Full Paper Effects of Metal Salophene and Saldach Complexes on Lymphoma and Leukemia Cells Annegret Hille 1 , Tanja Wolf 2 , Petra Schumacher 2 , Ingo Ott 3 , Ronald Gust 1 , and Brigitte Kircher 2 1 Free University of Berlin, Institute of Pharmacy, Berlin, Germany 2 Innsbruck Medical University, Department of Internal Medicine V – Hematology & Oncology, Immunobiology and Stem Cell Laboratory, Innsbruck, Austria 3 Technical University Braunschweig, Institute of Pharmaceutical Chemistry, Braunschweig, Germany Schiff base transition metal complexes are an important class of compounds with great potential for therapeutic interventions. However, data on antileukemic and antilymphoma effects of these complexes are limited. The activity of N,N 0 -bis(salicylidene)-1,2-phenylenediamine (salophene, 1), its iron(II/III) and manganese(II/III) complexes as well as rac-trans-N,N 0 -bis(salicylidene)-1,2- cyclohexanediamine (saldach, 2) and its respective iron(II/III) complexes was evaluated against U-937 non-Hodgkin’s lymphoma and the HL-60, SUP-B15, and K-562 leukemia cell lines. The free ligands induced in all cell lines, if at all, only marginal, concentration-dependent growth inhibitory effects, and did not trigger Cu/Zn superoxide dismutase (Cu/Zn SOD) release or induce apoptosis. [Fe II (salophene)] (3) and [Fe III (salophene)Cl] (4) blocked cellular growth, caused a strong release of Cu/Zn SOD and induced apoptosis. In contrast, the manganese analogs [Mn II (salophene)] (5) and [Mn III (salophene)OAc] (6) inhibited cell growth, caused the programmed cell death only at higher concentrations and did not provoke release of Cu/Zn SOD in any of the four cell lines. Weaker cell death-promoting effects were observed when the salophene moiety of 3 and 4 was replaced with saldach (complexes 7 and 8), indicating the influence exerted by the ligand structure. In conclusion, Schiff base transition metal complexes induce strong inhibitory effects on human lymphoma and leukemia cells. Keywords: Antileukemic compounds / Apoptosis / Bioinorganic chemistry / Cu/Zn superoxide dismutase / Schiff base complexes Received: August 18, 2010; Revised: October 8, 2010; Accepted: October 15, 2010 DOI 10.1002/ardp.201000237 Introduction Schiff base transition metal complexes have been used for decades in organic synthesis as catalytically acting species [1–8]. Presently, they are becoming more and more attractive lead structures for the design of cytostatics with a mode of action that differs from that of the frequently administered anticancer agent cisplatin and its second-generation deriva- tives such as carboplatin, which still induce non-tolerable side-effects and resistance. Furthermore, the diseases responding to platinum complexes are mainly solid tumors and the application of these compounds in leukemia is lim- ited [9]. A first step in the development of new anticancer com- pounds was the replacement of the ammine ligands with carrier ligands. We used 1,2-diarylethylenediamines as neu- tral ligands (see A in Scheme 1). The resulting platinum complexes accumulated in leukemic and tumor cells [10] and induced strong growth inhibitory effects through a mode of action comparable to that of cisplatin and depen- dent on the substituents in the aromatic rings [11, 12]. Another very promising carrier is 1,2-diaminocyclohexane (DACH). Its use in pharmaceutical research increased with the observation made by Kidani et al. in the early 1980s, namely that platinum complexes bearing DACH exhibit excellent Correspondence: Brigitte Kircher, Innsbruck Medical University, Department of Internal Medicine V – Hematology & Oncology, Immunobiology and Stem Cell Laboratory, Anichstr. 35, 6020 Innsbruck, Austria. E-mail: brigitte.kircher@i-med.ac.at Fax: þ43 512 504 23338 Arch. Pharm. Chem. Life Sci. 2011, 11, 217–223 217 ß 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim