Mechanism of Thymidylate Synthase Inhibition by N4-Hydroxy-(N4-Hydroxy-5-Fluoro)-dCMP in View of the Structure and Conformation of N4-Hydroxy-(N4Hydroxy-5-Fluoro)-Cytosine Calculated by the Ab Initio Quantum Mechanical Methods

  • Andrzej Leś
  • Ludwik Adamowicz
  • Wojciech Rode
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 338)


Thymidylate synthase (EC slow-binding inhibition by N4-hydroxy-dCMP (oh4dCMP) was shown to depend on conformation of the exocyclic N4-OH group, with the anti rotamer, relative to the ring N(3), indicated as an active species. 1 Potentiation of inhibition by the 5-fluoro substituent, observed for N4-hydroxy-5-fluoro-dCMP (oh4f5CMP), was explained in terms of hydrogen bonding between the N4-OH and C(5)-F groups, influencing an assumed syn-anti equilibrium by stabilization of the anti rotamer.1 In order to test the latter hypothesis two cytosine analogues, N4-hydroxy-cytosine (oh4C) and N4-hydroxy-5-fluorocytosine (oh4f5C), were theoretically studied, and their molecular structures determined, by ab initio quantum mechanical methods.


Tautomeric Form Self Consistent Field Transition State Structure Bond Saturation Self Consistent Field Method 
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  1. 1.
    W. Rode, Z. Zieliński, J.M. Dzik, T. Kulikowski, M. Bretner, B. Kierdaszuk, J. Cieśla, and D. Shugar,Biochemistry 29:10835 (1990).PubMedCrossRefGoogle Scholar
  2. 2.
    GAUSSIAN 90, Revision I, M.J. Frisch, M. Head-Gordon, G.W. Trucks, J.B. Foresman, H.B. Schlegel,K. Raghavachari, M. Robb, J.S. Binkley, C. Gonzalez, D.J. Defrees, D.J. Fox, R.A Whiteside, R. Seeger, C.F. Melius, J. Baker, R.L. Martin, L.R. Kahn, J.J.P. Steward, S. Topiol, and J.A Pople, Gaussian, Inc., Pittsburgh PA (1990).Google Scholar
  3. 3.
    J. Leszczyński, J. Phys. Chem. 96:1649 (1992).CrossRefGoogle Scholar
  4. 4.
    S. Goldstein, A.L. Pogolotti, Jr., E.P. Garvey, and D. Santi, J. Med. Chem. 27:1259 (1984).PubMedCrossRefGoogle Scholar
  5. 5.
    G.I. Bimbaum, T. Kulikowski, and D. Shugar, Can. J. Biochem. 57:308 (1979).CrossRefGoogle Scholar
  6. 6.
    D. Shugar, C.P. Huber, and G.I. Birnbaum, Biochim. Biophys. Acta 447:274 (1976).PubMedCrossRefGoogle Scholar
  7. 7.
    D.L. Barker, and R.E. Marsh, Acta Cryst. 17:1581 (1964).CrossRefGoogle Scholar
  8. 8.
    R.J. McClure, and B.M. Craven, Acta Cryst. 26:20 (1973).Google Scholar

Copyright information

© Springer Science+Business Media New York 1993

Authors and Affiliations

  • Andrzej Leś
    • 1
    • 2
  • Ludwik Adamowicz
    • 2
  • Wojciech Rode
    • 3
  1. 1.Department of ChemistryUniversity of WarsawWareawPoland
  2. 2.Department of ChemistiyUniversity of ArizonaTucsonUSA
  3. 3.Nencki Institute of Experimental BiologyPolish Academy of SciencesWarsawPoland

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