Computed redox potentials and the design of bioreductive agents

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Abstract

Anti-cancer agents that have been made selective for tumour cells by exploiting the known differences in the availability of oxygen between normal and transformed cells are a promising development in cancer chemotherapy1. We have recently suggested a new type of bioreductive activity which would depend on a two-electron reduction2–4. For rational design of such compounds, it is essential to be able to predict the redox potentials and the chemical modifications needed to produce the optimum redox value. Calculating redox potentials is a daunting task for the theoretician, however, as the effect of water solvation is clearly of major significance. Recent successful calculations5–10 of differences in the free energies of biologically important molecules in aqueous solution using the free-energy perturbation method prompted us to apply (he technique to the computation of two-electron redox potentials. The results are accurate to within 20 mV, suggesting that we should be able to manipulate redox potentials by successfully predicting structures with the appropriate value.

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References

  1. 1

    Adams, G. E. & Stratford, I. J., Biochem. Pharmac. 35, 71–76 (1986).

  2. 2

    Reynolds, C. A., Richards, W. G. & Goodford, P. Anti-Cancer Drug Design 1, 291–295 (1987).

  3. 3

    Reynolds, C. A., Richards, W. G. & Goodford, P. J. chem. Soc. 551–556 (1988).

  4. 4

    Burridge, J. M., Quarendon, P., Reynolds, C. A. & Goodford, P. J., J. molec. Graphics 5, 165–166 (1987).

  5. 5

    Cieplak, P., Singh, U. C. & Kollman, P. A. Int. J. quant. Chem. QBS14, 65–74 (1987).

  6. 6

    Wong, C. F. & McCammon, J. A. J. Am. chem. Soc. 108, 3830–3832 (1986).

  7. 7

    Singh, U. C., Brown, F. K., Bash, P. A. & Kollman, P. A., J. Am. chem. Soc. 109, 1607–1614 (1987).

  8. 8

    Bash, P. A., Singh, U. C., Brown, F. K., Langridge, R. & Kollman, P. A. Science 235, 574–575 (1987).

  9. 9

    Bash, P. A., Singh, U. C., Langridge, R. & Kollman, P. A. Science 236, 564–568 (1987).

  10. 10

    Rao, S. N., Singh, U. C., Bash, P. A. & Kollman, P. A. Nature 328, 551–554 (1987).

  11. 11

    Kennedy, K. A., Teicher, B. A., Rockwell, S. & Sartorelli, A. C. Biochem. Pharmac. 29, 1–8 (1980).

  12. 12

    Zwanzig, R. W. J. chem. Phys. 22, 1420–1426 (1954).

  13. 13

    Postma, J. P. M., Berendsen, H. J. & Haak, J. R., Faraday Symp. Chem. 17, 55–67 (1982).

  14. 14

    Tembe, B. L. & McCammon, J. A. Computers Chem. 8, 281–283 (1984).

  15. 15

    Lybrand, T. P., McCammon, J. A. & Wipff, G. Proc. natn. Acad. Sci. U.S.A. 83, 833–835 (1986).

  16. 16

    Jorgensen, W. L. & Ravimohan, C. J. chem. Phys. 83, 3050–3054 (1985).

  17. 17

    Singh, U. C., Weiner, P. K., Caldwell, J. W. & Kollman, P. A. AMBER Version 3.0 (Dept Pharmaceutical Chemistry, Univ. San Francisco, 1986).

  18. 18

    Roothaan, C. C. J. Rev. mod. Phys. 23, 69–89 (1951).

  19. 19

    Møller, C. & Plesset, M. S., Phys. Rev. 46, 618–622 (1934).

  20. 20

    Dewer, M. J. S. & Stewart, J. J. P., AMPAC, Quantum Chemistry Program Exchange Bulletin 6, 24 (1986).

  21. 21

    Clark, W. M., Oxidation-Reduction Potentials of Organic Systems (Balliere, Tindall & Cox, London, 1960).

  22. 22

    Jorgensen, W. L., Chandrasekhar, J., Madura, J., Impey, R. W. & Klein, M. L. J. chem. Phys. 79, 926–935 (1983).

  23. 23

    van Gunsteren, W. F. & Berendsen, H. J. C. Molec. Phys. 34, 1311–1327 (1977).

  24. 24

    Weiner, S. J. et al. J. Am. chem. Soc. 106, 765–784 (1984).

  25. 25

    Weiner, S. J., Kollman, P. A., Nguyen, D. T. & Case, D. A. J. comput., Chem. 7, 230–252 (1986).

  26. 26

    Singh, U. C. & Kollman, P. A. J. comput. Chem. 5, 129–145 (1984).

  27. 27

    Frisch, M. Gaussian 82 Revision H Version (Carnegie-Mellon University, Pittsburg, 1985).

  28. 28

    Amos, R. D. CADPAC 3.0 (University of Cambridge, 1986).

  29. 29

    Binkley, J. S., Pople, J. A. & Hehre, W. J. J. Am. chem. Soc. 102, 939–947 (1980).

  30. 30

    Hariharan, P. C. & Pople, J. A. Theor. chim. Acta 28, 213–222 (1973).

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