| Project/Area Number |
07672332
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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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| Project Period (FY) |
1995 – 1996
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| Project Status |
Completed (Fiscal Year 1996)
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| Budget Amount *help |
¥2,000,000 (Direct Cost: ¥2,000,000)
Fiscal Year 1996: ¥400,000 (Direct Cost: ¥400,000)
Fiscal Year 1995: ¥1,600,000 (Direct Cost: ¥1,600,000)
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| Keywords | Cisplatin / Cisplatin-resistant cancer cells / Platinum complex / Dinuclear complex / Anticancer platinum complex / DNA / Anticancer agent / Bioinorganic chemistry / 白金ジアミン錯体 / 核酸-金属錯体 / ピラゾール錯体 / シスプラチン耐性癌 |
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| Research Abstract |
Cisplatin, a DNA-damging agent, is one of the most widely used anticancer drugs. A current exciting challenge in platinum medicinal chemistry is to design new and more effective agents capable of overcoming cisplatin resistance based on the detailed knowledge of the cisplatin-DNA interaction. A new dinuclear platinum complex, mu-hydroxo-mu-pyrazolato-bis {cis-diammineplatinum (II) } dinitrate derived from cisplatin was prepared and characterized by nuclear magnetic resonance (NMR) and infrared spectroscopies. The reaction of the dinuclear platinum complex and cisplatin with guanosine-5'-mono-phasphate, 9-ethylguanine (9EG), and DNA was investigated kinetically by high performance liquid chromatography and NMR and circular dichromism spectrocsopies. The results of X-ray crystallographic analysis of the dinuclear complex-9EG adduct show that the bridged pyrazolato ligand is extremely inert while the bridged hydroxo ligand is substituted with two 9EG molecules and that one 9EG molecule binds to one platinum, and that stacking between the two 9EG molecules is observed. The presence of stacking between two nucleic acid bases suggests that the binding of this dinuclear complex to DNA may introduce only small conformational change. Since recently DNA-repair enzyme systems have been considered to recognize structural distortions of DNA introduced by platinum binding and to remove the platinums in the consequent biological processing, the only small DNA-distortion derived by the dinuclear platinum complex binding is suggested not to be recognized by the repair-enzyme systems. Cytotoxicity of the dinuclear complex against cisplatin-resistant cancer cell lines is considered to be attributted to insensitiveness of DNA-repair system to the dinuclear platinum complex binding.
The results obtained from this research project promise to lead to the development of new generation of platinum anticancer drugs.
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