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Multi-Functional Metal Complexes with DNA Base-Sequence Selectivity

Research Project

Project/Area Number 01470047
Research Category

Grant-in-Aid for General Scientific Research (B)

Allocation TypeSingle-year Grants
Research Field 無機・錯塩・放射化学
Research InstitutionTokyo University

Principal Investigator

KURODA Reiko  Tokyo Univ., Chemistry, Associate Professor, 教養学部, 助教授 (90186552)

Co-Investigator(Kenkyū-buntansha) YAMAGISHI Akihiko  Tokyo Univ., Chemistry, Associate Professor, 教養学部, 助教授 (70001865)
IWAMOTO Toshitake  Tokyo Univ., Chemistry, Professor, 教養学部, 教授 (60011532)
Project Period (FY) 1989 – 1990
Project Status Completed (Fiscal Year 1990)
Budget Amount *help
¥5,700,000 (Direct Cost: ¥5,700,000)
Fiscal Year 1990: ¥1,200,000 (Direct Cost: ¥1,200,000)
Fiscal Year 1989: ¥4,500,000 (Direct Cost: ¥4,500,000)
KeywordsDNA / Intercalator / porphyrin / インタカレ-ション
Research Abstract

We have studied the molecular basis of DNA-ligand interactions, particularly, sequence recognitions and interplay of multi-functions displayed by various DNA-binding proteins and antibiotics. We have chosen porphyrins as a probe for this study and synthesized various novel porphyrins. Free base porphyrins or their Cu, Ni complexes intercalated between the base pairs of DNA, while Mn complexes with axial ligands bound to DNA by nonintercalative mode. Porphyrins carrying four charged sidechains bound and intercalated similarly into DNA as measured by helix stabilization and DNA unwinding studies in the presence of DNA topoisomerase I. Despite their different bulky sidechains, these complexes gave essentially identical DNase I footprinting patterns. Comparison with single charged porphyrins with less bulky sidechains has shown that the presence of charged sidechains on the porphyrin rather than their identity appears to be critical for efficient DNA intercalation. All the porphyrins which bind to DNA by intercalative mode showed site-specific inhibition of Rsa I digestion of DNA. Out of two recognition sites, a site with GC-rich flanking sequence was selectively inhibited. DNase I footprinting of DNA involving the two sites has shown that 5' immediate to the inhibited cutting-site was protected from DNase I digestion. The protected regions were unexpectedly AT-rich.
We have extended the work to a synthesis of a new series of compounds whose interaction with DNA can be controlled by the second binding part introduced into the compound. At the end of hexamethylene sidechain of a porphyrin, an intercalator which is known to exhibit the same sequence specificity as bleomycin or a photocleaving agent was attached. Their binding with DNA has also been studied with helix stabilization, visible absorption spectroscopy. A crystals of a DNA hexamer-porphyrin complex have been obtained, although they are unfortunately too small for X-ray structural analysis.

Report

(3 results)
  • 1990 Annual Research Report   Final Research Report Summary
  • 1989 Annual Research Report
  • Research Products

    (24 results)

All Other

All Publications (24 results)

  • [Publications] R.Kuroda: "DNA binding and Interaction by Novel Porphyrins:Role of Charge and Substituents Probed by DNase I footprinting and Topoisomerase I Unwinding." FEBS Letters. 262. 293-298 (1990)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] J.SKelly: "Conformational Effects of Nucleotide Exchange in Ras P21 Proteins as Studied by Fluorescence Spectroscopy." FEBS Letters. 262. 127-130 (1990)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] O.M.Ni.Dhubhghaill: "Gold(I) Complexes of 1ーDiphenylphosphinoー2ーdiphenyl arsinoethane(appe):Solution Studies, Xーray Crystal Structures and Cytotoxicity of[(AuCl)_2(appe)]・0.5DMA and [Au(appe)_2]Cl・2H_2O." J.Chem.Soc.Dalton Transaction. 2913-2921 (1990)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] R.Kuroda: "Chiral Discriminations of Complexes with D_3 Symmetry.Molecular Structure and Crystal Packing Mode of (ー)_<589>ー Tris (ー)ーcyclicー0,0'ー1(R),2(R)dimethylethylenedithioー Phosphato Chromium(III),{Cr[(ー)bdtp]_3}." J.Chem.Soc.Dalton Transaction. 3393-3397 (1990)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] R.Kuroda: "Photocleavage of DNA by the pーNitrobenzoyl Group:Selective Attack in the Major or the Minor Groove of DNA." Nucleic Acids Research.

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] R.Kuroda: "Structures of Two Novel photonucleases: 3,6ーDiaminoー10ー[6ー(4ーnitrobenzoyloxy)hexyl]acridinium Chloride and 9ー[6ー(4ーNitrobenzoyloxy)hexylamino]acridine Hydrochloride." Acta Crystallographica.

