title: Cinnamaldehyde and cuminaldehyde thiosemicarbazones and their copper(II) and nickel(II) complexes: a study to understand their biological activity.
abstract: This paper reports the synthesis and characterization of trans-cinnamaldehyde thiosemicarbazone (Htcin), cuminaldehyde thiosemicarbazone (Htcum) and their copper and nickel complexes. All the compounds, which on healthy cells (human fibroblasts) show a neglectable cytotoxicity, were screened in vitro in cell line U937 for their antileukemic activity. These compounds, in spite of their molecular similarity, present variegated behaviors. Htcin shows no inhibition activity in U935 cells, while both its metal complexes inhibit proliferation with IC50 at μM concentrations. The other ligand, Htcum, and its metal complexes, besides inhibiting proliferation, induce apoptosis. The cell cycle analysis highlights a G2/M checkpoint stop suggesting a possible direct action on DNA or on topoisomerase IIa. From CD and UV spectroscopy experiments, the DNA results to be not the main target of all these molecules, while both copper complexes are effective topoisomerase IIa inhibitors. All of these molecules activate caspase-9 and caspase-3, while caspase-8 activity is significantly induced by both cinnamaldehyde metal complexes. Tests on PgP and intracellular metal concentrations (determined by mean of atomic absorption spectrometry) show that the compounds tend to accumulate in the cytoplasm and that the cells do not manage to pump out copper and nickel ions.
authors.affiliation: Department of Chemistry, University of Parma, Parco Area delle Scienze 17/A, 43124 Parma, Italy; C.I.R.C.M.S.B. - Consorzio Interuniversitario di Ricerca in Chimica dei Metalli nei Sistemi Biologici, Parma Local Unit, 43124 Parma, Italy.
authors.forename: Franco
authors.initials: F
authors.lastname: Bisceglie
authors.affiliation: C.I.R.C.M.S.B. - Consorzio Interuniversitario di Ricerca in Chimica dei Metalli nei Sistemi Biologici, Parma Local Unit, 43124 Parma, Italy; Department of Clinical and Experimental Medicine, University of Parma, Via Gramsci 14, 43126 Parma, Italy.
authors.forename: Silvana
authors.initials: S
authors.lastname: Pinelli
authors.affiliation: C.I.R.C.M.S.B. - Consorzio Interuniversitario di Ricerca in Chimica dei Metalli nei Sistemi Biologici, Parma Local Unit, 43124 Parma, Italy; Department of Clinical and Experimental Medicine, University of Parma, Via Gramsci 14, 43126 Parma, Italy.
authors.forename: Rossella
authors.initials: R
authors.lastname: Alinovi
authors.affiliation: Department of Clinical and Experimental Medicine, University of Parma, Via Gramsci 14, 43126 Parma, Italy; Workers Compensation Authority (INAIL), Research Center at the University of Parma, Via Gramsci 14, 43126 Parma, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Goldoni
authors.affiliation: Department of Clinical and Experimental Medicine, University of Parma, Via Gramsci 14, 43126 Parma, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Mutti
authors.affiliation: Department of Chemistry, University of Parma, Parco Area delle Scienze 17/A, 43124 Parma, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Camerini
authors.affiliation: Department of Chemistry, University of Parma, Parco Area delle Scienze 17/A, 43124 Parma, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Piola
authors.affiliation: Department of Chemistry, University of Parma, Parco Area delle Scienze 17/A, 43124 Parma, Italy; C.I.R.C.M.S.B. - Consorzio Interuniversitario di Ricerca in Chimica dei Metalli nei Sistemi Biologici, Parma Local Unit, 43124 Parma, Italy.
authors.forename: Pieralberto
authors.initials: P
authors.lastname: Tarasconi
authors.affiliation: Department of Chemistry, University of Parma, Parco Area delle Scienze 17/A, 43124 Parma, Italy; C.I.R.C.M.S.B. - Consorzio Interuniversitario di Ricerca in Chimica dei Metalli nei Sistemi Biologici, Parma Local Unit, 43124 Parma, Italy. Electronic address: giorgio.pelosi@unipr.it.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Pelosi
mesh_terms: D000171:Acrolein / Q000031:analogs & derivatives* / Q000737:chemistry; D001547:Benzaldehydes / Q000737:chemistry*; D003300:Copper / Q000737:chemistry*; D000081007:Cymenes; D009682:Magnetic Resonance Spectroscopy; D009532:Nickel / Q000737:chemistry*; D017550:Spectroscopy, Fourier Transform Infrared; D013882:Thiosemicarbazones / Q000737:chemistry*
chemical_list: D001547:Benzaldehydes; D000081007:Cymenes; D013882:Thiosemicarbazones; D000171:Acrolein; D003300:Copper; D009532:Nickel; C007165:cuminaldehyde; C012843:cinnamaldehyde
keywords: Caspase; Copper; DNA; Nickel; Thiosemicarbazone; Topoisomerase IIa