DNA alkylation sites of nitrogen mustards conjugated to polyamines and their implications for polyamine–DNA interactions

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Paul M. Cullis, Louise Merson-Davies and Richard Weaver


Abstract

Polyamines conjugated to the nitrogen mustard chlorambucil increase the efficiency of DNA alkylation at N7 of guanine by factors in the range 103 to 104; the sequence selectivity of this alkylation (the alkylation ‘finger-print’) is largely unchanged, which is consistent with flexible, electrostatic binding and incompatible with tight, sequence-specific binding of the polyamine moiety.


References

  1. O. Heby, Differentiation, 1981, 19, 1 CAS.
  2. C. W. Tabor and H. Tabor, Annu. Rev. Biochem., 1984, 53, 749 CrossRef CAS.
  3. H. R. Drew and R. E. Dickerson, J. Mol. Biol., 1981, 151, 535 CAS.
  4. D. Bancroft, L. D. Williams, A. Rich and M. Egli, Biochemistry, 1994, 33, 1073 CrossRef CAS.
  5. A. M. Liquori, L. Constantino, V. Crescenzi, V. Elia, E. Giglio, R. Puliti, S. M. DeSantis and V. Vitigliano, J. Mol. Biol., 1967, 24, 113 CrossRef CAS.
  6. I. S. Haworth, A. Rodger and W. G. Richards, J. Biomol. Struct. Dyn., 1992, 10, 195 Search PubMed.
  7. H.-J. Schneider and T. Blatter, Angew. Chem., Int. Ed. Engl., 1992, 31, 1207 CrossRef.
  8. K. Zakrzewski and B. Pullman, Biopolymers, 1986, 25, 375 CrossRef.
  9. L. W. Tari and A. S. Secco, Nucleic Acids Res., 1995, 23, 2065 CAS.
  10. P. M. Cullis, L. Merson-Davies and R. Weaver, J. Am. Chem. Soc., 1995, 117, 8033 CrossRef CAS.
  11. K. W. Kohn, J. A. Hartley and W. B. Mattes, Nucleic Acids Res., 1987, 15, 10 531 CAS; A. Sunters, C. J. Springer, K. D. Bagshawe, R. L. Souhami and J. A. Hartley, Biochem. Pharmacol., 1992, 44, 59 CrossRef CAS.
  12. A. Pullman and B. Pullman, Quart. Rev. Biophys., 1981, 14, 289 CrossRef CAS.
  13. A. S. Prakash, W. A. Denny, T. A. Gourdie, K. K. Valu, P. D. Woodgate and L. P. Wakelin, Biochemistry, 1990, 29, 9799 CrossRef CAS.
  14. Conjugate 1 was synthesised by our published method (G. M. Cohen, P. M. Cullis, J. A. Hartley, A. Mather, M. C. R. Symons and R. T. Wheelhouse, J. Chem. Soc., Chem. Commun., 1992, 298) and the remaining conjugates by analogous methods (R Weaver, PhD Thesis, University of Leicester) to be published elsewhere. The identity and purity of all compounds were confirmed to be > 95% by NMR, HPLC and HRMS analysis. All are stable as HCl salts at –40 °C but hydrolyse at very similar rates (t1/2 of ca. 20 min) in aqueous solutions at pH 7,37 °C Search PubMed.
  15. W. B. Mattes, J. A. Hartley and K. W. Kohn, Nucleic Acids Res., 1986, 14, 2971 CAS.
  16. P. M. Cullis, R. E. Green and M. E. Malone, J. Chem. Soc., Perkin Trans. 2, 1995, 1503 RSC.
  17. Molecular modeling and molecular dynamics refinements were performed on a duplex 19-mer canonical B-DNA, sequence d(CTATATTGGGCGGGATTAA)/d(TTAATCCCGCCCAATATAG)[where G is the first alkylation site], alkylated by 4 using InsightII and Discover (AMBER forcefield; MSI, San Diego, USA).
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