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 ′‐bis(salicylidene)‐1,2‐phenylenediamine (salophene, 1 ), its iron(II/III) and manganese(II/III) complexes as well as rac ‐trans‐ N , N ′‐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.

We demonstrate the cytotoxic potential of the Schiff base iron complex [FeIII(salophene)Cl] in vitro and ex vivo and illustrate its ability to overcome multiple drug resistance in vincristine and daunorubicine resistant leukemic cells (Nalm-6). Treatment of lymphoma cells (BJAB) with [FeIII(salophene)Cl] led to the exclusion of unspecific necrosis, a concentration-dependent inhibition of proliferation and a specific apoptotic cell death. We further detected a significant loss of the mitochondrial membrane potential in lymphoma cells and an up- and downregulation of various apoptosis relevant genes, respectively, indicating the involvement of the intrinsic mitochondrial pathway.

In this study, we investigated the anticancer properties of methoxy-substituted nickel(II)(salophene) derivatives. We demonstrated that the most active complex [NiII(3-OMe-salophene)] is not necrotic in Burkitt-like lymphoma cells (BJAB) and human B-cell precursor cells (Nalm-6). [NiII(3-OMe-salophene)] inhibited proliferation and induced apoptosis in a concentration dependent manner, giving evidence for the involvement of CD95 receptor-mediated, extrinsic pathway. Furthermore, [NiII(3-OMe-salophene)] overcame vincristine drug resistance in BJAB and Nalm-6 cells.

We synthesized methoxy-substituted iron(III)-salophene complexes ([Fe(III)(OMe-salophene)Cl] with salophene = N,N'-bis(salicylidene)-1,2-phenylenediamine) and analyzed their biological activity in MCF-7 and MDA-MB-231 breast cancer as well as in HT-29 colon carcinoma cells. The results obtained in a time-dependent chemosensitivity test clearly demonstrated the correlation between the cytotoxicity of the complexes and the position of methoxy substituents in the salicylidene moieties: 3-OCH(3) (4) < 5-OCH(3) (8) < H (2) < 4-OCH(3) (6) = 6-OCH(3) (10). Compounds 6 and 10 caused cytocidal effects already at a concentration of 0.5 μM. Both lead compound 2 and complex 8 showed similar time response curves, however, with a 5-fold lower activity compared to 6 and 10, respectively. Referring to [Fe(III)(salophene)Cl] (2), methoxy substitution was accompanied with the loss of tumor cell selectivity. Moreover, the free ligands (1, 3, 5, 7, and 9) were inactive.

( R , R )‐, ( S , S )‐ and ( R , S )‐ N,N ′‐bis(salicylidene)‐1,2‐diaminocyclohexane (saldach) and their iron(III) complexes were screened for anticancer activity against MCF‐7 and MDA‐MB 231 breast cancer as well as HT‐29 colon carcinoma cells. Antiproliferative effects depended on the presence of the central atom iron but were independent on the configuration at the saldach ligand. While the free ligands were inactive, the iron(III) derivatives displayed anticancer activity within a concentration range of 1 to 5 μM irrespective of the used cell line. At 5 μM they were even more active than cis ‐platin. A mode of action comparable to cis ‐platin can be excluded because it is very likely that the DNA is not the primary target of [Fe III (saldach)] complexes.

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.