Structural Chemistry

, Volume 16, Issue 5, pp 541–549 | Cite as

X-ray Crystal and Ab Initio Structures of 3′,5′-di-O-Acetyl-N(4)-Hydroxy-2′-Deoxycytidine and Its 5-Fluoro Analogue: Models of the N(4)-OH-dCMP and N(4)-OH-FdCMP Molecules Interacting with Thymidylate Synthase

  • Adam Jarmuła
  • Wojciech R. Rypniewski
  • Krzysztof Felczak
  • Wojciech Rode
Article

Abstract

The crystal and molecular structures of the 3′,5′-di-O-acetyl-N(4)-hydroxy-2′-deoxycytidine molecule and its 5-fluoro congener have been determined by X-ray single crystal diffraction. The 3′,5′-di-O-acetyl-N(4)-hydroxy-5-fluoro-2′-deoxycytidine molecule crystallizes in the space group C2 with the following unit cell parameters: a = 21.72 Å, b = 8.72 Å, c = 8.61 Å, and β = 90.42. 3′,5′-di-O-acetyl-N(4)-hydroxy-2′-deoxycytidine also belongs to the monoclinic space group C2 and the unit cell parameters are: a = 39.54 Å, b = 8.72 Å, c = 22.89 Å, and β = 95.26. The non-fluorine analogue demonstrates a rare example of crystal structure with five symmetry-independent molecules in the unit cell. All the molecules in both crystal structures have the sugar residue anti oriented with respect to the base, as well as have the N(4)-OH residue in cis conformation relatively to the N(3)-nitrogen atom. In addition to the molecular geometries from X-ray experiment, the optimized molecular geometries have been obtained with the use of theoretical ab initio calculations at the RHF/6-31G(d) level. The corresponding geometric parameters in the molecules of 3′,5′-di-O-acetyl-N(4)-hydroxy-2′-deoxycytidine and its 5-fluoro congener have been compared. The differences including the C(5)=C(6) bond shortening and C(4)—C(5)—C(6) angle widening in the fluorine analogue are discussed in this paper in relation to the molecular mechanism of enzyme, thymidylate synthase, inhibition by N(4)-hydroxy-2′-deoxycytidine monophosphate and its 5-fluoro congener.

