Synthesis, characterisation, activities, cell uptake and DNA binding of a trinuclear complex: [[trans-PtCl(NH3)]2mu-[trans-Pd(NH3)(2-hydroxypyridine)-(H2)N(CH2)6NH2)2]Cl4.
The trinuclear complex: [[trans-PtCl(NH3)](2)mu-[trans-Pd(NH(3))(2-hydroxypyridine)-(H(2)N(CH(2))(6)NH(2))(2)]Cl(4) (code named CH25) has been synthesized and characterized. The activity of the compound against human ovarian cancer cell lines: A2780, A2780 cisR and A2780 ZD0473R, cell up take, level of binding with DNA and nature of its interaction with pBR322 plasmid DNA have been determined. The compound is found to exhibit significant anticancer activity against the cell lines-about 45 times as active as cisplatin against A2780 cell line, about 76 times as active as cisplatin against A2780(cisR) cell line and about seven times as active as cisplatin against A2780cell line. The higher activity of CH25 suggests that the compound is able to overcome multiple mechanisms of resistance operating in A2780(cisR) and A2780(ZD0473R) cell lines. The compound is believed to form a range of interstrand GG adducts with duplex DNA that induces global changes in the DNA conformation, unlike cisplatin and ZD0473 [also known as AMD473 and JM473: cis-(2-methylpyridine)(ammine)dichloroplatinum(II)] that form mainly intrastrand adducts that induces a local kink in a DNA strand. The increasing prevention of BamH1 digestion of form I and form II pBR322 plasmid DNA with the increase in concentration of the compound is believed to be due to interstrand binding that brings about global changes in DNA conformation.
Cheng
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School of Biomedical Sciences, Cumberland Campus, The University of Sydney, Lidcombe, NSW, Australia.
Huq
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Beale
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Fisher
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K
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D004247:DNA / Q000235:genetics / Q000378:metabolism*; D004587:Electrophoresis, Agar Gel; D006801:Humans; D015394:Molecular Structure; D009944:Organoplatinum Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D010957:Plasmids / Q000235:genetics / Q000378:metabolism; D013057:Spectrum Analysis
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; C506666:bis(diamminechloroplatinum(II))-mu-(ammine(2-hydroxypyridine)bis(1,6-diaminohexane)platinum(II)); D004247:DNA; D002945:Cisplatin