C-Allyluridines and 3′-Spiro-γ-lactone Uridine Analogues. Acta Chem. Scand. 1996, 50, 1030-5.
31. Schmit, C.; Bévierre, M.-O.; De Mesmaeker, A.; Altmann K.-H. The Effects of 2′- and 3′-Alkyl Substituents on Oligonucleotide Hybridization and Stability. Bioorg. Med. Chem. Lett. 1994, 4, 1969-74.
32. Yoshimura, Y.; Sano, T.; Matsuda, A.; Ueda, T. Synthesis of 6,3′-Methanocytidine, 6,3′-Methanouridine, and Their 2′-Deoxynucleosides (Nucleosides and Nucleotides. LXXVII). Chem. Pharm. Bull. 1988, 36, 162-7.
33. Nielsen, P.; Pfundheller, H. M.; Wengel, J. A Novel Class of Conformationally Restricted Oligonucleotide Analogues: Synthesis of 2′,3′-Bridged Monomers and RNA-selective Hybridisation. Chem. Commun. 1997, 825-26.
34. Nielsen, P.; Pfundheller, H. M.; Olsen, C. E.; Wengel, J. Synthesis of 2′-O,3′-C-Iinked Bicyclic Nucleosides and Oligonucleotides. J. Chem. Soc., Perkin Trans. 1 1997, 3423-33.
35. Jørgensen, P. N.; Sørensen, U. S.; Pfundheller, H. M.; Olsen, C. E.; Wengel, J. Synthesis and Hybridization Properties of β- and α-Oligodeoxynucleotides Containing β- and α-1-(3-C-Allyl-2-deoxy-Derythro-pentofuranosyl)thymine and α-1-(3-C-(3-C-Aminopropyl)-2-deoxy-D-eryrthro-pentofuranosyl)thymine. J. Chem. Soc., Perkin Trans. 1 1997, 3275-84.
36. Koole, L. H.; Buck, H. M.; Vial, J.-M.; Chattopadhyaya, J. Synthesis and Conformation of 9-(3′-C-Methyl-β-D-xylo-furanosyl)adenine and 3′-C-Methyladenosine, Two Sugar-Methylated Nucleoside Analogues. Acta Chem. Scand. 1989, 43, 665-9.
37. Youssefyeh, R. D.; Verheyden, J. P. H.; Moffatt, J. G. 4′-Substituted Nucleosides. 4. Synthesis of Some 4′-Hydroxymethyl Nucleosides. J. Org. Chem. 1979, 44, 1301-9.
38. Jones, G. H.; Taniguchi, M.; Tegg, D.; Moffatt, J. G. 4′-Substituted Nucleosides. 5. Hydroxymethylation of Nucleoside 5′-Aldehydes. J. Org. Chem. 1979, 44, 1309-17.
39. Fensholdt, J.; Thrane, H.; Wengel, J. Synthesis of Oligodeoxynucleotides Containing 4′-C-(Hydroxymethyl)thymidine: Novel Promising Antisense Molecules. Tetrahedron Lett. 1995, 36, 2535-8.
40. Thrane, H.; Fensholdt, J.; Regner, M.; Wengel, J. Novel Linear and Branched Oligodeoxynucleotide Analogues Containing 4′-C-(Hydroxymethyl)thymidine. Tetrahedron 1995, 51, 10389-402.
41. Maag, H.; Schmidt, B.; Rose, S. J. Oligodeoxynucleotide Probes with Multiple Labels Linked to the 4′-Position of Thymidine Monomers: Excellent Duplex Stability and Detection Sensitivity. Tetrahedron Lett. 1994, 35, 6449-52.
42. Wang, G.; Seifert, W. F. Synthesis and Evaluation of Oligodeoxynucleotides Containing 4′-C-Substituted Thymidines. Tetrahedron Lett. 1996, 37, 6515-8.
43. Ueno, Y.; Nagasawa, Y.; Sugimoto, I.; Kojima, N.; Kanazaki, M.; Shuto, S.; Matsuda, A. Nucleosides and Nucleotides. 174. Synthesis of Oligodeoxynucleotides Containing 4′-C-[2-[[N-(2-Aminoethyl)-carbamoyl]oxy] ethyl] thymidine and Their Thermal Stability and Nuclease-Resistance Properties. J. Org. Chem. 1998, 63, 1660-7.
44. Nielsen, K. D.; Kirpekar, F.; Roepstorff, P.; Wengel, J. Oligonucleotide Analogues Containing 4′-C-(Hydroxymethyl)uridine: Synthesis, Evaluation and Mass Spectrometric Analysis. Bioorg. Med. Chem. 1995, 3, 1493-502.