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] R. Kuroda, E. Takahashi, C. A. Austin and L. M Fisher: "DNA binding and Interaction by Novel Porphyrins : Role of Charge and Substituents Probed by DNase I footprinting and Topoisomerase I Unwinding." FEBS Letters,. 262,. 293-298 (1990)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] J. V. Skelly, D. A. Suter, R. Kuroda, S. Neidle, J. F. Hancock and A. F. Drake: "Conformational Effects of Nucleotide Exchange in Ras P21 Proteins as Studied by Fluorescence Spectroscopy." FEBS Letters,. 262,. 127-130 (1990)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] O. M. Ni. Dhubhghaill, P. J. Sadler and R. Kuroda: "Gold (I) Complexes of 1-Diphenylphosphino-2-diphenyl-arsinoethane (appe) : Solution Studies, X-ray Crystal Structures and Cytotoxicity of [(AuCl)_2(appe)]・0.5DMA and [Au(appe)_2]Cl・2H_2O." J. Chem. Soc. Dalton,. 2913-2921 (1990)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] R. Kuroda and P. Biscarini: "Chiral Discriminations of Complexes with D_3 Symmetry. Molecular Structure and Crystal Packing Mode of (-)_<589>- Tris (-)-cyclic-0, 0'-1(R), 2(R)dimethylethylenedithiophosphato Chromium (III), {Cr[(-)bdtp]_3}." J. Chem. Soc. Dalton,. 3393-3397 (1990)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] R. Kuroda and M. H. shinomiya: "Photocleavage of DNA by the p-Nitrobenzoyl Group : Selective Attack in the Major or the Minor Groove of DNA." Nucleic Acids Research,.

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] R. Kuroda and M. H. Shinomiya: "Structures of Two Novel photonucleases : 3, 6-Diamino-10-[6-(4-nitrobenzoyloxy)hexyl] acridinium Chloride and 9-[6-(4-Nitrobenzoyloxy)hexylamino] acridine Hydrochloride." Acta Crystallographica,.

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] R.Kuroda: "DNA bindind and Interaction by Novel Porphyrins:Role of Charge and Substituents Probed by DNase I footprinting and Topoisomerase I Unwinding." FEBS Letters. 262. 293-298 (1990)

    • Related Report
      1990 Annual Research Report
  • [Publications] J.Skelly: "Conformational Effects of Nucleotide Exchange in Ras P21 Proteins as Studied by Fluorescence Spctroscopy." FEBS Letters. 262. 127-130 (1990)

    • Related Report
      1990 Annual Research Report
  • [Publications] O.M.Ni.Dhubhghaill: "Gold(I) Complexes、of 1ーDiphenylphosphinoー2ーdiphenylarsinoethane(appe):Solution Studies,Xーray Crystal Structures and Cytotoxicity of[(AuCl)_2(aPPe)]・0.5DMA and [Au(appe)_2]Cl・2H_2O." J.Chem.Soc.Dalton Transaction. 2913-2921 (1990)

    • Related Report
      1990 Annual Research Report
  • [Publications] R.Kuroda: "Chiral Discriminations of Complexes with D_3 Symmetry.Molecular Structure and Crystal Packing Mode of (-)_<589>Tris (-)ーcyclicー0,0'-1(R),2(R)dimethylethylenedithiophosphato Chromium(III),{Cr[(-)bdtp]_3}." J.Chem.Soc.Dalton Transaction. 3393-3397 (1990)

    • Related Report
      1990 Annual Research Report
  • [Publications] R.Kuroda: "Photocleavage of DNA by the pーNitrobenzoyl Group:Selective Attack in the Major or the Minor Groove of DNA." Nucleic Acids Research.

    • Related Report
      1990 Annual Research Report
  • [Publications] R.Kuroda: "Structures of Two Novel photonucleases:3,6ーDiaminoー10ー[6ー(4ーnitrobenzoyloxy)hexyl]acridinium Chloride and 9ー[6ー(4ーNitrobenzoyloxy)hexylamino]acridine Hydrochloride." Acta Crystallographica.

    • Related Report
      1990 Annual Research Report
  • [Publications] R.Kuroda: "DNA Binding and Interaction by Novel Porphyrins:Role of Charge and Substituents Probed by DNase I footprinting and Topoisomerase I Unwinding" FEBS Letters. in-press (1990)

    • Related Report
      1989 Annual Research Report
  • [Publications] R.C.McKenna: "Structure of Three DNA Cross-Linking Agents,Ethane-1,2-di(methylsulfonate),Propane-1,3-di(methlsulfonate)and n-Butane-1,4-di(methylsulfonate)." Acta Crystallographica. C45. 311-314 (1989)

    • Related Report
      1989 Annual Research Report
  • [Publications] R.Kuroda: "Host-Guest Chemistry in Biological Systems:Molecular Basis of DNA-Ligand Interactions." J.Synthetic Organic Chemistry. 47. 547-556 (1989)

    • Related Report
      1989 Annual Research Report
  • [Publications] P.Biscarini: "Stereoselective Synthesis and Characterization of the Optically Labile Chiral Cr(III) Complex -(+)_<589>-(Cr((-)bdtp)_3)." Inorganic Chimica Acta. 154. 209-214 (1989)

    • Related Report
      1989 Annual Research Report
  • [Publications] M.E.Cullen: "Cloning and Characterization of a DNA Gyrase A Gene from Escherichia coli that Confers Clinical Resistanceto 4-Quinolones." Antimicrobial Agents and Chemotherapy. 33. 886-894 (1989)

    • Related Report
      1989 Annual Research Report
  • [Publications] T.Yamamura: "Synthesis and Structure of a Thiolato Amine Nickel Complex.(N,N!-Ethylenebis(thiosalicylidenaminato) Nickel(II)." Chemistry Letters. 1245-1246 (1989)

    • Related Report
      1989 Annual Research Report

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Published: 1989-04-01   Modified: 2016-04-21  

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