Synthesis, characterization, and cytotoxic properties of mono- and di-nuclear cobalt(ii)-polypyridyl complexes

Abstract

We report the synthesis and characterisation of mono- and di-nuclear cobalt(ii) complexes (1-3) containing L1, a polypyridyl ligand with pyrazole moieties. DNA binding studies suggest that the mono-nuclear complex, 1, binds to DNA via the grooves prior to inducing oxidative DNA cleavage whereas the larger di-nuclear complexes, 2 and 3, bind to DNA via the grooves and through intercalation prior to inducing oxidative DNA cleavage. The cobalt(ii) complexes display micromolar potency towards U2OS (bone osteosarcoma), HepG2 (liver hepatocellular carcinoma), and GM05757 (normal human fibroblast) cells, comparable to clinically used platinum agents, cisplatin and carboplatin. The cellular mechanism of action studies show that the most effective cobalt(ii) complex, 2, enters U2OS cells, penetrates the nucleus, induces genomic DNA damage, and triggers caspase-dependent apoptosis in a p53-independent manner. This study highlights the potential of di-nuclear cobalt(ii) complexes as artificial oxidative metallonucleases and tangible cancer cell-potent agents.

Cobalt(II) Diphenylazodioxide Complexes Induce Apoptosis in SK-HEP-1 Cells

“…Similar behavior was observed by the same group for both mono- and bimetallic Co­(II) complexes of tris­(imidazolyl)­benzene, with the monometallic complex being more potent . Ghosh and co-workers showed that a bimetallic Co­(II) complex with 4,4′-azopyridine as the bridging ligand was able to induce apoptosis in osteosarcoma cells by a caspase- and p53-independent mechanism proposed to consist of DNA binding followed by the generation of reactive oxygen species (ROS) . Simpson and co-workers demonstrated that a series of Co­(II) and Ni­(II) complexes of benzyl carbazate-derived imines induced apoptosis in leukemia cells, though the mechanism of apoptosis induction was not identified .…”

“…Cobalt­(II) salts are known to induce oxidative DNA damage via the generation of reactive oxygen species such as hydroxyl radical and superoxide, akin to the iron-catalyzed Fenton reactions . Additionally, the mechanism of apoptosis induced by some cobalt complexes has been proposed to involve the generation of ROS and subsequent oxidative DNA damage. ,, Thus, we decided to examine the possibility of ROS involvement in the proapoptotic activities of 1 and 2 . We treated SK-HEP-1 cells with several different concentrations of 1 and 2 for an incubation time of 14 h and then ran a fluorescence-based ROS assay.…”

“…13 Ghosh and co-workers showed that a bimetallic Co(II) complex with 4,4′-azopyridine as the bridging ligand was able to induce apoptosis in osteosarcoma cells by a caspase- and p53-independent mechanism proposed to consist of DNA binding followed by the generation of reactive oxygen species (ROS). 14 Simpson and co-workers demonstrated that a series of Co(II) and Ni(II) complexes of benzyl carbazate-derived imines induced apoptosis in leukemia cells, though the mechanism of apoptosis induction was not identified. 15 Similarly, Katsaros and co-workers showed that a series of bimetallic Co(II) complexes with macrocyclic ligands were highly toxic to chronic myelogenous leukemia cells with little to no necrosis observed, but the mechanism of cell death (and potential apoptosis) was not identified.…”

A Dual-Targeting Ruthenium Nanodrug that Inhibits Primary Tumor Growth and Lung Metastasis by the PARP/ATM Pathway

“…We chose A549 cells to study the distribution of 2b in cells (33)(34)(35)(36). According to the manufacturer's instructions, we separated the nucleus and mitochondria by centrifugation and detected the content of ruthenium by ICP-MS (Figure 2F).…”

Various coordination modes of new coumarin Schiff bases toward Cobalt (III) ion: Synthesis, spectral characterization, in vitro cytotoxic activity, and investigation of apoptosis

“…[ 8–10 ] To avoid systemic toxicity posed by anticancer drugs, it is better to employ endogenous metal‐containing drugs rather than exogenous metal drugs (like platinum or arsenic) since the human body has evolved with stringent pathways the overload of endogenous metals like cobalt. [ 11 ] Over the past three decades, cobalt complexes have been studied for their anticancer activity due to their relatively high human tolerance. [ 2,12 ] It is reported that transcription factors associated with cancer progression have been inhibited by cobalt (III) bis (acetylacetone)ethylenediamine complex (Doxovir) and oligonucleotides.…”