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Binding of two ligands trans to each other by some transition metal complexes may be cooperative [Khoroshun et al., Mol Phys 2002, 100, 523]. Several interesting consequent effects include (i) inverse relationship between bond strength and binding affinity; (ii) smaller coordination barriers to formation of weaker bonds; (iii) enhancement of Lewis acidity with increased number of ligands. We describe a simple model, sigma trans promotion effect (TPE), which considers electronic reorganization between two Lewis structures, and predicts the above-mentioned effects. The applied result of present study is the unified perspective on several facts of heme chemistry. Particularly, we reiterate an important but often overlooked notion, developed previously within the spin pairing model [Drago and Corden, Acc Chem Res 1980, 13, 353], that, in hemoproteins, the proximal histidine and the distal ligand such as O2 or CO cooperate in promoting electronic reorganization. As a result, depopulation of dz2 orbital upon ligand binding contributes to the phenomenon of hemoglobin cooperativity. The presented density functional (B3LYP) calculations on realistic models, the processes of carbon monoxide binding by Fe(II) porphyrins and dinitrogen binding by triamido/triamidoamine Mo(III) complexes, particularly the evaluation of the coordination barriers due to spin-state change by location of the minima on seams of crossing, support the TPE model predictions. From a broader theoretical perspective, the present study would hopefully stimulate the development of much needed frameworks and tools for facile comparisons of wave functions and their properties between different geometries, species, and electronic states. Advancement of practical wave function comparisons may yield fresh qualitative perspectives on chemical reactivity, and promote better understanding of related concepts such as electronic reorganization.
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PMID:Electronic reorganization: origin of sigma trans promotion effect. 1714 66

The acidity constants, pK(a) values for protonation of some substituted thiazole derivatives were calculated by using AM1 and PM3 basis sets of semi-empirical methods and B3LYP/6-31G(d) basis sets of density functional theory (DFT) calculated physical and thermodynamic parameters. Correlation search among the experimental and calculated acidity constants, pK(a) values, revealed that the best correlation exist between the experimental and ab initio calculated pK(a) values with a regression of R(2)=0.98.
J Mol Graph Model 2007 Jul
PMID:Quantum chemical studies on protonation of some substituted thiazole derivatives. 1717 31

Density functional theory (DFT) calculations were carried out to study the influence of both electron-withdrawing fluorine and electron-donating amidogen meso-substituents on the inner hydrogen transfer in metal-free porphyrins. Twenty-four stable structures and 21 transition states among the stable structures are fully optimized at the B3LYP/6-31G (d) level, and vibration analyses are carried out to verify the optimized structures. It is found that the acidity of the transferred hydrogen atom, the basicity of the nitrogen atoms of the adjacent pyrrole ring, the distance from the transferred hydrogen atom to the nitrogen atom of the adjacent pyrrole ring, and the electronic nature of meso-substituents in transfer paths, all have significant influences on the potential energy barrier of the inner hydrogen transfer in porphyrins. The different transfer paths of each substituted porphyrin are compared, all the transfer barriers are compared to unsubstituted metal free porphyrin, and the infrared and electronic absorption spectra of some important complexes are described. By placing substituents appropriately, the cis-trans transition energy barrier can be greatly decreased, and the cis-porphyrin conformer which can be detected spectroscopically may be significantly stabilized. The present work would shed light on tuning the transition barrier by selecting the most appropriate paths and detecting cis-porphyrins experimentally.
J Mol Graph Model 2007 Jul
PMID:Density functional theory study of the inner hydrogen atom transfer in metal-free porphyrins: meso-substitutional effects. 1720 23

