[Fe(2)L(3)](4+) (L = C(25)H(20)N(4)) is a synthetic tetracationic supramolecular cylinder (with a triple helical architecture) that targets the major groove of DNA and can bind to DNA Y-shaped junctions. To explore the DNA-binding mode of [Fe(2)L(3)](4+), we examine herein the interactions of pure enantiomers of this cylinder with DNA by biochemical and molecular biology methods. The results have revealed that, in addition to the previously reported bending of DNA, the enantiomers extensively unwind DNA, with the M enantiomer being the more efficient at unwinding, and exhibit preferential binding to regular alternating purine-pyrimidine sequences, with the M enantiomer showing a greater preference. Also, interestingly, the DNA binding of bulky cylinders [Fe(2)(L-CF(3))(3)](4+) and [Fe(2)(L-Ph)(3)](4+) results in no DNA unwinding and also no sequence preference of their DNA binding was observed. The observation of sequence-preference in the binding of these supramolecular cylinders suggests that a concept based on the use of metallosupramolecular cylinders might result in molecular designs that recognize the genetic code in a sequence-dependent manner with a potential ability to affect the processing of the genetic code.

Institute of Biophysics Academy of Sciences of the Czech Republic v v i Královopolská 135 CZ 61265 Brno Czech Republic

Zobrazit více v PubMed

Lehn J-M. Supramolecular Chemistry – Concepts and Perspective. Wiley-VCH Weinheim; 1995.

Lehn JM. Toward complex matter: supramolecular chemistry and self-organization. Proc. Natl Acad. Sci. USA. 2002;99:4763–4768. PubMed PMC

Ruben M, Ziener U, Lehn JM, Ksenofontov V, Gutlich P, Vaughan GBM. Hierarchical self-assembly of supramolecular spintronic modules into 1D-and 2D-architectures with emergence of magnetic properties. Chem. Eur. J. 2004;11:94–100. PubMed

Hannon MJ, Childs LJ. Helices and helicates: beautiful supramolecular motifs with emerging applications. Supramol. Chem. 2004;16:7–22.

Meistermann I, Moreno V, Prieto MJ, Moldrheim E, Sletten E, Khalid S, Rodger PM, Peberdy JC, Isaac CJ, Rodger A, et al. Intramolecular DNA coiling mediated by metallosupramolecular cylinders: differential binding of P and M helical enantiomers. Proc. Natl Acad. Sci. USA. 2002;99:5069–5074. PubMed PMC

Moldrheim E, Hannon MJ, Meistermann I, Rodger A, Sletten E. Interaction between a DNA oligonucleotide and a dinuclear iron(II) supramolecular cylinder; an NMR and molecular dynamics study. J. Biol. Inorg. Chem. 2002;7:770–780. PubMed

Hannon MJ, Moreno V, Prieto MJ, Moldrheim E, Sletten E, Meistermann I, Isaac CJ, Sanders KJ, Rodger A. Intramolecular DNA coiling mediated by a metallo-supramolecular cylinder. Angew. Chem., Intl. Ed. 2001;40:879–884. PubMed

Uerpmann C, Malina J, Pascu M, Clarkson GJ, Moreno V, Rodger A, Grandas A, Hannon MJ. Design and DNA binding of an extended triple-stranded metallo-supramolecular cylinder. Chem. Eur. J. 2005;11:1750–1756. PubMed

Oleksi A, Blanco AG, Boer R, Usón I, Aymamí J, Rodger A, Hannon MJ, Coll M. Molecular recognition of a three-way DNA junction by a metallosupramolecular helicate. Angew. Chem., Intl. Ed. 2006;45:1227–1231. PubMed

Cerasino L, Hannon MJ, Sletten E. DNA three-way junction with a dinuclear iron(II) supramolecular helicate at the center: a NMR structural study. Inorg. Chem. 2007;46:6245–6251. PubMed

Malina J, Hannon MJ, Brabec V. Recognition of DNA three-way junctions by metallosupramolecular cylinders: gel electrophoresis studies. Chem. Eur. J. 2007;13:3871–3877. PubMed

Peberdy JC, Malina M, Khalid S, Hannon MJ, Rodger A. Influence of surface shape on DNA binding of bimetallo helicates. J. Inorg. Biochem. 2007;101:1937–1945. PubMed

Brabec V, Palecek E. Interaction of nucleic acids with electrically charged surfaces. II. Conformational changes in double-helical polynucleotides. Biophys. Chem. 1976;4:76–92. PubMed

Keck MV, Lippard SJ. Unwinding of supercoiled DNA by platinum ethidium and related complexes. J. Am. Chem. Soc. 1992;114:3386–3390.

