Skip to main content
NCBI home page
Nucleic Acids Research logoLink to Nucleic Acids Research
. 1997 Oct 15;25(20):4072–4078. doi: 10.1093/nar/25.20.4072

Minor groove binding of a bis-quaternary ammonium compound: the crystal structure of SN 7167 bound to d(CGCGAATTCGCG)2.

C J Squire 1, G R Clark 1, W A Denny 1
PMCID: PMC146996  PMID: 9321660

Abstract

The X-ray crystal structure of the complex between the synthetic antitumour and antiviral DNA binding ligand SN 7167 and the DNA oligonucleotide d(CGCGAATTCGCG)2 has been determined to an R factor of 18.3% at 2.6 A resolution. The ligand is located within the minor groove and covers almost 6 bp with the 1-methylpyridinium ring extending as far as the C9-G16 base pair and the 1-methylquinolinium ring lying between the G4-C21 and A5-T20 base pairs. The ligand interacts only weakly with the DNA, as evidenced by long range contacts and shallow penetration into the groove. This structure is compared with that of the complex between the parent compound SN 6999 and the alkylated DNA sequence d(CGC[e6G]AATTCGCG)2. There are significant differences between the two structures in the extent of DNA bending, ligand conformation and groove binding.

Full Text

The Full Text of this article is available as a PDF (160.0 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Atwell G. J., Cain B. F. Potential antitumor agents. 15. Bisquaternary salts. J Med Chem. 1974 Sep;17(9):930–934. doi: 10.1021/jm00255a004. [DOI] [PubMed] [Google Scholar]
  2. Atwell G. J., Yaghi B. M., Turner P. R., Boyd M., O'Connor C. J., Ferguson L. R., Baguley B. C., Denny W. A. Synthesis, DNA interactions and biological activity of DNA minor groove targeted polybenzamide-linked nitrogen mustards. Bioorg Med Chem. 1995 Jun;3(6):679–691. doi: 10.1016/0968-0896(95)00049-m. [DOI] [PubMed] [Google Scholar]
  3. Beerman T. A., Woynarowski J. M., Sigmund R. D., Gawron L. S., Rao K. E., Lown J. W. Netropsin and bis-netropsin analogs as inhibitors of the catalytic activity of mammalian DNA topoisomerase II and topoisomerase cleavable complexes. Biochim Biophys Acta. 1991 Aug 27;1090(1):52–60. doi: 10.1016/0167-4781(91)90036-l. [DOI] [PubMed] [Google Scholar]
  4. Broggini M., Coley H. M., Mongelli N., Pesenti E., Wyatt M. D., Hartley J. A., D'Incalci M. DNA sequence-specific adenine alkylation by the novel antitumor drug tallimustine (FCE 24517), a benzoyl nitrogen mustard derivative of distamycin. Nucleic Acids Res. 1995 Jan 11;23(1):81–87. doi: 10.1093/nar/23.1.81. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Brünger A. T., Kuriyan J., Karplus M. Crystallographic R factor refinement by molecular dynamics. Science. 1987 Jan 23;235(4787):458–460. doi: 10.1126/science.235.4787.458. [DOI] [PubMed] [Google Scholar]
  6. Carrondo M. A., Coll M., Aymami J., Wang A. H., van der Marel G. A., van Boom J. H., Rich A. Binding of a Hoechst dye to d(CGCGATATCGCG) and its influence on the conformation of the DNA fragment. Biochemistry. 1989 Sep 19;28(19):7849–7859. doi: 10.1021/bi00445a047. [DOI] [PubMed] [Google Scholar]
  7. Chen A. Y., Yu C., Gatto B., Liu L. F. DNA minor groove-binding ligands: a different class of mammalian DNA topoisomerase I inhibitors. Proc Natl Acad Sci U S A. 1993 Sep 1;90(17):8131–8135. doi: 10.1073/pnas.90.17.8131. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Chen S. M., Leupin W., Rance M., Chazin W. J. Two-dimensional NMR studies of d(GGTTAATGCGGT).d(ACCGCATTAACC) complexed with the minor groove binding drug SN-6999. Biochemistry. 1992 May 12;31(18):4406–4413. doi: 10.1021/bi00133a004. [DOI] [PubMed] [Google Scholar]
