Synthesis of Oligonucleotides and Oligonucleotide Analogues

  • Marvin H. Caruthers
Part of the Topics in Molecular and Structural Biology book series (TMSB)


The aim of this review is to outline modern methods for synthesizing natural oligodeoxynucleotides and certain analogues that may be inhibitors of gene expression. As a consequence, several DNA chemical synthesis methodologies such as the phosphate diester and phosphate triester approaches, which are now primarily only of historical interest, will not be discussed, even though they contributed significantly towards solving many important biological problems (Khorana et al., 1966, 1972; Caruthers, 1980; Itakura et al., 1984). Instead the more recent methodologies, which involve phosphorus(III) chemistry, will be emphasized (the phosphite triester and H-phosphonate approaches). There are two reasons. First, these chemistries are compatible with polymer-supported DNA synthesis procedures — a method that is uniquely suited to automation. Second, since phosphorus(III) intermediates can be oxidized to a large number of analogues, these approaches offer a versatility for modifying DNA that is not available with the earlier-developed methodologies. There are, however, certain analogues having potential as inhibitors of gene expression that are currently prepared using phosphorus(V) chemistry. The synthesis of these analogues will also be outlined.


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  1. Andrus, A., Efcavitch, W., McBride, L. J. and Giusti, B. (1988). Tetrahedron Lett., 29, 861CrossRefGoogle Scholar
  2. Applied Biosystems User Bulletin No. 13, Revised 1 April 1987, Applied Biosystems Inc., Foster City, Cal.Google Scholar
  3. Beaucage, S. L. and Caruthers, M. H. (1981). Tetrahedron Lett., 22, 1859CrossRefGoogle Scholar
  4. Bradbury, E. and Nagyvary, J. (1976). Nucl. Acids Res., 3, 2437PubMedCentralCrossRefPubMedGoogle Scholar
  5. Brennan, C. A., Van Cleve, M. D. and Gumport, R. I. (1986). J. Biol. Chem., 261, 7270PubMedGoogle Scholar
  6. Brill, W. K.-D. and Caruthers, M. H. (1987). Tetrahedron Lett., 28, 3205CrossRefGoogle Scholar
  7. Brill, W. K.-D., Nielsen, J. and Caruthers, M. H. (1988). Tetrahedron Lett., 29, 5517CrossRefGoogle Scholar
  8. Brill, W. K.-D., Tang, J.-Y., Ma, Y.-X. and Caruthers, M. H. (1989). J. Am. Chem. Soc., 111, 2321CrossRefGoogle Scholar
  9. Caruthers, M. H. (1980). Acc. Chem. Res., 13, 155CrossRefGoogle Scholar
  10. Caruthers, M. H. (1985). Science, N.Y., 230, 281CrossRefGoogle Scholar
  11. Caruthers, M. H., Barone, A. D., Beaucage, S. L., Dodds, D. R., Fisher, E. F., McBride, L. J., Matteucci, M. D., Stabinski, Z. and Tang, J.-Y. (1987). In Methods in Enzymology, 154, 287CrossRefPubMedGoogle Scholar
  12. Caruthers, M. H., Beaucage, S. L., Becker, C., Efcavitch, W., Fisher, E. F., Galluppi, G., Goldman, R., deHaseth, P., Martin, F., Matteucci, M. D. and Stabinski, Y. (1982). In Genetic Engineering, Principles and Methods (Setlow, J. and Hollaender, A., Eds.), Praeger Scientific, New YorkGoogle Scholar
  13. Chladek, S. and Nagyvary, J. (1972). J. Am. Chem. Soc., 94, 2079CrossRefPubMedGoogle Scholar
