title: Novel Antitumor Platinum(II) Conjugates Containing the Nonsteroidal Anti-inflammatory Agent Diclofenac: Synthesis and Dual Mechanisms of Antiproliferative Effects.
abstract: One concept how to improve anticancer effects of conventional metallodrugs consists in conjugation of these compounds with other biologically (antitumor) active agents, acting by a different mechanism. Here, we present synthesis, biological effects, and mechanisms of action of new Pt(II) derivatives containing one or two nonsteroidal anti-inflammatory diclofenac (DCF) ligands also known for their antitumor effects. The antiproliferative properties of these metallic conjugates show that these compounds are potent and cancer cell selective cytotoxic agents exhibiting activity in cisplatin resistant and the COX-2 positive tumor cell lines. One of these compounds, compound 3, in which DCF molecules are coordinated to Pt(II) through their carboxylic group, is more potent than parental conventional Pt(II) drug cisplatin, free DCF and the congeners of 3 in which DCF ligands are conjugated to Pt(II) via a diamine. The potency of 3 is due to several factors including enhanced internalization that correlates with enhanced DNA binding and cytotoxicity. Mechanistic studies show that 3 combines multiple effects. After its accumulation in cells, it releases Pt(II) drug capable of binding/damaging DNA and DCF ligands, which affect distribution of cells in individual phases of the cell cycle, inhibit glycolysis and lactate transport, collapse mitochondrial membrane potential, and suppress the cellular properties characteristic of metastatic progression.
authors.affiliation: Department of Chemistry, University of Bari "Aldo Moro" , 70125 Bari, Italy.
authors.forename: Francesco Paolo
authors.initials: FP
authors.lastname: Intini
authors.affiliation: Institute of Biophysics, Academy of Sciences of the Czech Republic , Kralovopolska 135, 61265 Brno, Czech Republic.|Department of Biophysics, Faculty of Science, Palacky University , Slechtitelu 27, 78371 Olomouc, Czech Republic.
authors.forename: Juraj
authors.initials: J
authors.lastname: Zajac
authors.affiliation: Institute of Biophysics, Academy of Sciences of the Czech Republic , Kralovopolska 135, 61265 Brno, Czech Republic.
authors.forename: Vojtech
authors.initials: V
authors.lastname: Novohradsky
authors.affiliation: Department of Chemistry, University of Bari "Aldo Moro" , 70125 Bari, Italy.
authors.forename: Teresa
authors.initials: T
authors.lastname: Saltarella
authors.affiliation: Department of Chemistry, University of Bari "Aldo Moro" , 70125 Bari, Italy.
authors.forename: Concetta
authors.initials: C
authors.lastname: Pacifico
authors.affiliation: Institute of Biophysics, Academy of Sciences of the Czech Republic , Kralovopolska 135, 61265 Brno, Czech Republic.|Department of Biophysics, Faculty of Science, Palacky University , Slechtitelu 27, 78371 Olomouc, Czech Republic.
authors.forename: Viktor
authors.initials: V
authors.lastname: Brabec
authors.affiliation: Department of Chemistry, University of Bari "Aldo Moro" , 70125 Bari, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Natile
authors.affiliation: Institute of Biophysics, Academy of Sciences of the Czech Republic , Kralovopolska 135, 61265 Brno, Czech Republic.
authors.forename: Jana
authors.identifier: http://orcid.org/0000-0002-5279-5381
authors.initials: J
authors.lastname: Kasparkova
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004008:Diclofenac / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D015394:Molecular Structure; D009944:Organoplatinum Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D004008:Diclofenac