2006 Fiscal Year Final Research Report Summary
Novel reactions of hydroxo-bridged dinuclear platinum complexes with antitumor activity
| Project/Area Number |
16590037
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Physical pharmacy
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| Research Institution | Osaka University of Pharmaceutical Sciences |
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Principal Investigator |
CHIKUMA Masahiko Osaka University of Pharmaceutical Sciences, Department of Pharmaceutical Sciences, Professor, 薬学部, 教授 (50025699)
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| Co-Investigator(Kenkyū-buntansha) |
SAITO Yoshihiro Osaka University of Pharmaceutical Sciences, Department of Pharmaceutical Sciences, Lecturer, 薬学部, 講師 (90186974)
SATO Takaji Osaka University of Pharmaceutical Sciences, Department of Pharmaceutical Sciences, Research Associate, 薬学部, 助手 (80257899)
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| Project Period (FY) |
2004 – 2006
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| Keywords | Cisplatin / Platinum complex / Cisplatin resistance / DNA / Antitumor agent / Non-covalent interaction with DNA / substitution reaction of platinum complex / Bioinorganic chemistry |
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| Research Abstract |
Cisplatin is one of the most effective antitumor agents. In an attempt to search for more active metallopharmaceuticals and to overcome cisplatin resistance, we have developed a dinuclear platinum complex, [{cis-Pt(NH_3)_2}_2(μ-pyrazolato)μ-hydroxo]]^<2+> (AMPZ) and its derivatives with pyrazolate analogs. They were effective against cisplatin resistant cell lines. In order to study the relationship between the antitumor activity and the chemical characteristics of the dinuclear complexes, the following three novel reactions were investigated in this project : (1) Proton-assisted substitution reaction, (2) Non-covalent interaction with DNA, and (3) Isomerization, that is, Pt atom migration from N2 to N3, on interaction of 1,2,3-triazole-bridged dinuclear platinum(II) complexes with 9-ethylguanine. The result of each reaction study is as follows.
1 The substitution reaction of the dinuclear platinum(II) complex was investigated in the presence of chloride as a nucleophile by HPLC, 1H-NMR
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and electronic spectral methods. In 0.2 mol/l sodium chloride the dinuclear platinum(II) complex did not react at neutral pH region within 60 min, but reacted on the addition of hydroperchloric acid to give [{cis-Pt(NH_3)_2}_2(μ-pyrazolato)(μ-Cl)]^<2+> as one of the intermediates and [{cis-Pt(NH_3)_2 Cl}_2(μ-pyrazolato)]^<2+> as the final product. Overall equilibrium reactions among the complexes were proposed.
2 AMPZ reacts with 5'-GMP at pH 7 to give AMPZ-(GMP)_2 with Pt-N7 bonds, and its reaction is extremely slow. For example, it took about 24hr to finish the reaction at 330K when AMPZ (1x10^<-3> mol/l) was reacted with 5'-GMP (4x10^<-3> mol/l) in the phosphate buffer (1x10^<-3> mol/l, pH 7). On the other hand, CD spectra of DNA were changed at pH 7 immediately after the addition of AMPZ and the intact spectra of DNA were obtained by the addition of sodium chloride. Binding study by the equilibrium dialysis method showed that AMPZ bound to DNA was removed by the addition of sodium chloride. These two experiments show that AMPZ can bind DNA in a non-covalent fashion.
3 The isomerization reaction was studied using 1H-NMR spectroscopy. When a triazolato-bridged complex was reacted with 9-ethylguanine, the Pt atom, initially bound to N2, migrates to N3 on the triazolato ring, upon reaction with N7 site of the 9-ethylguanine-.
In the three novel reactions, non-covalent interaction with DNA is the most interesting, because that of several antitumor metal complexes has been recently reported. Further study is required about the relationship between non-covalent interaction with DNA and antitumor activity. Less
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Research Products
(8 results)
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[Book] 生命元素事典2006
Author(s)
千熊正彦
Total Pages
180-186, 252-257
Publisher
オーム社
Description
「研究成果報告書概要(和文)」より
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