Intermediate Detection in the Casiopeina–Cysteine Interaction Ending in the Disulfide Bond Formation and Copper Reduction

Abstract

A strategy to improve the cancer therapies involves agents that cause the depletion of the endogenous antioxidant glutathione (GSH), increasing its efflux out of cells and inducing apoptosis in tumoral cells due to the presence of reactive oxygen species. It has been shown that Casiopeina copper complexes caused a dramatic intracellular GSH drop, forming disulfide bonds and reducing CuII to CuI. Herein, through the determination of the [CuII]–SH bond before reduction, we present evidence of the adduct between cysteine and one Casiopeina as an intermediate in the cystine formation and as a model to understand the anticancer activity of copper complexes. Evidence of such an intermediate has never been presented before.

Casiopeinas of Third Generations: Synthesis, Characterization, Cytotoxic Activity and Structure–Activity Relationships of Mixed Chelate Compounds with Bioactive Secondary Ligands

“…Casiopeinas have shown good cytotoxic activity against several cancer cell lines and antineoplastic activity in vitro and in vivo [ 16 , 17 ]. Several mechanisms of action have been proposed to explain these activities, including genotoxicity as a result of DNA interaction [ 18 , 19 ] and overproduction of reactive oxygen species (ROS) [ 20 , 21 ] mediated by endogenous reducers [ 22 ] and mitochondrial imbalance [ 23 , 24 ]. On the contrary, it has been shown that Casiopeinas do not present considerable cytotoxic effects in normal cells, which highlights them as potential antitumor agents; in fact, one molecule is already being tested in a clinical phase 1 trial in Mexico.…”

Casiopeinas® as SARS-CoV-2 main protease (Mpro) inhibitors: a combined DFT, molecular docking and ONIOM approach

“…For instance, the copper atom of Casiopeinas can form Cu-O and Cu-N bonds with phosphate groups and nitrogenous bases founded in DNA, 29,32 and the interaction between glutathione and Casiopeinas can generate adducts by the Cu-S linkage. 33 Typically, Casiopeinas and related Cu II compounds are pyramidal or octahedral compounds in solid state. 34,35 The equatorial plane is constituted by the aromatic diimine (N-N) and the secondary (L-L) donors.…”

“…In aqueous solution, conductivity and electron paramagnetic resonance measurements suggest that the nitrato ligands can be replaced by solvent molecules. 36 In biological media, nucleotides 37,38 and other relevant biological species [27][28][29][30]32,33,35 interact with copper compounds through donor exchange mechanism. In Scheme 1, Casiopeinas examined in this study are presented.…”

Redox Active Molecules in Cancer Treatments

“… Natural plant compounds (naringenin [ 3 ], papaverine [ 4 ], polyphenols isolated from Myrciaria trunciflora [ 5 ] or Anneslea fragrans [ 6 ], and seed-derived peptides [ 7 ]), natural compounds also found in animals (melatonin [ 2 , 8 ]), and peptides as well as proteins from Jellyfish venom [ 9 ]. Synthetic compounds, i.e., alkyl thiols [ 10 ], dimethyl sulfoxide [ 11 ], metformin and S63845 [ 12 ], the ruthenium complex [Ru(Phen) 3 ] 2+ [ 13 ], and copper-based compounds—Casiopeinas [ 14 ]. Different formulations, i.e., peptide fractions from germinated soybeans conjugated to Fe 3 O 4 nanoparticles [ 15 ] and astaxanthin microparticles in combination with pentoxifylline [ 16 ].…”

“…Synthetic compounds, i.e., alkyl thiols [ 10 ], dimethyl sulfoxide [ 11 ], metformin and S63845 [ 12 ], the ruthenium complex [Ru(Phen) 3 ] 2+ [ 13 ], and copper-based compounds—Casiopeinas [ 14 ].…”