New cyclometalated gold (III) complex targeting thioredoxin reductase: exploring as cytotoxic agents and mechanistic insights

Recent development of gold(i) and gold(iii) complexes as therapeutic agents for cancer diseases

“…The apoptotic study of complex 330 demonstrated that at a low concentration (5 μM) of about 25.42% and at a high concentration (10 μM) of about 36.22% of MCF-7 cells were in the early apoptotic phase. 237 In 2020, Arojojoye et al designed and synthesized two chiral quinoline ligand gold( iii ) complexes 331 – 332 . The inhibitory effects of the two complexes on cell growth were monitored by the crystal violet method, and the antiproliferative activities of the two complexes and ligands were determined.…”

Complexation of Gold(III) with Pyridoxal 5′-Phosphate-Derived Hydrazones in Aqueous Solution

“…Gold has two main oxidation states, +1 and +3. While the Au + complexes have been synthesized in abundance, and their antimicrobial and antifungal properties have been thoroughly studied (including well-known compounds used for other medical purposes, e.g., auranofin, an antiarthritic agent [ 2 ]), the gold(III) complexes, on the contrary, are mainly investigated as antitumor agents based on their similarity to platinum(II) preparations [ 3 , 4 , 5 , 6 ]. A small number of Au 3+ compounds have been tested for efficacy against pathogens (see, e.g., reviews [ 7 , 8 ] and papers [ 9 , 10 , 11 , 12 , 13 , 14 ]).…”

“…From the analysis of the literature data, it can be concluded that there are two, at least, main mechanisms of the biological action of gold. First, metal has a genotoxic effect associated with the binding of coordination compounds to DNA (both intercalation [ 3 , 4 , 6 , 15 , 16 , 17 , 18 ] and covalent binding in grooves [ 5 , 19 , 20 ]) or with the cleavage of DNA caused by the formation of free cationic radicals from N-donor ligands in the presence of Au 3+ ions [ 21 ] or the unwinding of the DNA double helix of DNA [ 15 ]. Second, it may cause the inhibition of thioredoxin reductase, which leads to oxidative stress and apoptosis.…”

“…The study of binding between Au 3+ complexes and proteins and DNA is often conducted [ 3 , 4 , 5 , 6 , 9 , 15 , 16 , 17 , 18 , 19 , 20 , 35 , 36 ]. However, in the referenced papers [ 3 , 4 , 5 , 6 , 9 , 15 , 16 , 17 , 18 , 19 , 20 , 35 , 36 ], the possible dissociation of the metal complex and separate binding of the ligand and cation to the biomolecule are not taken into account (despite the process of dissociation of metal complexes in the presence of DNA or protein being possible and abundant [ 30 , 37 , 38 ]).…”

Role of the Enzymatic Environment in the Reactivity of the AuIII-C^N^C Anticancer Complexes

“…In cancer and normal cells, the activity of the TrxR enzyme is essential for cell growth and survival; therefore, it might be viewed as a target for research on antitumor chemotherapy and other diseases. − ,− In the literature, there are a large number of gold compounds that target the mitochondrial and cytoplasmic TrxR and can overcome resistance to traditional drugs such as cisplatin. ,,− Soft metal ions such as Au 1+ and their coordination compounds show high affinity for −SH or −Se – residues, which leads them to specifically target proteins or enzymes containing thiol and selenates groups. , Thereby, gold­(I) complexes have been considered as potential chemical agents for cancer therapy. ,, Indeed, crystal structures of gold–protein adducts have evidenced that Au I –S covalent bonds with active-site thiols are responsible for the strong inhibition of the enzyme activity. ,− Gold­(III) complexes have also been profiled as important chemotherapeutic agents. ,, Indeed, results have shown that stable gold­(III) complexes act at the interface of the TrxR dimer, showing an effective inhibitory effect of TrxR action. ,− Gold­(III) complexes are less stable than platinum­(II) analogues under physiological conditions and can be easily reduced to Au I derivatives by intracellular thiols such as glutathione (GSH) and cysteine (Cys) or by disulfide-reductase enzymes. ,,, The oxidation of these biomolecules leads to the formation of the RSSR sulfur-bridged dimers (2RSH → RSSR + 2H + + 2e – ), providing the electrons for gold­(III) complex reduction. , Studies of reaction mechanisms for gold­(III) complexes in the cellular environment are scarce. ,, However, it is evident that the ability of gold to form stable complexes is an important factor to improve their behavior under physiological conditions and, at the same time, for their biological action mechanisms. The perspective of Glišić et al about the reactivity of gold­(III) complexes containing N-donor ligands and chlorine concluded that the reactions with sulfur-containing amino acids and peptides primarily proceed through reduction of Au III and oxidation of the sulfur side chain.…”