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

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.

Quantum Chemical Investigations on the Hydrolysis of Gold(III)-Based Anticancer Drugs and Their Interaction with Amino Acid Residues.

A comprehensive hydrolysis mechanism of the promising class of Au(III) anticancer drugs [Au(DMDT)Cl2] (DMDT = N,N-dimethyldithiocarbamate) (R) and [Au(damp)Cl2] (damp = 2-[(dimethylamino)methyl]phenyl) (R') was done by means of density functional theory (DFT) in combination with the CPCM solvation model to explore the solution behavior and stability under physiological conditions. The activation free energies (ΔG) for the second hydrolysis, R (13.7 kcal/mol) and R' (10.0 kcal/mol) are found to be relatively lower in comparison to the first hydrolysis, and their rate constant values are computed to be 5.62 × 102 and 2.90 × 105 s-1, respectively. Besides these, the interaction mechanisms of aquated R and R' with the potential protein-binding sites cysteine (Cys) and selenocysteine (Sec) were also investigated in detail. The kinetic study and activation Gibbs free energy profiles reveal that the aquated complexes of R and R' bind more effectively to the Se site of Sec than to the S site of Cys. Intra- and intermolecular hydrogen bonding play a pivotal role in stabilizing the intermediates and transition states involved in the ligand substitution reactions of R and R'. Natural population analysis (NPA) was done to determine the charge distributions on important atoms during the hydrolysis and ligand substitution reactions.

A Density Functional Theory Study on Et-BAC-Catalyzed 1,6-Conjugate Addition of p-Chlorobenzaldehyde to p-Quinone Methide for the Synthesis of α,α'-Diarylated Ketones.

Umpolung-based organocatalysis has made a remarkable breakthrough in the field of synthetic organic chemistry. Among a plethora of umpolung catalysts, bis(amino)cyclopropenylidenes (BACs) have emerged as efficient organocatalysts with potential applications in synthesizing numerous essential organic moieties. In this study, a plausible mechanism for bis(diethylamino)cyclopropenylidene (Et-BAC)-catalyzed synthesis of α,α'-diarylated ketones has been established using the density functional theory (DFT) method. The proposed catalytic cycle of the studied reaction initiates with the nucleophilic interaction of Et-BAC with p-chlorobenzaldehyde to form a zwitterionic intermediate, which is then transformed to a reactive Breslow intermediate. The Breslow intermediate further undergoes a chemoselective and stereoselective 1,6-conjugate addition reaction with p-quinone methide to form a new C-C bond connection. Finally, the generated adduct undergoes a proton shift reaction with the assistance of both 8-diazabicyclo(5.4.0)undec-7-ene (DBU) and protonated DBU to yield the desired product. Conceptual DFT-derived reactivity indices and frontier molecular orbital theory analysis have been successfully utilized to unravel the role of Et-BAC in this studied reaction. In addition to Et-BAC, DBU and protonated DBU also play a very important role in lowering the activation energy barrier of proton transfer steps. This investigation will help in the rational designing of simple nonheterocyclic carbene-mediated novel organic transformations.