45. Bolli, M.; Trafelet, H. U.; Leumann, C. Watson-Crick Base-pairing Properties of Bicyclo-DNA. Nucleic Acids Res. 1996, 24, 4660-7.
46. Altmann, K.-H.; Kesselring, R.; Francotte, E.; Rihs, G. 4′,6′-Methano Carbocyclic Thymidine: A Conformationally Constrained Building Block for Oligonucleotides. Tetrahedron Lett. 1994, 35, 2331-4.
47. Altmann, K. H.; Imwinkelried, R.; Kesselring, R.; Rihs, G. 1′,6′-Methano Carbocyclic Thymidine: Synthesis, X-ray Crystal Structure, and Effect on Nucleic Acid Duplex Stability. Tetrahedron Lett. 1994, 35, 7625-8.
48. Marquez, V. E.; Siddiqui, M. A.; Ezzitouni, A.; Russ, P.; Wang, J.; Wagner, R. W.; Matteucci, M. D. Nucleosides with a Twist. Can Fixed Forms of Sugar Ring Pucker Influence Biological Activity in Nucleosides and Oligonucleotides? J. Med. Chem. 1996, 39, 3739-47.
49. Steffens, R.; Leumann, C. J. Tricyclo-DNA: A Phosphodiester-Backbone Based DNA Analogue Exhibiting Strong Complementary Base-Pairing Properties. J. Am. Chem. Soc. 1997, 119, 11548-9.
50. Christensen, N. K.; Petersen, M.; Nielsen, P.; Jacobsen, J. P.; Olsen, C. E. Wengel, J. A Novel Class of Oligonucleotide Analogues Containing 2′-O,3′-C-Linked [3.2.0]Bicycloarabinonucleoside Monomers: Synthesis, Thermal Affinity Studies, and Molecular Modeling. J. Am. Chem. Soc. 1998, 120, 5458-63.
51. We have earlier estimated the preferred conformation of nucleoside 20 to be 4′-exo based on simple molecular modeling. However, as the 1′-exo conformation reported for 20 in ref 49 is based on integrated NMR and molecular modeling, this conformation is considered the more reliable.
52. A conformational shift of monomers N and O when present in a duplex cannot be ruled out; NMR experiments on duplexes are ongoing to further analyze this aspect.
53. Singh, S. K.; Nielsen, P.; Koshkin, A. K.; Olsen, C. E.; Wengel, J. LNA (Locked Nucleic Acids): Synthesis and High-affinity Nucleic Acid Recognition. Chem. Commun. 1998, 455-6.
54. Koshkin, A. A.; Singh, S. K.; Nielsen, P.; Rajwanshi, V. K.; Kumar, R.; Meldgaard, M.; Olsen, C. E.; Wengel, J. LNA (Locked Nucleic Acids): Synthesis of the Adenine, Cytosine, Guanine, 5-Methylcytosine, Thymine and Uracil Bicyclonucleoside Monomers, Oligomerisation, and Unprecedented Nucleic Acid Recognition. Tetrahedron 1998, 54, 3607-30.
55. We have defined LNA as an ON containing one or more 2′-O,4′-C-methylene bicyclonucleoside LNA monomers.
56. 3′-endo Sugar Puckering. Tetrahedron Lett. 1997, 38, 8735-8.
57. Obika, S.; Nanbu, D.; Hari, Y.; Andoh, J.; Morio, K.; Doi, T.; Imanishi, T. Stability and Structural Features of the Duplexes Containing Nucleoside Analogues with a Fixed N-Type Conformation, 2′-O,4′-C-Methyleneribonucleosides. Tetrahedron Lett. 1998, 39, 5401-4.
58. Koshkin, A. A.; Rajwanshi, V. K.; Wengel, J. Novel Convenient Syntheses of LNA [2.2.1]Bicyclo Nucleosides. Tetrahedron Lett. 1998, 39, 4381-4.
59. Singh, S. K.; Wengel, J. Universality of LNA-mediated High-affinity Nucleic Acid Recognition. Chem. Commun. 1998, 1247-8.
60. Koshkin, A. A.; Nielsen, P.; Meldgaard, M.; Rajwanshi, V. K.; Singh, S. K.; Wengel, J. LNA (Locked Nucleic Acid): An RNA Mimic Forming Exceedingly Stable LNA:LNA Duplexes. J. Am. Chem. Soc., in press.
61. The A-form character of duplexes involving LNA is expected from the N-type conformational restriction of the monomeric LNA nucleosides.