Wyatt MD, Garbiras BJ, Haskell MK, Lee M, Souhami RL, Hartley JA. Structure-activity relationship of a series of nitrogen mustard- and pyrrole-containing minor groove-binding agents related to distamycin. Anti-Cancer Drug Des. 1994;1:511–529. PubMed

Fox KR, Waring MJ. High-resolution footprinting studies of drug-DNA complexes using chemical and enzymatic probes. In: Chairs JB, Waring MJ, editors. Drug Nucleic Acid Interactions.? San Diego/CA: Academic Press Inc; 2001. pp. 412–430. PubMed

Kemp S, Wheate NJ, Buck DP, Nikac M, Collins JG, Aldrich-Wright JR. The effect of ancillary ligand chirality and phenanthroline functional group substitution on the cytotoxicity of platinum(II)-based metallointercalators. J. Inorg. Biochem. 2007;101:1049–1058. PubMed

Fairall L, Rhodes D. A new approach to the analysis of DNase I footprinting data and its application to the TFIIIA/5S DNA complex. Nucleic Acids Res. 1992;20:4727–4731. PubMed PMC

Bellon SF, Coleman JH, Lippard SJ. DNA unwinding produced by site-specific intrastrand cross-links of the antitumor drug cis-diamminedichloroplatinum(II) Biochemistry. 1991;30:8026–8035. PubMed

Kartalou M, Essigmann JM. Recognition of cisplatin adducts by cellular proteins. Mutation Res. 2001;478:1–21. PubMed

Brabec V. DNA modifications by antitumor platinum and ruthenium compounds: their recognition and repair. Prog. Nucleic Acids Res. Mol. Biol. 2002;71:1–68. PubMed

Brabec V, Kasparkova J. Molecular aspects of resistance to antitumor platinum drugs. Drug Resist. Updates. 2002;5:147–161. PubMed

Brabec V, Kasparkova J. Modifications of DNA by platinum complexes: relation to resistance of tumors to platinum antitumor drugs. Drug Resist. Updates. 2005;8:131–146. PubMed

Fairall L, Harrison SD, Travers AA, Rhodes D. Sequence-specific DNA-binding by a 2 zinc-finger peptide from the Drosophila-melanogaster tramtrack protein. J. Mol. Biol. 1992;226:349–366. PubMed

Lahm A, Weston SA, Suck D. Structure of DNase I. In: Eckstein F, Lilley DMJ, editors. Nucleic Acids and Molecular Biology. Berlin, Heidelberg: Springer; 1991. pp. 171–186.

Mah SC, Price MA, Townsend CA, Tullius TD. Features of DNA recognition for oriented binding and cleavage by calicheamicin. Tetrahedron. 1994;50:1361–1378.

Ikemoto N, Kumar R, Ling T, Ellestad G, Danishefsky S, Patel D. calicheamicin-DNA complexes: warhead alignment and saccharide recognition of the minor groove. Proc. Natl Acad. Sci. USA. 1995;92:10506–10510. PubMed PMC

Kerckhoffs JMCA, Peberdy JC, Meistermann I, Childs LJ, Isaac CJ, Pearmund CR, Reudegger V, Khalid S, Alcock NW, Hannon MJ, et al. Enantiomeric resolution of supramolecular helicates with different surface topographies. Dalton Trans. 2007:734–742. PubMed

Hannon MJ, Painting CL, Jackson A, Hamblin J, Errington W. An inexpensive approach to supramolecular architecture. Chem. Commun. 1997:1807–1808.

Glycoconjugated Metallohelices have Improved Nuclear Delivery and Suppress Tumour Growth In Vivo