title: New Acridine Thiourea Gold(I) Anticancer Agents: Targeting the Nucleus and Inhibiting Vasculogenic Mimicry.
abstract: Two new 1-acridin-9-yl-3-methylthiourea Au(I) DNA intercalators [Au(ACRTU)2]Cl (2) and [Au(ACRTU) (PPh3)]PF6(3) have been prepared. Both complexes were highly active in the human ovarian carcinoma cisplatin-sensitive A2780 cell line, exhibiting IC50values in the submicromolar range. Compounds 2 and 3 are also cytotoxic toward different phenotypes of breast cancer cell lines MDA-MB-231 (triple negative), SK-BR-3 (HER2+, ERα-, and ERβ-), and MCF-7 (ER+). Both complexes induce apoptosis through activation of caspase-3 in vitro. While inhibition of some proteins (thiol-containing enzymes) seems to be the main mechanism of action for cytotoxic gold complexes, 2 and 3 present a DNA-dependent mechanism of action. They locate in the cell nucleus according to confocal microscopy and transmission electronic microscopy. The binding to DNA resulted to be via intercalation as shown by spectroscopic methods and viscometry, exhibiting a dose-dependent response on topoisomerase I mediated DNA unwinding. In addition, 2 and 3 exhibit potent antiangiogenic effects and are also able to inhibit vasculogenic mimicry of highly invasive MDA-MB-231 cells.
authors.affiliation: Departamento de Química Inorgánica, Facultad de Química, Biomedical Research Institute of Murcia (IMIB-Arrixaca-UMU), Universidad de Murcia , E-30071 Murcia, Spain.
authors.forename: Sergio A
authors.initials: SA
authors.lastname: Pérez
authors.affiliation: Departamento de Química Inorgánica, Facultad de Química, Biomedical Research Institute of Murcia (IMIB-Arrixaca-UMU), Universidad de Murcia , E-30071 Murcia, Spain.
authors.forename: Concepción
authors.initials: C
authors.lastname: de Haro
authors.affiliation: Departamento de Química Inorgánica, Facultad de Química, Biomedical Research Institute of Murcia (IMIB-Arrixaca-UMU), Universidad de Murcia , E-30071 Murcia, Spain.
authors.forename: Consuelo
authors.initials: C
authors.lastname: Vicente
authors.affiliation: Departamento de Química Inorgánica, Facultad de Química, Biomedical Research Institute of Murcia (IMIB-Arrixaca-UMU), Universidad de Murcia , E-30071 Murcia, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Donaire
authors.affiliation: Departamento de Química Inorgánica, Facultad de Química, Biomedical Research Institute of Murcia (IMIB-Arrixaca-UMU), Universidad de Murcia , E-30071 Murcia, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Zamora
authors.affiliation: Institute of Biophysics, Academy of Sciences of the Czech Republic , v.v.i., Kralovopolska 135, 612 65 Brno, Czech Republic.|Department of Biophysics, Faculty of Science, Palacky University , Slechtitelu 27, 783 71 Olomouc, Czech Republic.
authors.forename: Juraj
authors.initials: J
authors.lastname: Zajac
authors.affiliation: Institute of Biophysics, Academy of Sciences of the Czech Republic , v.v.i., Kralovopolska 135, 612 65 Brno, Czech Republic.
authors.forename: Hana
authors.initials: H
authors.lastname: Kostrhunova
authors.affiliation: Institute of Biophysics, Academy of Sciences of the Czech Republic , v.v.i., Kralovopolska 135, 612 65 Brno, Czech Republic.
authors.forename: Viktor
authors.initials: V
authors.lastname: Brabec
authors.affiliation: SAI, Universidad de Murcia , E-30071-Murcia, Spain.
authors.forename: Delia
authors.initials: D
authors.lastname: Bautista
authors.affiliation: Departamento de Química Inorgánica, Facultad de Química, Biomedical Research Institute of Murcia (IMIB-Arrixaca-UMU), Universidad de Murcia , E-30071 Murcia, Spain.
authors.forename: José
authors.identifier: 0000-0002-0834-337X
authors.initials: J
authors.lastname: Ruiz
mesh_terms: D000166:Acridines / Q000737:chemistry; D020533:Angiogenesis Inhibitors / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D006046:Gold / Q000737:chemistry; D006801:Humans; D007364:Intercalating Agents / Q000737:chemistry* / Q000494:pharmacology; D018716:Molecular Mimicry; D009361:Neoplasm Invasiveness / Q000517:prevention & control; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D013890:Thiourea / Q000737:chemistry
chemical_list: D000166:Acridines; D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D007364:Intercalating Agents; D006046:Gold; D013890:Thiourea