Influência do ambiente enzimático na reatividade de complexos anticâncer de ouro(iii)

Abstract

Gold(III) complexes are promising compounds for cancer chemotherapy with mechanisms of action that involve steps dependent on their redox stability. The choice of the ligand is crucial to adjust their reactivity and biological activity. Tertiary phosphines (PR3) are among the most used auxiliary ligands in these compounds. The redox stability of [AuIII(C^N^C)(PR3)]+ (C^N^C=2,6-diphenylpyridine) (A) and [AuIII(N^N^N)(PR3)]3+ (N^N^N=2,2′:6′,2″-terpyridine) (B) complexes was herein investigated for a set of 41 phosphines, using the predicted standard reduction potential (Eo ) for Au3+/Au1+ electrochemical system as reference. For complexes (A), E o spread over 829 mV and all values were negative; for complexes (B), the E o values were positive and covered a narrower range of 507 mV. Phosphines with high steric impact decrease the complex stability despite being strong σdonors. Steric and electronic properties were used to build quantitative structure-property relationship models (QSPR), with the volume buried being the main factor in the stability of the studied compounds. In the case of compounds (B), the steric impact is more pronounced in gold(I) species. The electron-donating ability of phosphines has greater weight in the redox stability of compounds (B) compared to compounds (A). Later, fifteen compounds with different bidentate (bident) and tridentate (trident) ligands, keeping the chloride fixed as an auxiliary ligand ([AuIII(bident)Cl2] 3+n (bident = N^N and C^N) and [AuIII(trident)Cl]3+n (trident = N^N^N, C^N^N, C^C^N, C^N^C and N^C^N)), were studied. The calculated Eo values covered a wide range of 2600 mV. The compounds of the type [AuIII(C^C^N)Cl] showed the greatest stability with Eo of approximately -1.60 V in aqueous solution. The analysis of natural orbitals and Eo indicated that the inclusion of the AuC bond is less efficient for stabilizing the compound in the lateral position compared to the central position. The consecutive positioning of two pyridine ligands disfavors the reduction of gold(III) complexes. In the case of the compound [AuIII(C^N^N)Cl], the bipy ligand (N^N) behaves as a non-innocent redox ligand, actively participating in the reduction process without a significant structural change after reduction. The reported results help predict the redox stability of gold(III) complexes, which affects their chemical reactivity against important biological targets. Finally, molecular models were proposed for [AuIII(C^N^C)(SHCys-R)]+ adduct, with the [AuIII(C^N^C)]+ moiety bonded to residue Cys498 of TrxR, which represents the product of the first ligand exchange reaction. The original compound [AuIII(C^N^C)Cl] showed E° = - 8 1.20 V, which enlarges to ⁓ +0.30 V for the studied models of the adduct, showing that Eo is mainly influenced by auxiliary ligand exchange (eg: Clby SR) with a small effect of the enzyme structure. Furthermore, the final C^N^C/Cys497 substitution reaction was addressed, which showed to be dependent on the protonation state of Cys497. Thermodynamic and kinetic studies suggest that this reaction is exergonic, exhibiting an energy barrier of 20.2 kcal mol-1 . The complete transfer of the Au ion to the enzyme's active site would lead to the total inhibition of its activity, causing cancer cell death.