Reactivity of N-Heterocyclic Carbene Half-Sandwich Ru-, Os-, Rh-, and Ir-Based Complexes with Cysteine and Selenocysteine: A Computational Study

The structure and the reactivity of four half-sandwich metal complexes of Ru-II, Os-II, Rh-III, and Ir-III were investigated by means of density functional theory approaches. These piano-stool complexes, grouped in cym-bound complexes, Ru-II(cym)(dmb)Cl-2, 1, and Os-II(cym)(dmb)Cl-2, 2, and Cp*-bound complexes, Rh-III(Cp*)(dmb)Cl-2, 3, and Ir-III(Cp*)(dmb)-Cl-2, 4, with cym = eta(6)-p-cymene, Cp* = eta(5)-pentamethylcyclopentadienyl, and dmb = 1,3-dimethylbenzimidazol-2-ylidene, were recently proposed as anticancer metallodrugs that preferably target Cys- or Sec-containing proteins. Thus, density functional theory calculations were performed here to characterize in detail the thermodynamics and the kinetics underlining the targeting of these metallodrugs at either neutral or anionic Cys and Sec side chains. Calculations evidenced that all these complexes preferably target at Cys or Sec via chloro exchange, although cym-bound and Cp*-bound complexes resulted to be more prone to bind at neutral or anionic forms, respectively, of these soft protein sites. Further decomposition analyses of the activation free energies for the reaction between 1-4 complexes and either Cys or Sec, paralleled with the comparison among the optimized transition-state structures, allowed us to spotlight the significant role played by solvation in determining the overall reactivity and selectivity expected for these prototypical metallodrugs.