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

Abstract

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)-salophene catalyzes redox cycles that induce phospholipid peroxidation and deplete cancer cells of ferroptosis-protecting cofactors

“…SCs are potent inducers of cell death in several cancer cell lines [ 29 , 31 , 33 , 42 , 43 , 67 , 68 ], including cisplatin-resistant cells [ 31 , 42 , 68 ]. To further explore the therapeutic potential of SCs in the treatment of therapy-resistant cancers, we investigated the cytotoxic activity of [Chlorido (Fe(III)-salophene)] ( 1 ) and its two close structural derivatives [Chlorido (Fe(III)-salophene)]-F ( 2 ) and [Chlorido (Fe(III)-salophene)]-Cl ( 3 ) ( Fig.…”

Therapeutic strategies of targeting non-apoptotic regulated cell death (RCD) with small-molecule compounds in cancer

“…In addition, chlorido[4-carboxy-1,2-disalicylideneaminobenzene]iron(III) derivatives have been reported to not only induce ferroptosis but also induce necroptosis to reduce the viability of HL-60 cells 243 . Similarly, chlorido[4-propoxycarbonyl- N , N ′-bis(salicylidene)-1,2-phenylenediamine]cobalt(III) and chlorido[4-butoxycarbonyl- N , N ′-bis(salicylidene)-1,2-phenylenediamine]cobalt(III) have been found to induce necroptosis in A2780 and HL-60 cells ( Supporting Information Table S3 ) 297 . At present, most compounds have been found to regulate necroptosis by directly or indirectly acting on RIPK1, RIPK3, and MLKL.…”

Transferrin Receptor-Mediated Cellular Uptake of Fluorinated Chlorido[N,N′-bis(salicylidene)-1,2-phenylenediamine]iron(III) Complexes

“…Platinum complexes derived from the most studied antitumor drug cisplatin − are important tools for cancer treatment; however, more recently metal complexes of iron, gold, ruthenium, or gallium have also shown potent anticancer activity. − In particular, salophene complexes (salophene = N , N ′-bis(salicylidene)-1,2-phenylenediamine) are of interest, as they are readily accessible from cheap precursors, show catalytic activity, and can form stable complexes with transition metals. − The knowledge on the antitumor effect of salophene complexes containing metal ions, such as Ni 2+ , Co 2+ , or Zn 2+ , however, is limited but may be explained by their reduced cytotoxic activity in comparison to their Fe 2+/3+ counterparts. − …”