Synthesis and cytotoxicity of three trans-palladium complexes containing planaramine ligands in human ovarian tumor models.
The present study deals with the synthesis, characterization, and activity against human ovarian cancer cell lines A2780, A2780(cisR), A2780(ZD0473R), and SKOV-3 of three trans-planaramine-palladium(II) complexes of the form trans-PdL(2)Cl(2), coded as EH1, EH3, and EH4, for which L = 2-methylpyridine, imidazole, and 1,2-α-imidazopyridine, respectively. The cellular accumulation of palladium, palladium-DNA binding levels, and the nature of interactions of the compounds with salmon sperm and pBR322 plasmid DNA were also determined. All three compounds were found to be less active than cisplatin, but unlike cisplatin they were found to be equally or more active against the resistant cell lines A2780(cisR) and A2780(ZD0473R) than against the parent cell line A2780. Among the three palladium complexes, EH4 (which has the bulkiest carrier ligand) was found to be most active, in line with the highest cellular accumulation of palladium and highest level of palladium-DNA binding resulting from the compound. EH4 was also found to cause the greatest conformational change to pBR322 plasmid DNA. The results of this study illustrate structure-activity relationships; in particular, they support the idea that the decreased reactivity of trans-palladium complexes through the introduction of bulky ligands can make them more active against tumors.
Discipline of Biomedical Science, School of Medical Sciences, Faculty of Medicine, The University of Sydney, P.O. Box 170, 75 East Street, Lidcombe, NSW 1825, Australia.
Mohammed Ehsanul Hoque
ME
Mazumder
Philip
P
Beale
Charles
C
Chan
Jun Qing
JQ
Yu
Fazlul
F
Huq
D000588:Amines / Q000737:chemistry; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000627:therapeutic use; D056831:Coordination Complexes / Q000138:chemical synthesis* / Q000627:therapeutic use / Q000633:toxicity; D004247:DNA / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005260:Female; D006801:Humans; D007536:Isomerism; D008024:Ligands; D010051:Ovarian Neoplasms / Q000188:drug therapy; D010165:Palladium / Q000737:chemistry*
D000588:Amines; D056831:Coordination Complexes; D008024:Ligands; D010165:Palladium; D004247:DNA; D002945:Cisplatin