title: Gold(I)-NHC complexes of antitumoral diarylimidazoles: structures, cellular uptake routes and anticancer activities.
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.
authors: Organic Chemistry Laboratory, University of Bayreuth, Bayreuth, Germany.
authors: Leonard
authors: L
authors: Kaps
authors: Bernhard
authors: B
authors: Biersack
authors: Helge
authors: H
authors: Müller-Bunz
authors: Katharina
authors: K
authors: Mahal
authors: Julienne
authors: J
authors: Münzner
authors: Matthias
authors: M
authors: Tacke
authors: Thomas
authors: T
authors: Mueller
authors: Rainer
authors: R
authors: Schobert
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D027682:Cation Transport Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D000079922:Copper Transport Proteins; D018360:Crystallography, X-Ray; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006046:Gold / Q000737:chemistry*; D018922:HL-60 Cells; D019073:HT29 Cells; D006571:Heterocyclic Compounds / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D056511:Metallochaperones; D008697:Methane / Q000031:analogs & derivatives / Q000737:chemistry; D008958:Models, Molecular; D018832:Molecular Chaperones / Q000378:metabolism; D015394:Molecular Structure; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology; D027701:Organic Cation Transport Proteins / Q000378:metabolism; D009942:Organometallic Compounds / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D014404:Tubulin / Q000378:metabolism
chemical_list: C474500:ATOX1 protein, human; D000970:Antineoplastic Agents; D027682:Cation Transport Proteins; D000079922:Copper Transport Proteins; D006571:Heterocyclic Compounds; D007093:Imidazoles; D056511:Metallochaperones; D018832:Molecular Chaperones; D027701:Organic Cation Transport Proteins; D009942:Organometallic Compounds; D014404:Tubulin; C030011:carbene; D006046:Gold; D008697:Methane