Keywords

Crystal structure ab initio structure nucleoside analogues of N(4)-OH-dCMP and N(4)-OH-FdCMP thymidylate synthase 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Santi, D. V.; Danenberg, P. V. In Folates and Pterines; Blakely, R.~L.; Benkovic, S. J., Eds.; Wiley: New York, 1984; Vol. 1, Chemistry and Biochemistry of Folates; pp. 345–398.Google Scholar
  2. 2.
    Carreras, C. W.; Santi, D. V. Annu. Rev. Biochem. 1995, 64, 721.CrossRefPubMedGoogle Scholar
  3. 3.
    Stroud, R. M.; Finer-Moore, J. S. Biochemistry 2003, 42, 239.CrossRefPubMedGoogle Scholar
  4. 4.
    Finer-Moore, J. S.; Santi, D. V.; Stroud, R. M. Biochemistry 2003, 42, 248.CrossRefPubMedGoogle Scholar
  5. 5.
    Danenberg, P. V. Biochim. Biophys. Acta 1977, 473, 73.PubMedGoogle Scholar
  6. 6.
    Heidelberger, C.; Danenberg, P. V.; Moran, R. G. Adv. Enzymol. 1983, 54, 57.Google Scholar
  7. 7.
    Jackman, A. L.; Jones, T. R.; Calvert, A. H.; In Experimental and Clinical Progress in Cancer Chemotherapy; Muggia, F. M., Ed.; Martinus Nijhoff Publishers: Boston, 1985; pp. 155–210.Google Scholar
  8. 8.
    Ealick, S. E.; Armstrong, S. R. Curr. Opin. Struct. Biol. 1993, 3, 861.CrossRefGoogle Scholar
  9. 9.
    Lewis, C. A., Jr.; Dunlap, R. B. In Topics in Molecular Pharmacology; Burgen, A. S. V.; Roberts, G. C. K., Eds.; Elsevier/North-Holland Biomedical: New York, 1981; pp. 170–219.Google Scholar
  10. 10.
    Santi, D. V. J. Med. Chem. 1980, 23, 103.CrossRefPubMedGoogle Scholar
  11. 11.
    De Clercq, E.; Balzarini, J.; Torrence, P. F.; Mertes, M. P.; Schmidt, C. L.; Shugar, D.; Barr, P. J.; Jones, A. S.; Verhelst, G.; Walker, R. T. Mol. Pharmacol. 1981, 19, 321.PubMedGoogle Scholar
  12. 12.
    Hartman, K. R.; Heidelberger, C. J. Biol. Chem. 1958, 236, 3006.Google Scholar
  13. 13.
    Heidelberger, C. Prog. Nucl. Acid Res. Mol. Biol. 1965, 4, 1.Google Scholar
  14. 14.
    Rode, W.; Zieliński, Z.; Dzik, J. M.; Kulikowski, T.; Bretner, M.; Kierdaszuk, B.; Cieśla, J.; Shugar, D. Biochemistry 1990, 29, 10835.CrossRefPubMedGoogle Scholar
  15. 15.
    Lorenson, M. Y.; Maley, G. F.; Maley, F. J. Biol. Chem. 1967, 242, 3332.PubMedGoogle Scholar
  16. 16.
    Goldstein, S.; Pogolotti, A. L.; Garvey, E. P., Jr.; Santi, D. V. J. Med. Chem. 1984, 27, 1259.CrossRefPubMedGoogle Scholar
  17. 17.
    Leś, A.; Adamowicz, L.; Rode, W. Biochim. Biophys. Acta 1993, 1173, 39.PubMedGoogle Scholar
  18. 18.
    Felczak, K.; Miazga, A.; Poznański, J.; Bretner, M.; Kulikowski, T.; Dzik, J. M.; Gołos, B.; Zieliński, Z.; Cieśla, J.; Rode, W. J. Med. Chem. 2000, 43, 4647.CrossRefPubMedGoogle Scholar
  19. 19.
    Sheldrick, G. M. Acta Crystallogr. 1990, A46, 467.Google Scholar
  20. 20.
    Sheldrick, G. M. SHELXL-97, Program for Crystal Structure Refinement; University of Gottingen: Germany, 1997; Release 97-2.Google Scholar
  21. 21.
    Wilson, A. J. C., Ed. International Tables for Crystallography; Kluwer Academic Publishers: Dordrecht, 1992; Volume C.Google Scholar
  22. 22.
    Kissel, L. P.; Pratt, R. H. Acta Crystallogr. 1990, A46, 170.Google Scholar
  23. 23.
    Cromer, D. T. J. Appl. Crystallogr. 1983, 16, 437.CrossRefGoogle Scholar
  24. 24.
    Farrugia, L. J. J. Appl. Crystallogr. 1999, 32, 837.CrossRefGoogle Scholar
  25. 25.
    Allen, F. H.; Johnson, O.; Shields, G. P.; Smith, B. R.; Towler, M. J. Appl. Crystallogr. 2004, 37, 335.CrossRefGoogle Scholar
  26. 26.
    Farrugia, L. J. J. Appl. Crystallogr. 1997, 30, 565.CrossRefGoogle Scholar
  27. 27.
    ISIS/Draw; MDL Information Systems, Inc., 1990–2001; Ver. 2.4.Google Scholar
  28. 28.
    Schmidt, M. W.; Baldridge, K. K.; Boatz, J. A.; Elbert, S. T.; Gordon, M. S.; Jensen, J. H.; Koseki, S.; Matsunaga, N.; Nguyen, K. A.; Su, S. J.; Windus, T. L.; Dupuis, M.; Montgomery, J. A. J. Comput. Chem. 1993, 14, 1347.CrossRefGoogle Scholar
  29. 29.
    Niedźwiecka-Hornaś, A.; Kierdaszuk, B.; Stolarski, R.; Shugar, D. Biophys. Chem. 1998, 71, 87.CrossRefGoogle Scholar
  30. 30.
    Shugar, D.; Huber, C. P.; Birnbaum, G. I. Biochim. Biophys. Acta 1976, 447, 274.PubMedGoogle Scholar
  31. 31.
    Stepanenko, T.; Lapinski, L.; Sobolewski, A. L.; Nowak, M. J.; Kierdaszuk, B. J. Phys. Chem. A 2000, 104, 9459.CrossRefGoogle Scholar
  32. 32.
    Jarmuła, A.; Anulewicz, R.; Leś, A.; Cyrański, M. K.; Adamowicz, L.; Bretner, M.; Felczak, K.; Kulikowski, T.; Krygowski, T. M.; Rode, W. Biochim. Biophys. Acta 1998, 1382, 277.PubMedGoogle Scholar
  33. 33.
    Walsh, A. D. Discuss. Faraday Soc. 1947, 2, 18.CrossRefGoogle Scholar
  34. 34.
    Bent, H. A. Chem. Rev. 1961, 61, 275.CrossRefGoogle Scholar
  35. 35.
    Bent, H. A. J. Inorg. Nucl. Chem. 1961, 19, 43.CrossRefGoogle Scholar
  36. 36.
    Gillespie, R. J.; Nyholm, R. S. Quart. Rev. 1957, 11, 339.CrossRefGoogle Scholar
  37. 37.
    Gillespie, R. J. Molecular Geometry; Van-Nostrand-Reinhold: London, 1972.Google Scholar
  38. 38.
    Gillespie, R. J.; Hargittai, I. In The VSEPR Model of Molecular Geometry; Allyn & Bacon: Needham Heights, MA, 1991.Google Scholar
  39. 39.
    Jarmuła, A.; Cyrański, M. K.; Leś, A.; Krygowski, T. M.; Rode, W. Pol. J. Chem. 1998, 72, 1958.Google Scholar
  40. 40.
    Matthews, D. A.; Villafranca, J. E.; Janson, C. A.; Smith, W. W.; Welsh, K.; Freer, S. J. Mol. Biol. 1990, 214, 937.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science + Business Media, Inc. 2005

Authors and Affiliations

  • Adam Jarmuła
    • 1
  • Wojciech R. Rypniewski
    • 2
  • Krzysztof Felczak
    • 3
  • Wojciech Rode
    • 1
  1. 1.Nencki Institute of Experimental BiologyPolish Academy of SciencesWarszawaPoland
  2. 2.Institute of Bioorganic ChemistryPolish Academy of SciencesPoznańPoland
  3. 3.Institute of Biochemistry and BiophysicsPolish Academy of SciencesWarszawaPoland

Personalised recommendations