Synthesis, characterization, activities, cell uptake and DNA binding of trinuclear complex: [{trans-PtCl(NH(3))}(2)mu-{trans-Pt(NH(3))(2-hydroxypyridine)-(H(2)N(CH(2))(6)NH(2))(2)]Cl(4).
The trinuclear complex: [{trans-PtCl(NH(3))}(2)mu-{trans-Pt(NH(3))(2-hydroxypyridine)-(H(2)N(CH(2))(6)NH(2))(2)]Cl(4) (code named CH9) 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. Although the compound is found to be less active (about a half time as active as cisplatin) against the parent ovary cell line A2780, it is found to be more active than cisplatin against resistant cell lines: A2780(cisR) (3.6 times more) and A2780(ZD0473R) (3.4 times more). The higher activity of CH9 against the resistant cell lines suggests that the compound has been able to overcome multiple mechanisms of resistance operating in A2780(cisR) and A2780(ZD0473R) cell lines. Like other multicentered complexes, the compound is believed to form a range of interstrand GG adducts with duplex DNA that induces permanent global changes in the DNA conformation. This binding is different from that of cisplatin and ZD0473 that form mainly intrastrand adducts, inducing a local kink in a DNA strand. Increasing prevention of BamH1 digestion of form I and form II pBR322 plasmid DNA with the increase in concentration of CH9 provides support to the idea that global changes in DNA conformation are induced as a result of its interaction with the compound.
Cheng
Howard
H
School of Biomedical Sciences, Cumberland Campus, C42, The University of Sydney, East Street, PO Box 170, Lidcombe, NSW 1825, Australia.
Huq
Fazlul
F
Beale
Philip
P
Fisher
Keith
K
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D004247:DNA / Q000187:drug effects / Q000378:metabolism*; D004586:Electrophoresis; D005260:Female; D006801:Humans; D013058:Mass Spectrometry; D009944:Organoplatinum Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013055:Spectrophotometry, Infrared
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; C506666:bis(diamminechloroplatinum(II))-mu-(ammine(2-hydroxypyridine)bis(1,6-diaminohexane)platinum(II)); D004247:DNA; D002945:Cisplatin