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Gold(I) phosphine derivatives have previously attracted interest as potential antitumour agents but hepatotoxicity was encountered during preclinical development. A series of bidentate pyridyl phosphine gold(I) and silver(I) complexes were synthesised covering a range of lipophilic/hydrophilic properties. Previously we reported that their lipophilicity greatly affects cellular uptake and cytotoxicity in a CH1 cell line. Herein we examined their in vitro uptake and cytotoxicity in a panel of human ovarian tumor cell lines and isolated hepatocytes. Sulforhodamine B assay and lactate dehydrogenase release assay were used to determine tumor cell growth inhibition and hepatocyte viability. Gold content was analyzed by inductively coupled plasma mass spectrometry. The in vitro cytotoxicity of bidentate pyridyl phosphine complexes to isolated hepatocytes and ovarian tumor cell lines correlated with their lipophilicity and rate of gold uptake. The 3- and 4-pyridyl derivatives showed less hepatotoxicity, slower cellular uptake and marked cytotoxicity to 2-deoxy-D-glucose-sensitive tumor cell lines. The cellular uptake of the 2-pyridyl gold(I) phosphine complex was partially inhibited by the membrane potential inhibitor valinomycin, and was higher in mitochondria relative to cytosolic and nuclear fractions. Unlike the phenyl phosphine gold(I) complex, the 2- and 4-pyridyl derivatives did not induce hepatotoxicity in vivo and showed lower gold accumulation in liver relative to tumor. In conclusion, the in vitro cytotoxicity of bidentate pyridyl phosphine gold(I) and silver(I) complexes to isolated hepatocytes and tumor cell lines correlated with their lipophilic/hydrophilic properties and cellular uptake. Their hepatotoxicity and antitumour activity may be due to their direct cytotoxicity, interference with energy metabolism and preferential accumulation in mitochondria. The Auckland Medical Research Foundation, the Wellcome Trust, and the Auckland Division of the Cancer Society of New Zealand supported the work.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]