Tunable Anticancer Activity of Furoylthiourea-Based RuII–Arene Complexes and Their Mechanism of Action

Fourteen new Ru^II–arene (p-cymene/benzene) complexes ( C1 – C14 ) have been synthesized by varying the N-terminal substituent in the furoylthiourea ligand and satisfactorily characterized by using analytical and spectroscopic techniques. Electrostatic potential maps predicted that the electronic effect of the substituents was mostly localized, with some influence seen on the labile chloride ligands. The structure–activity relationships of the Ru–p-cymene and Ru–benzene complexes showed opposite trends. All the complexes were found to be highly toxic towards IMR-32 cancer cells, with C5 (Ru–p-cymene complex containing C₆H₂(CH₃)₃ as N-terminal substituent) and C13 (Ru–benzene complex containing C₆H₄(CF₃) as N-terminal substituent) showing the highest activity among each set of complexes, and hence they were chosen for further study. These complexes showed different behavior in aqueous solutions, and were also found to catalytically oxidize glutathione. They also promoted cell death by apoptosis and cell cycle arrest. Furthermore, the complexes showed good binding ability with the receptors Pim-1 kinase and vascular endothelial growth factor receptor 2, commonly overexpressed in cancer cells.     

Isolation of a Dosage Dependent Lethal Mutation in Ubiquitin Gene of Saccharomyces Cerevisiae

Summary: Ubiquitin is a small protein with a highly conserved sequence, playing a pivotal role in ubiquitin proteasome system (UPS). Considering the central role UPS has in cellular homeostasis, several drugs have been developed to target UPS to remove cells responsible for cancer and other neurodegenerative diseases. As an alternative to the above approach, in the present study we have isolated dose dependent lethal form of ubiquitin gene by in vitro evolution. In vitro evolution is a powerful tool for developing proteins with novel and desirable properties. The ubiquitin gene of Saccharomyces cerevisiae was subjected to in vitro evolution and lethal mutations were selected. The ubiquitin of S. cerevisiae differs only by three residues from human ubiquitin. The mutants were selected by expressing the protein in temperature sensitive ubi4 deletion mutants of ubiquitin. Most of the mutations in ubiquitin gene failed to complement UBI4 phenotype under heat shock. Only one of the mutants caused cell lysis, even at permissive temperature. Interestingly, expression of the same protein in wild type S. cerevisiae cells left them unaffected, establishing the mutant protein as a competitive inhibitor for UPS. Sequencing of the mutant gene showed four completely novel amino acid substitutions. They are namely, Ser20 to Phe, Ala46 to Ser, Leu50 to Pro and Ile61 to Thr. Construction of the mutant ubiquitin gene and characterization of the mutant phenotype along with the nature and location of the mutations are presented.     

Reaction mechanism of cysteine proteases model compound HSH with diketone inhibitor PhCOCOCH3−nXn, (X = F,Cl, n = 0, 1, 2)

Caspases are a family of cysteine proteases, which play a crucial role in apoptosis and inflammation. The reaction mechanisms involving the cysteine proteases model compound HSH with diketone (PhCOCOCH_3‐nX_n, (X = F, Cl, n = 0, 1, 2) substrate have been studied using B3LYP/6‐311+G* level of density functional theory method. The harmonic vibrational frequencies were calculated at the same level of theory used for the characterization of stationary points and zero‐point vibrational energy corrections. The condensed Fukui functions have been calculated to find the favorable reactive site for the electrophilic (f), nucleophilic (f), and radical (f) attacks in the reactants. The transition states were connected with reactants, intermediate, and products, and the minimum energy paths have been confirmed through intrinsic reaction coordinate calculation. The potential energy barrier between each step of the reactions has been calculated to find the most favorable reaction path. The binding nature of cysteine model compound with diketone substrate has been studied through the interaction energies, bond lengths, electron density, natural bond orbital, and atoms in molecules theory analysis. © 2009 Wiley Periodicals, Inc. Int J Quantum Chem, 2010     

Long‐range charge transfer in donor‐peptide bridge‐acceptor model systems—A theoretical study

The quantum mechanical calculations were performed to study the effect of geometrical fluctuations of peptide on charge transfer in model oligopeptides linked between donor and acceptor molecules. The charge transfer parameters have been calculated based on the density functional theory method. Results show that the overall charge transfer in peptide mediated donor–acceptor complexes is determined by the conformations and chain length of the intermediate peptide bridge. The analysis of excess charge distribution show that the localization of an excess positive and negative charge are strongly depend on the conformations and chain length of the donor–bridge‐acceptor system. © 2010 Wiley Periodicals, Inc. Int J Quantum Chem, 2011     

Machine learning-based modeling to predict inhibitors of acetylcholinesterase

Molecular Diversity - Acetylcholinesterase enzyme is responsible for the degradation of acetylcholine and is an important drug target for the treatment of Alzheimer’s disease. When this...     

A theoretical study on decomposition and rearrangement reaction mechanism of trichloroacetyl chloride (CCl3COCl)

In the present study, the possible decomposition and rearrangement reaction profile of trichloroacetyl chloride have been studied using UMP2/6‐311++G (2d, 2p) level of ab initio and UB3LYP/6‐311++G (2d, 2p) level of density functional theory methods. The harmonic vibrational frequencies were calculated at the same level of theory used for the characterization of stationary points and zero‐point vibrational energy corrections. The potential energy barrier and activation energy between each step of the reaction have been calculated for the seven possible reaction pathways (Ia–c, IIa–b, IIIa–b). The trichloroacetyl chloride is an asymmetric ketone where the two α bonds of acetyl chloride, the C? C and C? Cl bonds are strong with dissociation energy of 72 kcal/mol. The phosgene (COCl₂), dichloroketene (CCl₂CO), carbon dichloride (CCl₂), carbon tetrachloride (CCl₄), and carbon monoxide (CO) are the major dominant products on the decomposition of the trichloroacetyl chloride. These resultant products are more hazards than the parent trichloroacetyl chloride molecules. The positive value of the reaction energy indicate that the overall reaction profile is found to be endothermic at the UMP2 and UBLYP/6‐311++G(2d, 2p) levels of theory, respectively, at UMP2/6‐311G** optimized geometry. © 2010 Wiley Periodicals, Inc. Int J Quantum Chem, 2011     

A combined experimental and computational study on the sulfoxidation by high-valent iron bispidine complexes

Iron-bispidine complexes are efficient catalysts for the oxidation of thioanisole to phenylmethylsulfoxide with iodosylbenzene as oxidant. With the tetradentate bispidine ligand L(1) (L(1) = 2,4-pyridyl-3,7-diazabicyclo[3.3.1]nonane)) the catalytic efficiency is smaller than with the pentadentate bispidine ligand L(2) (L(2) = 2,4-pyridyl-7-(pyridine-2-ylmethyl)-3,7-diazabicyclo[3.3.1]nonane)). Based on the redox potentials (iron complexes with L(1) are stronger oxidants than with L(2)) and known efficiencies in catalytic olefin oxidation and C-H activation reactions, the expectations were different. A DFT-based analysis is used to explain the apparent contradiction, and this is based on differences in the electronic ground states of the ferryl complexes as well as in the oxygen transfer transition states.