Bis(N-heterocyclic carbene) platinum(II), cis-diammine platinum(II) and N,N'-disubstituted cyclic thiourea silver(I) complexes : synthesis, anti-cancer properties and mechanism of action studies

Abstract

The indispensable clinical application of cisplatin and related platinum compounds in cancer chemotherapy has made the development of anti-cancer metal complexes an important research area. However, the widespread use of cisplatin and its derivatives is limited due to the undesired toxicity and emergence of drug resistance. While DNA targeting is often considered to be the mode of action of anticancer metal compounds following the cisplatin paradigm, interactions with various metabolites, peptides, and proteins are also important. Herein, silver(I) and platinum(II) complexes were designed and characterized for their anti-cancer properties. The mechanisms of the action of these complexes were also investigated by proteomic approaches aiming at protein targets identification. In Chapter 3, platinum(II) complexes bearing bis(N-heterocyclic carbene) and benzo[b]thiophene ligands were studied. A prototype of these platinum(II) complexes was previously shown to accumulate in cytoplasm instead of nucleus and engage asparagine synthetase as an anticancer target via covalent interaction. In this work, platinum(II) complexes with new bis(N-heterocyclic carbene) ligands were synthesized and characterized. They exhibited potent cytotoxicity, among which, complex 2 displayed effective anti-tumor activity in nude mice implanted with NCI-H460 lung cancer xenograft. Since the bis(N-heterocyclic carbene) platinum(II) moieties were found to covalently bind to the cysteine residues of proteins, cysteine profiling analysis was conducted using desthiobiotin polyethyleneoxide iodoacetamide probe to determine protein targets. Results revealed that thioredoxin, an antioxidant enzyme that regulates cellular redox balance and drives cancer cell proliferation, is an important target of complex 2. In Chapter 4, new cis-diammine platinum(II) complexes with luminescent benzo[b]thiophene ligands were designed with an aim to deliver the active cis-diammine platinum(II) moiety to cancer cells. These cis-diammine platinum(II) complexes exhibit higher cellular uptake efficiency and cytotoxicity in comparison with cisplatin. Among them, PtNMe with strong cellular luminescence that favors the investigation of cellular localization and activation of platinum(II) species, is focused in this work. Compared with cisplatin, treatment of PtNMe resulted in less cellular platinum-DNA adducts in cis-diammine platinum-DNA immunological assay and less DNA double stand breaks as revealed by γH2AX immunofluorescence detection. Thermal proteome profiling (TPP) analysis identified protein DnaJ homolog subfamily C member 3, an endoplasmic reticulum protein that regulates unfolded protein response, as a potential target of PtNMe. Furthermore, PtNMe displayed effective anti-tumor activity in nude mice bearing NCI-H460 lung cancer xenograft without causing body weight loss. In Chapter 5, the anti-cancer properties of silver(I) complexes with N,N’-disubstituted cyclic thiourea ligands (TU) were studied. The lipophilic TU ligands were found to facilitate the cellular uptake of silver(I) complexes, thereby increasing the cytotoxicity and anti-tumor activity. AgTU compound was demonstrated to suppress invasive activities of NCI-H460 lung cancer cells and tube formation property of endothelial cells, revealing its potential anti-metastatic and anti-angiogenic properties. In addition, AgTU could inhibit the growth of NCI-H460 lung cancer xenograft in nude mice with no mice body weight loss observed. By applying TPP analysis, AgTU was found to engage cytoplasmic protein thioredoxin reductase 1 and mitochondrial protein hydroxyacyl-CoA dehydrogenase, which play critical roles in cancer cell antioxidative defense and mitochondrial fatty acid metabolism, respectively.