Synthesis, activity and binding with DNA of [{trans-PtCl(NH(3))(2)}(2)micro-{trans-Pd(4-hydroxypyridine) (2) (H(2)N(CH(2))(6)NH(2))(2)]Cl(4) (TH8).
This paper describes the synthesis, characterization, cytotoxicity of a new trinuclear Pt-Pd-Pt complex code named TH8 containing two 4-hydroxypyridine ligands bound to the central metal ion. In addition to its activity against human ovarian cancer cell lines: A2780, A2780(cisR) and A2780(ZD0473R), cell uptake, level of DNA-binding and nature of interaction of the compound with pBR322 plasmid DNA have also been determined. TH8 is found to be less active than cisplatin against the parent cell line A2780 but is more active against the cisplatin-resistant cell line A2780(cisR). Whereas the resistance factors for cisplatin as applied to the cell lines A2780 and A2780(cisR), and A2780 and A2780(ZD0473R) are 12.9 and 3.0 respectively, the corresponding values for TH8 are 1.4 and 2.1. The results suggest that TH8 has been better able to overcome the resistance operating in A2780(cisR) cell line. Whereas cisplatin binds with DNA forming mainly intrastrand GG adduct that causes local bending of a DNA strand, TH8 is expected to bind with DNA forming mainly interstrand GG adducts that would cause more of a global change in DNA conformation.
Huq
Fazlul
F
Discipline of Biomedical Science, Faculty of Medicine, The University of Sydney, PO Box 170, 75 East Street, Lidcombe, NSW 1825, Australia. F.Huq@usyd.edu.au
Tayyem
Hasan
H
Yu
Jun Qing
JQ
Beale
Philip
P
Fisher
Keith
K
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D001692:Biological Transport; D045744:Cell Line, Tumor; D004247:DNA / Q000378:metabolism*; D015245:Deoxyribonuclease BamHI / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D008024:Ligands; D009944:Organoplatinum Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D010957:Plasmids / Q000235:genetics; D011725:Pyridines / Q000737:chemistry; D011728:Pyridones; D013057:Spectrum Analysis
D000970:Antineoplastic Agents; D008024:Ligands; D009944:Organoplatinum Compounds; D011725:Pyridines; D011728:Pyridones; C534143:4-pyridone; D004247:DNA; D015245:Deoxyribonuclease BamHI