Abstract
Five new heterocyclic gold carbene complexes were prepared, four chlorido-[1,3-dimethyl-4,5-diarylimidazol-2-ylidene]gold complexes 6a-d and a chlorido-[1,3-dibenzylimidazol-2-ylidene]gold complex 11, and three of them were characterised by X-ray single crystal analyses. They were tested for cytotoxicity against a panel of four human cancer cell lines and non-malignant fibroblasts, for tubulin interaction, and for the pathways of their uptake into 518A2 melanoma cells. All complexes showed cytotoxic activity in the micromolar IC(50) range with distinct selectivities for certain cell lines. In stark contrast to related metal-free 1-methyl-4,5-diarylimidazoles, the complexes 6 and 11 did not noticeably inhibit the polymerisation of tubulin to give microtubules. The cellular uptake of complexes 6 occurred mainly via the copper transporter (Ctr1) and the organic cation transporters (OCT-1/2). Complex 11 was accumulated preferentially via the organic cation transporters and by Na(+)/K(+)-dependent endocytosis. The new gold carbene complexes seem to operate by a mechanism different from that of the parent 1-methylimidazolium ligands.
Copyright © 2011 Elsevier Inc. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents / chemistry*
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Antineoplastic Agents / pharmacokinetics
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Antineoplastic Agents / pharmacology
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Cation Transport Proteins / metabolism
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Cell Line, Tumor
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Cell Survival / drug effects
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Cells, Cultured
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Copper Transport Proteins
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Crystallography, X-Ray
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Fibroblasts / cytology
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Fibroblasts / drug effects
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Fibroblasts / metabolism
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Gold / chemistry*
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HL-60 Cells
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HT29 Cells
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Heterocyclic Compounds / chemistry*
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Heterocyclic Compounds / pharmacokinetics
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Heterocyclic Compounds / pharmacology
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Humans
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Imidazoles / chemistry
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Imidazoles / pharmacokinetics
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Imidazoles / pharmacology
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Metallochaperones
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Methane / analogs & derivatives
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Methane / chemistry
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Models, Molecular
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Molecular Chaperones / metabolism
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Molecular Structure
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Neoplasms / metabolism
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Neoplasms / pathology
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Organic Cation Transport Proteins / metabolism
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Organometallic Compounds / chemistry*
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Organometallic Compounds / pharmacokinetics
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Organometallic Compounds / pharmacology
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Tubulin / metabolism
Substances
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ATOX1 protein, human
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Antineoplastic Agents
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Cation Transport Proteins
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Copper Transport Proteins
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Heterocyclic Compounds
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Imidazoles
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Metallochaperones
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Molecular Chaperones
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Organic Cation Transport Proteins
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Organometallic Compounds
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Tubulin
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carbene
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Gold
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Methane