Quantum Chemical Investigation on Hydrolysis of Orally Active Organometallic Ruthenium(II) and Osmium(II) Anticancer Drugs and Their Interaction with Histidine

Abstract

Influence of the metal center on hydrolysis of organometallic anticancer complexes containing an N-phenyl-2-pyridinecarbothioamide (PCA) ligand, [M(η6-p-cymene)(N-phenyl-2-pyridinecarbothioamide)Cl] + (M = RuII, 1A, and OsII, 2A), as well as their N-fluorophenyl derivatives [M(η6-p-cymene)(N-fluorophenyl-2-pyridinecarbothioamide)Cl] + (M = RuII, 1B, and OsII, 2B) have been investigated using the DFT method in aqueous medium. The activation energy barriers for the hydrolysis of 1A (21.5 kcal/mol) and 1B (20.7 kcal/mol) are found to be significantly lower than those of their corresponding osmium analogs 2A (28.6 kcal/mol) and 2B (27.5 kcal/mol). DFT evaluated results reveal the inertness of Os(II)–PCA complex toward the hydrolysis that rationalizes the experimental observations. However, the incorporation of fluoride substituent slightly decreases the activation energy for the hydrolysis of Ru(II)– and Os(II)–PCA. In addition, the interaction of hydrolyzed Ru(II)–PCAs (1AH and 1BH) and Os(II)–PCAs (2AH and 2BH) complexes with the histidine (Hist) have also been investigated. The aquated 1BH and 2BH show an enhanced propensity toward the interaction with histidine, and their activation Gibbs free energies are calculated to be 15.9 and 18.9 kcal/mol, respectively. ONIOM (QM/MM) study of the resulting aquated complexes inside histone protein shows the maximum stability of the 2BH complex having a binding energy of −43.6 kcal/mol.

More-Is-Better Strategy for Constructing Homoligand Polypyridyl Ruthenium Complexes as Photosensitizers for Infrared Two-Photon Photodynamic Therapy

“…The synthesis of Ru1 – Ru3 and their characterization, including 1 H NMR (Figure S1), 13 C NMR, ESI-MS, and microanalysis, are shown in the Supporting Information. In comparison to Cl-coordinated Ru­(II)-arene complexes, coordination-saturated PRCs are known to be inert to ligand substitution. , By examining the absorption spectral changes of Ru­(II) complexes in the absence of light, no hydrolysis was observed for Ru1 – Ru3 in the aqueous solution (Tris–HCl buffer, Figure S2) or RPMI 1640 cell culture medium (Figure S3). Upon light irradiation with a 450 nm LED (50 mW cm –2 ) or an 808 nm LPL (100 mW cm –2 ), Ru1 – Ru3 are also stable, as the spectra showed nearly no change in the MLCT bands.…”

Anticancer Properties of Ru and Os Half‐Sandwich Complexes of N,S Bidentate Schiff Base Ligands Derived from Phenylthiocarbamide

“…Apart from hydrogen bonding, van der Waals and π−π stacking interactions also stabilized the receptor‐protein adduct. The binding energy for the interaction of aqua/hydroxido complexes 2 aH was observed to be −103.19 kcal/mol which is approximately ~3 folds higher than the previously reported aquated Plecstatin complex inside the histone protein [19] . Therefore, these strong binding interactions of aqua/hydroxido complex 2 aH inside the histone proteins may serve as a solid foundation for its experimental validation and anticipation as a potential candidate for the development of an organometallic anticancer agent.…”

“…The rate of hydrolysis is an important parameter that provides insight into the activation profile of an investigational metallodrug [18] therefore the activation‐free energies for the hydrolysis of organoruthenium complexes of 2 a and 3 a as well as the interaction of their hydrolyzed complexes with Hist idine molecule have been evaluated by DFT studies in details. Organoruthenium complexes 2 a and 3 a have been selected for the hydrolysis studies due to their nature to undergo faster metal‐halide ligand exchange reaction than osmium complexes [19] . In ligand substitution reaction simple acronyms have been used instead of full chemical formula.…”

“…The confirmation of stationary points and incorporation of thermal corrections to Gibbs free energy and enthalpy were achieved through harmonic vibrational frequency analysis. The transition states are also determined and transition state theory is applied to determine the rate constants of the hydrolysis steps to have an insight into the feasibility of the reaction [34] . $$$\vcenter{\openup.5em\halign{$\displaystyle{#}$\cr k\left(T\right)={{{TK}_{B}}\over{h}}{e}^{{\Delta G}^{{\ne} }/RT}\hfill\cr}}$$$ …”

“…Organoruthenium complexes 2 a and 3 a have been selected for the hydrolysis studies due to their nature to undergo faster metal-halide ligand exchange reaction than osmium complexes. [19] In ligand substitution reaction simple acronyms have been used instead of full chemical formula. Transition states as (TS), aqua/hydroxido species as 2 aH and 3 aH, and Hist complexes 2 a-Hist and 3 a-Hist, respectively.…”