title: Effects of histidin-2-ylidene vs. imidazol-2-ylidene ligands on the anticancer and antivascular activity of complexes of ruthenium, iridium, platinum, and gold.
abstract: Couples of N-heterocyclic carbene complexes of ruthenium, iridium, platinum, and gold, each differing only in the carbene ligand being either 1,3-dimethylimidazol-2-ylidene (IM) or 1,3-dimethyl-N-boc-O-methylhistidin-2-ylidene (HIS), were assessed for their antiproliferative effect on seven cancer cell lines, their interaction with DNA, their cell cycle interference, and their vascular disrupting properties. In MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assays only the platinum complexes were cytotoxic at single-digit micromolar IC50concentrations with the (HIS)Pt complex being on average twice as active as the (IM)Pt complex. The former was highly efficacious against cisplatin-resistant HT-29 colon carcinoma cells where the latter had no effect. Both Pt complexes were accumulated by cancer cells and bound to double-helical DNA equally well. Only the (HIS)Pt complex modified the electrophoretic mobility of circular DNA in vitro due to the HIS ligand causing greater morphological changes to the DNA. Both platinum complexes induced accumulation of 518A2 melanoma cells in G2/M and S phase of the cell cycle. A disruption of blood vessels in the chorioallantoic membrane of fertilized chicken eggs was observed for both platinum complexes and the (IM)gold complex. The (HIS)platinum complex was as active as cisplatin in tumor xenografted mice while being tolerated better. We found that the HIS ligand may augment the cytotoxicity of certain antitumoral metal fragments in two ways: by acting as a transmembrane carrier increasing the cellular accumulation of the complex, and by initiating a pronounced distortion and unwinding of DNA. We identified a new (HIS)platinum complex which was highly cytotoxic against cancer cells including cisplatin-resistant ones.
authors: Organic Chemistry Laboratory, University of Bayreuth, Universitätsstraße 30, 95447 Bayreuth, Germany.
authors: Florian
authors: F
authors: Schmitt
authors: School of Chemistry and Chemical Biology, University College Dublin, Belfield, Dublin 4, Ireland.
authors: Kate
authors: K
authors: Donnelly
authors: Organic Chemistry Laboratory, University of Bayreuth, Universitätsstraße 30, 95447 Bayreuth, Germany.
authors: Julienne K
authors: JK
authors: Muenzner
authors: Organic Chemistry Laboratory, University of Bayreuth, Universitätsstraße 30, 95447 Bayreuth, Germany.
authors: Tobias
authors: T
authors: Rehm
authors: Institute of Biophysics, Academy of Sciences of the Czech Republic, CZ-61265 Brno, Czech Republic.
authors: Vojtech
authors: V
authors: Novohradsky
authors: Institute of Biophysics, Academy of Sciences of the Czech Republic, CZ-61265 Brno, Czech Republic.
authors: Viktor
authors: V
authors: Brabec
authors: Department of Biophysics, Faculty of Science, Palacky University, 17. listopadu 12, CZ-77146 Olomouc, Czech Republic.
authors: Jana
authors: J
authors: Kasparkova
authors: School of Chemistry and Chemical Biology, University College Dublin, Belfield, Dublin 4, Ireland.
authors: Martin
authors: M
authors: Albrecht
authors: Organic Chemistry Laboratory, University of Bayreuth, Universitätsstraße 30, 95447 Bayreuth, Germany. Electronic address: Rainer.Schobert@uni-bayreuth.de.
authors: Rainer
authors: R
authors: Schobert
authors: Department of Internal Medicine IV, Oncology/Hematology, Martin-Luther-University Halle-Wittenberg, 06120 Halle-Saale, Germany.
authors: Thomas
authors: T
authors: Mueller
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D002642:Chick Embryo; D006046:Gold / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D007495:Iridium / Q000737:chemistry / Q000494:pharmacology; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010984:Platinum / Q000737:chemistry / Q000494:pharmacology; D012428:Ruthenium / Q000737:chemistry / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D007093:Imidazoles; D007495:Iridium; D010984:Platinum; D006046:Gold; D012428:Ruthenium
keywords: Anticancer agent; Gold complex; Histidin-2-ylidene; N-heterocyclic carbene complex; Platinum complex; Vascular-disrupting agent