title: Gold(I) biscarbene complexes derived from vascular-disrupting combretastatin A-4 address different targets and show antimetastatic potential.
abstract: Gold N-heterocyclic carbene (NHC) complexes are an emerging class of anticancer drugs. We present a series of gold(I) biscarbene complexes with NHC ligands derived from the plant metabolite combretastatin A-4 (CA-4) that retain its vascular-disrupting effect, yet address different cellular and protein targets. Unlike CA-4, these complexes did not interfere with tubulin, but with the actin cytoskeleton of endothelial and cancer cells. For the highly metastatic 518A2 melanoma cell line this effect was accompanied by a marked accumulation of cells in the G1 phase of the cell cycle and a suppression of active prometastatic matrix metalloproteinase-2. Despite these mechanistic differences the complexes were as strongly antivascular as CA-4 both in vitro in tube formation assays with human umbilical vein endothelial cells, and in vivo as to blood vessel disruption in the chorioallantoic membrane of chicken eggs. The antiproliferative effect of the new gold biscarbene complexes in a panel of six human cancer cell lines was impressive, with low sub-micromolar IC50 values (72 h) even against CA-4-refractory HT-29 colon and multidrug-resistant MCF-7 breast carcinoma cells. In preliminary studies with a mouse melanoma xenograft model the complexes led to significant decreases in tumor volume while being very well tolerated.
authors.affiliation: Department of Organic Chemistry, University Bayreuth, Universitätsstraße 30, 95440 Bayreuth (Germany).
authors.forename: Julienne K
authors.initials: JK
authors.lastname: Muenzner
authors.forename: Bernhard
authors.initials: B
authors.lastname: Biersack
authors.forename: Hussein
authors.initials: H
authors.lastname: Kalie
authors.forename: Ion C
authors.initials: IC
authors.lastname: Andronache
authors.forename: Leonard
authors.initials: L
authors.lastname: Kaps
authors.forename: Detlef
authors.initials: D
authors.lastname: Schuppan
authors.forename: Florenz
authors.initials: F
authors.lastname: Sasse
authors.forename: Rainer
authors.initials: R
authors.lastname: Schobert
mesh_terms: D008841:Actin Cytoskeleton / Q000187:drug effects; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D001632:Bibenzyls / Q000737:chemistry*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D056831:Coordination Complexes / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006046:Gold / Q000737:chemistry*; D019073:HT29 Cells; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D061986:MCF-7 Cells; D008545:Melanoma / Q000188:drug therapy / Q000473:pathology; D008697:Methane / Q000031:analogs & derivatives* / Q000737:chemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D018919:Neovascularization, Physiologic / Q000187:drug effects; D014404:Tubulin / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D001632:Bibenzyls; D056831:Coordination Complexes; D014404:Tubulin; C030011:carbene; D006046:Gold; C040105:combretastatin; D008697:Methane
keywords: antimetastatic agents; carbene ligands; gold; matrix metalloproteinases; vascular-disrupting agents