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.
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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.
Carreras, C. W.; Santi, D. V. Annu. Rev. Biochem. 1995, 64, 721.
Stroud, R. M.; Finer-Moore, J. S. Biochemistry 2003, 42, 239.
Finer-Moore, J. S.; Santi, D. V.; Stroud, R. M. Biochemistry 2003, 42, 248.
Danenberg, P. V. Biochim. Biophys. Acta 1977, 473, 73.
Heidelberger, C.; Danenberg, P. V.; Moran, R. G. Adv. Enzymol. 1983, 54, 57.
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.
Ealick, S. E.; Armstrong, S. R. Curr. Opin. Struct. Biol. 1993, 3, 861.
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.
Santi, D. V. J. Med. Chem. 1980, 23, 103.
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.
Hartman, K. R.; Heidelberger, C. J. Biol. Chem. 1958, 236, 3006.
Heidelberger, C. Prog. Nucl. Acid Res. Mol. Biol. 1965, 4, 1.
Rode, W.; Zieliński, Z.; Dzik, J. M.; Kulikowski, T.; Bretner, M.; Kierdaszuk, B.; Cieśla, J.; Shugar, D. Biochemistry 1990, 29, 10835.
Lorenson, M. Y.; Maley, G. F.; Maley, F. J. Biol. Chem. 1967, 242, 3332.
Goldstein, S.; Pogolotti, A. L.; Garvey, E. P., Jr.; Santi, D. V. J. Med. Chem. 1984, 27, 1259.
Leś, A.; Adamowicz, L.; Rode, W. Biochim. Biophys. Acta 1993, 1173, 39.
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.
Sheldrick, G. M. Acta Crystallogr. 1990, A46, 467.
Sheldrick, G. M. SHELXL-97, Program for Crystal Structure Refinement; University of Gottingen: Germany, 1997; Release 97-2.
Wilson, A. J. C., Ed. International Tables for Crystallography; Kluwer Academic Publishers: Dordrecht, 1992; Volume C.
Kissel, L. P.; Pratt, R. H. Acta Crystallogr. 1990, A46, 170.
Cromer, D. T. J. Appl. Crystallogr. 1983, 16, 437.
Farrugia, L. J. J. Appl. Crystallogr. 1999, 32, 837.
Allen, F. H.; Johnson, O.; Shields, G. P.; Smith, B. R.; Towler, M. J. Appl. Crystallogr. 2004, 37, 335.
Farrugia, L. J. J. Appl. Crystallogr. 1997, 30, 565.
ISIS/Draw; MDL Information Systems, Inc., 1990–2001; Ver. 2.4.
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.
Niedźwiecka-Hornaś, A.; Kierdaszuk, B.; Stolarski, R.; Shugar, D. Biophys. Chem. 1998, 71, 87.
Shugar, D.; Huber, C. P.; Birnbaum, G. I. Biochim. Biophys. Acta 1976, 447, 274.
Stepanenko, T.; Lapinski, L.; Sobolewski, A. L.; Nowak, M. J.; Kierdaszuk, B. J. Phys. Chem. A 2000, 104, 9459.
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.
Walsh, A. D. Discuss. Faraday Soc. 1947, 2, 18.
Bent, H. A. Chem. Rev. 1961, 61, 275.
Bent, H. A. J. Inorg. Nucl. Chem. 1961, 19, 43.
Gillespie, R. J.; Nyholm, R. S. Quart. Rev. 1957, 11, 339.
Gillespie, R. J. Molecular Geometry; Van-Nostrand-Reinhold: London, 1972.
Gillespie, R. J.; Hargittai, I. In The VSEPR Model of Molecular Geometry; Allyn & Bacon: Needham Heights, MA, 1991.
Jarmuła, A.; Cyrański, M. K.; Leś, A.; Krygowski, T. M.; Rode, W. Pol. J. Chem. 1998, 72, 1958.
Matthews, D. A.; Villafranca, J. E.; Janson, C. A.; Smith, W. W.; Welsh, K.; Freer, S. J. Mol. Biol. 1990, 214, 937.
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Jarmuła, A., Rypniewski, W.R., Felczak, K. et al. 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. Struct Chem 16, 541–549 (2005). https://doi.org/10.1007/s11224-005-6058-9
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DOI: https://doi.org/10.1007/s11224-005-6058-9