  9. Chiang S. Y., Welch J., Rauscher F. J., 3rd, Beerman T. A. Effects of minor groove binding drugs on the interaction of TATA box binding protein and TFIIA with DNA. Biochemistry. 1994 Jun 14;33(23):7033–7040. doi: 10.1021/bi00189a003. [DOI] [PubMed] [Google Scholar]
  10. Clark G. R., Squire C. J., Gray E. J., Leupin W., Neidle S. Designer DNA-binding drugs: the crystal structure of a meta-hydroxy analogue of Hoechst 33258 bound to d(CGCGAATTCGCG)2. Nucleic Acids Res. 1996 Dec 15;24(24):4882–4889. doi: 10.1093/nar/24.24.4882. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Coll M., Frederick C. A., Wang A. H., Rich A. A bifurcated hydrogen-bonded conformation in the d(A.T) base pairs of the DNA dodecamer d(CGCAAATTTGCG) and its complex with distamycin. Proc Natl Acad Sci U S A. 1987 Dec;84(23):8385–8389. doi: 10.1073/pnas.84.23.8385. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Denny W. A., Atwell G. J., Baguley B. C., Cain B. F. Potential antitumor agents. 29. Quantitative structure-activity relationships for the antileukemic bisquaternary ammonium heterocycles. J Med Chem. 1979 Feb;22(2):134–150. doi: 10.1021/jm00188a005. [DOI] [PubMed] [Google Scholar]
  13. Denny W. A., Atwell G. J., Baguley B. C., Cain B. F. Potential antitumor agents. 29. Quantitative structure-activity relationships for the antileukemic bisquaternary ammonium heterocycles. J Med Chem. 1979 Feb;22(2):134–150. doi: 10.1021/jm00188a005. [DOI] [PubMed] [Google Scholar]
  14. Dorn A., Affolter M., Müller M., Gehring W. J., Leupin W. Distamycin-induced inhibition of homeodomain-DNA complexes. EMBO J. 1992 Jan;11(1):279–286. doi: 10.1002/j.1460-2075.1992.tb05050.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Edwards K. J., Jenkins T. C., Neidle S. Crystal structure of a pentamidine-oligonucleotide complex: implications for DNA-binding properties. Biochemistry. 1992 Aug 11;31(31):7104–7109. doi: 10.1021/bi00146a011. [DOI] [PubMed] [Google Scholar]
  16. Gao Y. G., Sriram M., Denny W. A., Wang A. H. Minor groove binding of SN6999 to an alkylated DNA: molecular structure of d(CGC[e6G]AATTCGCG)-SN6999 complex. Biochemistry. 1993 Sep 21;32(37):9639–9648. doi: 10.1021/bi00088a016. [DOI] [PubMed] [Google Scholar]
  17. Henderson D., Hurley L. H. Molecular struggle for transcriptional control. Nat Med. 1995 Jun;1(6):525–527. doi: 10.1038/nm0695-525. [DOI] [PubMed] [Google Scholar]
  18. Kopka M. L., Yoon C., Goodsell D., Pjura P., Dickerson R. E. The molecular origin of DNA-drug specificity in netropsin and distamycin. Proc Natl Acad Sci U S A. 1985 Mar;82(5):1376–1380. doi: 10.1073/pnas.82.5.1376. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Krowicki K., Balzarini J., De Clercq E., Newman R. A., Lown J. W. Novel DNA groove binding alkylators: design, synthesis, and biological evaluation. J Med Chem. 1988 Feb;31(2):341–345. doi: 10.1021/jm00397a012. [DOI] [PubMed] [Google Scholar]
  20. Lavery R., Sklenar H. The definition of generalized helicoidal parameters and of axis curvature for irregular nucleic acids. J Biomol Struct Dyn. 1988 Aug;6(1):63–91. doi: 10.1080/07391102.1988.10506483. [DOI] [PubMed] [Google Scholar]
  21. Lee M., Rhodes A. L., Wyatt M. D., D'Incalci M., Forrow S., Hartley J. A. In vitro cytotoxicity of GC sequence directed alkylating agents related to distamycin. J Med Chem. 1993 Apr 2;36(7):863–870. doi: 10.1021/jm00059a011. [DOI] [PubMed] [Google Scholar]
  22. Leupin W., Chazin W. J., Hyberts S., Denny W. A., Wüthrich K. NMR studies of the complex between the decadeoxynucleotide d-(GCATTAATGC)2 and a minor-groove-binding drug. Biochemistry. 1986 Oct 7;25(20):5902–5910. doi: 10.1021/bi00368a010. [DOI] [PubMed] [Google Scholar]
