Synthesis and biological evaluation of salophen nickel(II) and cobalt(III) complexes as potential anticancer compounds

Recent in vitro investigations of N,N′‐bis(salicylidene)‐1,2‐phenylenediamine (SAP) iron(III) complexes substituted with alkyl (ethyl, propyl, butyl) carboxylates at position 4 in tumor and leukemia cells revealed strong cytotoxic activity. In continuation of this study, analogous nickel(II) and cobalt(III) complexes were synthesized and tested in HL‐60 leukemia, and cisplatin‐sensitive and ‐resistant A2780 ovarian cancer cell lines. The biological activity depended on the extent of cellular uptake and the formation of reactive oxygen species (ROS). Inactive [(Ni(II)SAP] complexes (1−3) only marginally accumulated in tumor cells and did not induce ROS. The cellular uptake of [Co(III)SAP]Cl complexes (4−6) into the cells depended on the length of the ester alkyl chain (ethyl, 4 < propyl, 5 < butyl, 6). The cytotoxicity correlated with the presence of ROS. The low cytotoxic complex 4 induced only few ROS, while 5 and 6 caused a good to outstanding antiproliferative activity, exerted high ROS generation, and induced cell death after 48 h. Necrostatin‐1 prevented the biological effects, proving necroptosis as part of the mode of action. Interestingly, the effects of 5 and 6 were not reversed by Ferrostatin‐1, but even enhanced upon simultaneous application to the tumor cells. Iron(III) complexes of N,N'‐bis(salicylidene)‐1,2‐phenylenediamine were already described as promising anticancer compounds. In continuation and extension to the iron triad, analogous nickel(II) and cobalt(III) complexes were synthesized, characterized, and comprehensively investigated with respect to their biological properties (e.g., antiproliferative and antimetabolic activity, cell‐death induction, and generation of reactive oxygen species).