  14. Connolly, B. A., Potter, V. L., Eckstein, F., Pingond, A. and Grotjahn, L. (1984). Biochemistry, 23, 3443CrossRefPubMedGoogle Scholar
  15. Cook, A. F. (1970). J. Am. Chem. Soc., 92, 190CrossRefGoogle Scholar
  16. Cook, A. F., Holman, M. J. and Nussbaum, A. L. (1969). J. Am. Chem. Soc., 91, 1523Google Scholar
  17. Cosstick, R. and Eckstein, F. (1985). Biochemistry, 24, 3630CrossRefPubMedGoogle Scholar
  18. Dahl, B. H., Nielsen, J. and Dahl, O. (1987). Nucl. Acids Res., 15, 1729PubMedCentralCrossRefPubMedGoogle Scholar
  19. Damha, M. J., Usman, N. and Ogilvie, K. K. (1987). Tetrahedron Lett., 28, 1633CrossRefGoogle Scholar
  20. Dorman, M. A, Noble, S. A., McBride, L. J. and Caruthers, M. H. (1984). Tetrahedron, 40, 95CrossRefGoogle Scholar
  21. Dubendorff, J. W., deHaseth, P. L., Rosendahl, M. S. and Caruthers, M. H. (1987). J. Biol. Chem., 262, 892PubMedGoogle Scholar
  22. Efcavitch, J. W. and Heiner, C. (1985). Nucleosides and Nucleotides, 4, 267CrossRefGoogle Scholar
  23. Froehler, B. C. (1986a). Tetrahedron Lett., 27, 5565Google Scholar
  24. Froehler, B. C. (1986b). Tetrahedron Lett., 27, 5575CrossRefGoogle Scholar
  25. Froehler, B. C. and Metteucci, M. D. (1983). Nucl. Acids Res., 11, 8031PubMedCentralCrossRefPubMedGoogle Scholar
  26. Froehler, B. C., Ng, P. and Matteucci, M. D. (1986). Nucl. Acids Res., 14, 5399PubMedCentralCrossRefPubMedGoogle Scholar
  27. Froehler, B. C., Ng, P. and Matteucci, M. (1988). Nucl. Acids Res., in pressGoogle Scholar
  28. Gallo, K. A., Shao, K.-L., Phillips, L. R., Regan, J. B., Koziolkiewicz, M., Uznanski, B., Stec, W. J. and Zon, G. (1986). Nucl. Acids Res., 14, 7405PubMedCentralCrossRefPubMedGoogle Scholar
  29. Grandas, A., Marshall, W. S., Nielsen, J. and Caruthers, M. H. (1989). Tetrahedron Lett., 30, 543CrossRefGoogle Scholar
  30. Greene, G. L. and Letsinger, R. L. (1975). Nucl. Acids Res., 2, 1123PubMedCentralCrossRefPubMedGoogle Scholar
  31. Gregg, P. S., Lindh, J., Regberg, T. and Stawinski, J. (1987). Tetrahedron Lett., 27, 4051CrossRefGoogle Scholar
  32. Itakura, K., Rossi, J. and Wallace, R. B. (1984). Ann. Rev. Biochem., 53, 323CrossRefPubMedGoogle Scholar
  33. Jäger, A. and Engels, J. (1984). Tetrahedron Lett., 25, 1437CrossRefGoogle Scholar
  34. Jäger, A., Levy, M. J. and Hecht, S. A. (1988). Biochemistry, 27, 7237CrossRefPubMedGoogle Scholar
  35. Khorana, H. G., Agarwal, K. L., Büchi, H., Caruthers, M. H., Gupta, N. K., Kleppe, K., Kumar, A., Ohtsuka, E., Raj Bhandary, U. L., van de Sande, J. H., Sgaramella, V., Terao, T., Weber, H. and Yamada, T. (1972). J. Molec. Biol., 72, 209CrossRefPubMedGoogle Scholar
  36. Khorana, H. G., Büchi, H., Ghosh, H., Gupta, N., Jacob, T. M., Kossel, H., Morgan, A. R., Narang, S. A, Ohtsuka, E. and Wells, R. D. (1966). Cold Spring Harbor Symp. Quant. Biol., 31, 39CrossRefPubMedGoogle Scholar
  37. Koziolkiewicz, M., Uznanski, B., Stec, W. J. and Zon, G. (1986). Chemica Scripta, 26, 251Google Scholar
  38. Kume, A., Iwase, R., Sekine, M. and Hata, T. (1984). Nucl. Acids Res., 12, 8525PubMedCentralCrossRefPubMedGoogle Scholar
  39. Letsinger, R. L. and Haevner, G. A. (1975). Tetrahedron Lett., 16, 147CrossRefGoogle Scholar
