The chemotherapy with gold complexes has been attempted since the 90s after the clinical success of auranofin, a gold(I) coordination complex. Currently, the organometallics compounds have shown promise in cancer therapy, mainly in those complexes containing N-heterocylic carbenes (NHC) as a ligand. The present study shows a kinetic analysis of the reaction of six alkyl-substituted NHC with cysteine (Cys), which is taken as an important bionucleophile representative. The first and second ligand exchange processes were analyzed with the complete description of the mechanism and energy profiles. For the first reaction step, which is the rate-limiting step of the whole substitution reaction, the activation enthalpy follows the order 1/Me2 < 2/Me,Et < 4/n-Bu2 < 3/i-Pr2 < 6/Cy2 < 5/t-Bu2, which is fully explained by steric and electronic features. From a steric point of view, the previous reactivity order is correlated with the r(Au-S) calculated for the transition state structures where S is the sulfur ligand from the Cys entering group. This means that longer r(Au-S) leads to higher activation enthalpy and is consistent with the effectiveness of gold shielding from nucleophile attack by bulkier alkyl-substituted NHC ligand. When electronic effect was addressed we found that higher activation barrier was predicted for strongly electron-donating NHC ligand, represented by the eigenvalue of σ-HOMO orbital of the free ligands. The molecular interpretation of the electronic effects is that strong donating NHC forms strong metal-ligand bond. For the second reaction step, similar structure-reactivity relationships were obtained, however the activation energies are less sensitive to the structure.

Gold complexes are promising compounds used in cancer chemotherapy. Besides their steric features, which enable biomolecule interactions, the redox instability and the high affinity of gold with cellular nucleophiles influence the biological action in these complexes. Both features were herein theoretically investigated for the [Au(C^N^C)Cl] probe complex (C^N^C = 2,6-diphenylpyridine) using HO, CHSH/CHS, CHSe and meim-4-H (4-methylimidazole) as biomimetic nucleophiles. Based on the results, the lowest energy reaction path followed two consecutive steps: (1) chloride-exchange ([Formula: see text] = 4.14 × 10 M s) and (2) reduction of the resulting Au(III) metabolite to the corresponding Au(I) analog with chelate ring-opening ([Formula: see text] =+0.15 V-data based on the reaction with CHSe). These findings bring new insights about the mechanism of the Au(III) complex/biomolecule interaction in the cell, which is responsible for triggering biological responses.

: Trypanosomatid parasites are responsible for many Neglected Tropical Diseases (NTDs). NTDs are a group of illnesses that prevail in low-income populations, such as in tropical and subtropical areas of Africa, Asia and the Americas. The three major human diseases caused by trypanosomatids are African trypanosomiasis, Chagas disease, and leishmaniasis. There are known drugs for the treatment of these diseases that are used extensively and are affordable, however, the use of these medicines is limited by several drawbacks: development of chemo-resistance, side effects such as cardiotoxicity, low selectivity and others. Therefore, there is a need to develop new chemotherapeutics against these tropical parasitic diseases. Metal-based drugs against NTDs have been discussed over the years as alternative ways to overcome the difficulties presented by approved antiparasitic agents. The study of late transition metal-based drugs as chemotherapeutics is an exciting research field in chemistry, biology and medicine due to the ability of developing multitarget antiparasitic agents. The evaluation of the late transition metal complexes for the treatment of Trypanosomatid diseases is provided here, as well as some insights about their mechanism of actions.

The action mechanism of anticancer gold(III) complexes is a multi-step process and depends on their redox stability. First, the gold(III) complex undergoes a ligand exchange reaction in the presence of cellular thiols, such as those available in the active site of the enzyme TrxR, and then, the Au III → Au I reduction occurs. Most experimental and theoretical studies describe these processes under chemical conditions without considering the enzyme structure effect. In the present study, molecular models are proposed for the [Au III (C^N^C)(SHCys-R)] + adduct, with the [Au III (C^N^C)] + moiety bonded to the Cys498 residue in the C-terminal arm of the TrxR. This one represents the product of the first ligand exchange reaction. Overall, our results suggest that the exchange of the auxiliary ligand (for instance, Cl − to S-R) plays a primary role in increasing the reduction potential, with the enzyme structure having a small effect. The parent compound [Au III (C^N^C)Cl] has E°= −1.20 V, which enlarges to −0.72 V for [Au III (C^N^C)CH 3 SH] + and to −0.65 V for the largest model studied, Au-trx. In addition to the effect of the enzyme structure on the redox stability, we also analyze the Au transfer to the enzyme using a small peptide model (a tetramer). This reaction is dependent on the Cys497 protonation state. Thermodynamics and kinetic analysis suggests that the C^N^C ligand substitution by Cys497 is an exergonic process, with an energy barrier estimated at 20.2 kcal mol −1 . The complete transfer of the Au ion to the enzyme's active site would lead to a total loss of enzyme activity, generating oxidative damage and, consequently, cancer cell death.

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