title: Exploring the Influence of the Aromaticity on the Anticancer and Antivascular Activities of Organoplatinum(II) Complexes.
abstract: A series of new organometallic PtIIcomplexes of the type [Pt(C^N)Cl(DMSO)] (C^N=N,N-dimethyl-1-(2-aryl)methanamine-κ2C2,N; aryl=phenyl 2 a, biphenyl 2 b, p-terphenyl 2 c, naphthyl 2 d, anthracenyl 2 e, or pyrenyl 2 f) have been synthesized to explore the influence of the aromaticity on their anticancer activity. The best performers, 2 b and d, are more active than cisplatin (CDDP) in epithelial ovarian carcinoma cells A2780, with 2 d having a higher selectivity factor than CDDP in all the tested cell lines. In addition, all the new compounds overcome the acquired resistance in A2780cisR cells and interestingly, show low micromolar IC50values towards the triple negative breast cancer cell line MDA-MB-231 and the highly metastatic 518A2 melanoma cells. This study shows that the hydrophobicity, accumulation into cells, and metal levels on nuclear DNA for the complexes are consistent with their cytotoxicity. Complexes 2 b and d induce apoptosis in a caspase-independent manner and suppress the intracellular ROS generation without modifying the mitochondria membrane potential. In addition, 2 a-f effectively inhibit angiogenesis in the endothelial cell line EA.hy926 at sub-cytotoxic concentrations and 2 b and d show in vivo antivascular effects on the chorioallantoic membrane (CAM) of fertilized SPF-eggs (SPF=specific-pathogen-free). Inhibition of tubulin polymerization and degeneration of cytoskeleton organization in 518A2 melanoma cells are presented as a preliminary mechanism of its antimetastatic activity.
authors.affiliation: Departamento de Química Inorgánica and Regional Campus of International Excellence "Campus Mare Nostrum", Universidad de Murcia, and Institute for Bio-Health, Research of Murcia (IMIB-Arrixaca), 30071, Murcia, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Zamora
authors.affiliation: Departamento de Química Inorgánica and Regional Campus of International Excellence "Campus Mare Nostrum", Universidad de Murcia, and Institute for Bio-Health, Research of Murcia (IMIB-Arrixaca), 30071, Murcia, Spain.
authors.forename: Sergio A
authors.initials: SA
authors.lastname: Pérez
authors.affiliation: Organic Chemistry Laboratory, University Bayreuth, Universitaetsstrasse 30, 95440, Bayreuth, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Rothemund
authors.affiliation: Departamento de Química Inorgánica and Regional Campus of International Excellence "Campus Mare Nostrum", Universidad de Murcia, and Institute for Bio-Health, Research of Murcia (IMIB-Arrixaca), 30071, Murcia, Spain.
authors.forename: Venancio
authors.initials: V
authors.lastname: Rodríguez
authors.affiliation: Organic Chemistry Laboratory, University Bayreuth, Universitaetsstrasse 30, 95440, Bayreuth, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Schobert
authors.affiliation: Institut für Anorganische Chemie und Strukturchemie, Heinrich-Heine-Universität Düsseldorf, Universitätsstr. 1, 40225, Düsseldorf, Germany.
authors.forename: Christoph
authors.identifier: http://orcid.org/0000-0002-6288-9605
authors.initials: C
authors.lastname: Janiak
authors.affiliation: Departamento de Química Inorgánica and Regional Campus of International Excellence "Campus Mare Nostrum", Universidad de Murcia, and Institute for Bio-Health, Research of Murcia (IMIB-Arrixaca), 30071, Murcia, Spain.
authors.forename: José
authors.identifier: http://orcid.org/0000-0002-0834-337X
authors.initials: J
authors.lastname: Ruiz
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008545:Melanoma / Q000737:chemistry* / Q000188:drug therapy; D009389:Neovascularization, Pathologic; D009944:Organoplatinum Compounds / Q000737:chemistry / Q000494:pharmacology*; D014404:Tubulin / Q000737:chemistry*
chemical_list: D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D014404:Tubulin; D002945:Cisplatin
keywords: angiogenesis; anticancer; antivascular; cyclometalated; platinum