  23. OETTGEN H. F., CLIFFORD P., BURCHENAL J. H. Malignant lymphoma involving the jaw in African children: treatment with 2-chloro-4',4'-di-2-imidazolin-2-ylterephthalanilide dihydrochloride. Cancer Chemother Rep. 1963 Mar;27:45–54. [PubMed] [Google Scholar]
  24. Pjura P. E., Grzeskowiak K., Dickerson R. E. Binding of Hoechst 33258 to the minor groove of B-DNA. J Mol Biol. 1987 Sep 20;197(2):257–271. doi: 10.1016/0022-2836(87)90123-9. [DOI] [PubMed] [Google Scholar]
  25. Prakash A. S., Valu K. K., Wakelin L. P., Woodgate P. D., Denny W. A. Synthesis and anti-tumour activity of the spatially-separated mustard bis-N,N'-[3-(N-(2-chloroethyl)-N-ethyl)amino-5-[N,N-dimethylamino)methy l)-aminophenyl]-1,4-benzenedicarboxamide, which alkylates DNA exclusively at adenines in the minor groove. Anticancer Drug Des. 1991 Jul;6(3):195–206. [PubMed] [Google Scholar]
  26. Quintana J. R., Lipanov A. A., Dickerson R. E. Low-temperature crystallographic analyses of the binding of Hoechst 33258 to the double-helical DNA dodecamer C-G-C-G-A-A-T-T-C-G-C-G. Biochemistry. 1991 Oct 22;30(42):10294–10306. doi: 10.1021/bi00106a030. [DOI] [PubMed] [Google Scholar]
  27. Rydzewski J. M., Leupin W., Chazin W. The width of the minor groove affects the binding of the bisquaternary heterocycle SN-6999 to duplex DNA. Nucleic Acids Res. 1996 Apr 1;24(7):1287–1293. doi: 10.1093/nar/24.7.1287. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Singh M. P., Joseph T., Kumar S., Bathini Y., Lown J. W. Synthesis and sequence-specific DNA binding of a topoisomerase inhibitory analog of Hoechst 33258 designed for altered base and sequence recognition. Chem Res Toxicol. 1992 Sep-Oct;5(5):597–607. doi: 10.1021/tx00029a003. [DOI] [PubMed] [Google Scholar]
  29. Sriram M., van der Marel G. A., Roelen H. L., van Boom J. H., Wang A. H. Conformation of B-DNA containing O6-ethyl-G-C base pairs stabilized by minor groove binding drugs: molecular structure of d(CGC[e6G]AATTCGCG complexed with Hoechst 33258 or Hoechst 33342. EMBO J. 1992 Jan;11(1):225–232. doi: 10.1002/j.1460-2075.1992.tb05045.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Sriram M., van der Marel G. A., Roelen H. L., van Boom J. H., Wang A. H. Structural consequences of a carcinogenic alkylation lesion on DNA: effect of O6-ethylguanine on the molecular structure of the d(CGC[e6G]AATTCGCG)-netropsin complex. Biochemistry. 1992 Dec 1;31(47):11823–11834. doi: 10.1021/bi00162a022. [DOI] [PubMed] [Google Scholar]
  31. Sundberg R. J., Dahlhausen D. J., Manikumar G., Mavunkel B., Biswas A., Srinivasan V., Musallam H. A., Reid W. A., Jr, Ager A. L. Cationic antiprotozoal drugs. Trypanocidal activity of 2-(4'-formylphenyl)imidazo[1,2-a]pyridinium guanylhydrazones and related derivatives of quaternary heteroaromatic compounds. J Med Chem. 1990 Jan;33(1):298–307. doi: 10.1021/jm00163a049. [DOI] [PubMed] [Google Scholar]
  32. Welch J. J., Rauscher F. J., 3rd, Beerman T. A. Targeting DNA-binding drugs to sequence-specific transcription factor.DNA complexes. Differential effects of intercalating and minor groove binding drugs. J Biol Chem. 1994 Dec 9;269(49):31051–31058. [PubMed] [Google Scholar]
  33. Westhof E. Re-refinement of the B-dodecamer d(CGCGAATTCGCG) with a comparative analysis of the solvent in it and in the Z-hexamer d(5BrCG5BrCG5BrCG). J Biomol Struct Dyn. 1987 Dec;5(3):581–600. doi: 10.1080/07391102.1987.10506414. [DOI] [PubMed] [Google Scholar]

Articles from Nucleic Acids Research are provided here courtesy of Oxford University Press

RESOURCES