  40. Letsinger, R. L. and Schott, M. E. (1981). J. Am. Chem. Soc., 103, 7394CrossRefGoogle Scholar
  41. Letsinger, R. L., Singman, C. N., Histand, G. and Salunkhe, M. (1988). J. Am. Chem. Soc., 110, 4470CrossRefGoogle Scholar
  42. McBride, L. J. and Caruthers, M. H. (1983a). Tetrahedron Lett., 24, 245CrossRefGoogle Scholar
  43. McBride, L. J. and Caruthers, M. H. (1983b). Tetrahedron Lett., 24, 2953CrossRefGoogle Scholar
  44. McBride, L. J., Eady, J. S., Efcavitch, J. W. and Andrus, W. A. (1987). Nucleosides and Nucleotides, 6, 297CrossRefGoogle Scholar
  45. McBride, L. J., Kierzek, R., Beaucage, S. L. and Caruthers, M. H. (1986). J. Am. Chem. Soc., 108, 2040CrossRefGoogle Scholar
  46. McLaughlin, L. W., Benseier, F., Graeser, E., Piel, N. and Scholtissek, S. (1987). Biochemistry, 26, 7238CrossRefPubMedGoogle Scholar
  47. Marcus-Sekura, C. J., Woerner, A. M., Shinozuka, K., Zon, G. and Quinnan, G. V., Jr. (1987). Nucl. Acids Res., 15, 5749PubMedCentralCrossRefPubMedGoogle Scholar
  48. Matteucci, M. D. and Caruthers, M. H. (1981). J. Am. Chem. Soc., 103, 3185CrossRefGoogle Scholar
  49. Miller, P. S., Chandrasegaran, S., Dru, D., Pulford, S. W. and Kan, L. S. (1982). Biochemistry, 21, 5468CrossRefPubMedGoogle Scholar
  50. Nemer, M. J. and Ogilvie, K. K. (1980). Tetrahedron Lett., 21, 4149CrossRefGoogle Scholar
  51. Nielsen, J., Brill, W. K.-D. and Caruthers, M. H. (1988). Tetrahedron Lett., 29, 2911CrossRefGoogle Scholar
  52. Nielsen, J. and Caruthers, M. H. (1988). J. Am. Chem. Soc., 110, 6275CrossRefPubMedGoogle Scholar
  53. Noble, S. A., Fisher, E. F. and Caruthers, M. H. (1984). Nucl. Acids Res., 12, 3387PubMedCentralCrossRefPubMedGoogle Scholar
  54. Patel, A. D., Schrier, W. H. and Nagyvary, J. (1980). J. Org. Chem., 45, 4830CrossRefGoogle Scholar
  55. Schulhof, J. C., Molko, D. and Teoule, R. (1987). Nucl. Acids Res., 15, 397PubMedCentralCrossRefPubMedGoogle Scholar
  56. Seela, F. and Driller, H. (1985). Nucl. Acids Res., 13, 911PubMedCentralCrossRefPubMedGoogle Scholar
  57. Sinha, N. D., Biernat, J., McManus, J. and Koster, H. (1984). Nucl. Acids Res., 12, 4539PubMedCentralCrossRefPubMedGoogle Scholar
  58. Smith, C. C., Aurelian, L., Reddy, M. P., Miller, P. S. and Ts’O, P. O. P. (1986). Proc. Natl Acad. Sci. USA, 83, 2787PubMedCentralCrossRefPubMedGoogle Scholar
  59. Stec, W. J. and Zon, G. (1984). Tetrahedron Lett., 25, 5275CrossRefGoogle Scholar
  60. Stec, W. J., Zon, G., Egan, W., Byrd, R. A., Phillips, L. R. and Gallo, K. A. (1985a). J. Org. Chem., 50, 3908CrossRefGoogle Scholar
  61. Stec, W. J., Zon, G., Egan, W. and Stec, B. (1984). J. Am. Chem. Soc., 106, 6077CrossRefGoogle Scholar
  62. Stec, W. J., Zon, G., Gallo, K. A., Byrd, R. A., Uznanski, B. and Guga, P. (1985b). Tetrahedron Lett., 26, 2191CrossRefGoogle Scholar
  63. Vyle, J. and Cosstick, R. (1988). J. Chem. Soc. Chem. Commun., 922Google Scholar

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© The Contributors 1989

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  • Marvin H. Caruthers

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