title: [N,N'-Bis(salicylidene)-1,2-phenylenediamine]metal complexes with cell death promoting properties.
abstract: We developed N,N'-bis(salicylidene)-1,2-phenylenediamine (salophene, 1) as a chelating agent for metal ions such as Mn(II/III), Fe(II/III), Co(II), Ni(II), Cu(II), and Zn(II). The resulting complexes, from which owing to the carrier ligand a selective mode of action is assumed, were tested for antiproliferative effects on the MCF-7 breast cancer cell line. The cytotoxicity in this assay depended on the nature of the transition metal used. Iron complexes in oxidation states +II and +III (3, 4) strongly reduced cell proliferation in a concentration-dependent manner, whereas, e.g., the manganese analogues 5 and 6 were only marginally active. Therefore, the [N,N'-bis(salicylidene)-1,2-phenylenediamine]iron(II/III) complexes 3 and 4 were selected for studies on the mode of action. Both complexes possessed high activity against various tumor cells, for instance, MDA-MB-231 mammary carcinoma cells as well as HT-29 colon carcinoma cells. They were able to generate reactive oxygen species, showed DNA binding, and induced apoptosis. Exchange of 1 by N,N'-bis(salicylidene)-1,2-cyclohexanediamine (saldach, 2) yielding complexes 7 and 8 reduced the in vitro effects drastically. An unequivocal mode of action cannot be deduced from these results, but it seems to be very likely that cell death is caused by interference with more than one intracellular target.
authors.affiliation: Institute of Pharmacy, Freie Universität Berlin, Berlin, Germany.
authors.forename: Annegret
authors.initials: A
authors.lastname: Hille
authors.forename: Ingo
authors.initials: I
authors.lastname: Ott
authors.forename: Ana
authors.initials: A
authors.lastname: Kitanovic
authors.forename: Igor
authors.initials: I
authors.lastname: Kitanovic
authors.forename: Hamed
authors.initials: H
authors.lastname: Alborzinia
authors.forename: Elke
authors.initials: E
authors.lastname: Lederer
authors.forename: Stefan
authors.initials: S
authors.lastname: Wölfl
authors.forename: Nils
authors.initials: N
authors.lastname: Metzler-Nolte
authors.forename: Sven
authors.initials: S
authors.lastname: Schäfer
authors.forename: William S
authors.initials: WS
authors.lastname: Sheldrick
authors.forename: Caroline
authors.initials: C
authors.lastname: Bischof
authors.forename: Ulrich
authors.initials: U
authors.lastname: Schatzschneider
authors.forename: Ronald
authors.initials: R
authors.lastname: Gust
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000188:drug therapy; D002277:Carcinoma / Q000188:drug therapy; D002417:Cattle; D045744:Cell Line, Tumor; D002614:Chelating Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002942:Circular Dichroism; D003110:Colonic Neoplasms / Q000188:drug therapy; D004247:DNA / Q000378:metabolism; D017097:Electric Impedance; D005260:Female; D006801:Humans; D008670:Metals / Q000737:chemistry* / Q000494:pharmacology; D010084:Oxidation-Reduction; D010101:Oxygen Consumption / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D012459:Salicylates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013950:Thymus Gland / Q000378:metabolism
chemical_list: D002614:Chelating Agents; D008670:Metals; D017382:Reactive Oxygen Species; D012459:Salicylates; C090416:salophen; D004247:DNA