[N,N'-Bis(salicylidene)-1,2-phenylenediamine]metal complexes with cell death promoting properties.
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.
Hille
Annegret
A
Institute of Pharmacy, Freie Universität Berlin, Berlin, Germany.
Ott
Ingo
I
Kitanovic
Ana
A
Kitanovic
Igor
I
Alborzinia
Hamed
H
Lederer
Elke
E
Wölfl
Stefan
S
Metzler-Nolte
Nils
N
Schäfer
Sven
S
Sheldrick
William S
WS
Bischof
Caroline
C
Schatzschneider
Ulrich
U
Gust
Ronald
R
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
D002614:Chelating Agents; D008670:Metals; D017382:Reactive Oxygen Species; D012459:Salicylates; C090416:salophen; D004247:DNA