title: Novel copper(II) complexes as new promising antitumour agents. A crystal structure of [Cu(1,10-phenanthroline-5,6-dione)2(OH2)(OClO3)](ClO4).
abstract: The cytotoxic properties of copper(II) complexes with 1,10-phenanthroline (phen) can be modified by substitution in the phen backbone. For this purpose, Cu(II) complexes with phen, 1,10-phenanthrolin-5,6-dione (phendione) and 1,10-phenanthrolin-5,6-diol (phendiol) have been synthesised and characterised. The crystal structure of [Cu(phendione)2(OH2)(OClO3)](ClO4) is discussed. The complex formation equilibria between Cu(II) and phen or phendione were studied by potentiometric measurements at 25 and 37°C in 0.1 M ionic strength (NaCl). The antitumour activity of the compounds has been tested in vitro against a panel of tumour (DU-145, HEP-G2, SK-MES-1, CCRF-CEM, CCRF-SB) and normal (CRL-7065) human cell lines. The studied compounds generally present an antiproliferative effect greater than that of cisplatin. The phen and phendione ligands present a similar antiproliferative effect against all the tested cells. Phendiol presents an antiproliferative effect 1.3 to 18 times greater than that of phen or phendione for leukemic, lung, prostatic and fibroblast cells, while it presents less activity towards hepatic cells. Complexes with two ligands are more cytotoxic towards all the tested cell lines than complexes with one ligand and are generally more cytotoxic than the ligand alone. Complexes [Cu(phendiol)2(OH2)](ClO4)2 and [Cu(phendione)2(OH2)(OClO3)](ClO4) appear to be the most active compounds for the treatment of SK-MES-1 and HEP-G2 cells, respectively, being at least 18 times more cytotoxic than cisplatin. The studied Cu(II) complexes are characterised by a strong DNA affinity and were found to interact with DNA mainly by groove binding or electrostatic interactions. The complexes appear to act on cells with a mechanism different from that of cisplatin.
authors.affiliation: Dipartimento di Scienze Chimiche e Geologiche, University of Cagliari, Cittadella Universitaria, 09042 Monserrato, CA, Italy. Electronic address: tpivetta@unica.it.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Pivetta
authors.affiliation: Dipartimento di Scienze Chimiche e Geologiche, University of Cagliari, Cittadella Universitaria, 09042 Monserrato, CA, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Trudu
authors.affiliation: Dipartimento di Scienze Chimiche e Geologiche, University of Cagliari, Cittadella Universitaria, 09042 Monserrato, CA, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Valletta
authors.affiliation: Dipartimento di Scienze Chimiche e Geologiche, University of Cagliari, Cittadella Universitaria, 09042 Monserrato, CA, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Isaia
authors.affiliation: Dipartimento di Chimica, University of Milano, Via C. Golgi, 19-20133 Milano, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Castellano
authors.affiliation: Dipartimento di Chimica, University of Milano, Via C. Golgi, 19-20133 Milano, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Demartin
authors.affiliation: Dipartimento di Scienze Biomediche, University of Cagliari, Cittadella Universitaria, 09042 Monserrato, CA, Italy.
authors.forename: Rossana
authors.initials: R
authors.lastname: Tuveri
authors.affiliation: Dipartimento di Scienze Biomediche, University of Cagliari, Cittadella Universitaria, 09042 Monserrato, CA, Italy.
authors.forename: Sarah
authors.initials: S
authors.lastname: Vascellari
authors.affiliation: Dipartimento di Scienze Biomediche, University of Cagliari, Cittadella Universitaria, 09042 Monserrato, CA, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Pani
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D056831:Coordination Complexes / Q000138:chemical synthesis* / Q000494:pharmacology; D003300:Copper / Q000737:chemistry*; D018360:Crystallography, X-Ray; D003603:Cytotoxins / Q000138:chemical synthesis* / Q000494:pharmacology; D004247:DNA / Q000737:chemistry; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D007364:Intercalating Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D009928:Organ Specificity; D010618:Phenanthrolines / Q000737:chemistry*; D055672:Static Electricity; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D056831:Coordination Complexes; D003603:Cytotoxins; D007364:Intercalating Agents; D010618:Phenanthrolines; C037153:1,10-phenanthroline-5,6-dione; D003300:Copper; D004247:DNA; C427203:calf thymus DNA; D002945:Cisplatin
keywords: Copper complexes; Crystal structure; Cytotoxicity; DNA binding; Solution equilibria