Nickel is a cofactor for various microbial enzymes, yet as a trace element, its scavenging is challenging. In the case of the pathogen Helicobacter pylori, nickel is essential for the survival in the human stomach, because it is the cofactor of the important virulence factor urease. While nickel transport across the cytoplasmic membrane is accomplished by the nickel permease NixA, the mechanism by which nickel traverses the outer membrane (OM) of this Gram-negative bacterium is unknown. Import of iron-siderophores and cobalamin through the bacterial OM is carried out by specific receptors energized by the TonB/ExbB/ExbD machinery. In this study, we show for the first time that H. pylori utilizes TonB/ExbB/ExbD for nickel uptake in addition to iron acquisition. We have identified the nickel-regulated protein FrpB4, homologous to TonB-dependent proteins, as an OM receptor involved in nickel uptake. We demonstrate that ExbB/ExbD/TonB and FrpB4 deficient bacteria are unable to efficiently scavenge nickel at low pH. This condition mimics those encountered by H. pylori during stomach colonization, under which nickel supply and full urease activity are essential to combat acidity. We anticipate that this nickel scavenging system is not restricted to H. pylori, but will be represented more largely among Gram-negative bacteria.
Mol Microbiol 2007 Feb
PMID:Novel nickel transport mechanism across the bacterial outer membrane energized by the TonB/ExbB/ExbD machinery. 1723 22

Chemical reactions are involved at many stages of the drug design process. This starts with the analysis of biochemical pathways that are controlled by enzymes that might be downregulated in certain diseases. In the lead discovery and lead optimization process compounds have to be synthesized in order to test them for their biological activity. And finally, the metabolism of a drug has to be established. A better understanding of chemical reactions could strongly help in making the drug design process more efficient. We have developed methods for quantifying the concepts an organic chemist is using in rationalizing reaction mechanisms. These methods allow a comprehensive modeling of chemical reactivity and thus are applicable to a wide variety of chemical reactions, from gas phase reactions to biochemical pathways. They are empirical in nature and therefore allow the rapid processing of large sets of structures and reactions. We will show here how methods have been developed for the prediction of acidity values and of the regioselectivity in organic reactions, for designing the synthesis of organic molecules and of combinatorial libraries, and for furthering our understanding of enzyme-catalyzed reactions and of the metabolism of drugs.
J Comput Aided Mol Des
PMID:Modeling chemical reactions for drug design. 1725 78

The absorption and fluorescence spectral properties of 2,6-diaminoanthraquinone (DAAQ) have been investigated in a series of organic solvents of different polarity and in aqueous solutions with H o/pH/H_ in the range -10 to 17. The Stokes shift of DAAQ is correlated with various polarity scales. The study reveals the fluorescence of DAAQ dication is red shifted on protonation. The abnormal fluorescence of DAAQ dication is found to be due to large solvent relaxation in polar medium. The acidity constants for various prototropic reactions in S o and S1 states are determined and discussed.
Spectrochim Acta A Mol Biomol Spectrosc 2007 Nov
PMID:Photophysical behaviour of 2,6-diaminoanthraquinone in different solvents and at various pH. 1732 Nov 96

Manganese chloride can form large particles with nucleic acids by electrostatic forces, which results in strong enhancement of resonance light scattering (RLS) signals. Based on this phenomenon, a novel and very simple assay of DNA was established. The work conditions have been investigated including the concentration of probe, the acidity of solution, the effect of ionic strength and the selectivity. In acidic solution, the enhanced RLS intensity at 389.5 nm was proportional to the concentration of nucleic acids in the range 0.05-10.0 microg ml(-1) for both ctDNA and fsDNA and 1.0-10.0 microg ml(-1) for yRNA. The limits of detection (LOD, 3sigma) were 0.17, 0.13 and 0.53 ng ml(-1) for ctDNA, fsDNA and yRNA, respectively. Synthetic samples were determined satisfactorily.
Spectrochim Acta A Mol Biomol Spectrosc 2007 Oct
PMID:Micro-determination of nucleic acids with a simple probe manganese chloride based on the fine enhanced resonance light scattering. 1732 43

The absorption and fluorescence spectral characteristics of some biologically active indoles have been studied as a function of acidity and basicity (H_/pH/H(o)) in cationic (cetyltrimethylammonium bromide, CTAB), anionic (sodium dodecylsulphate, SDS) and aqueous phases at a given surfactant concentration. The prototropic equilibrium reactions of these probes have been studied in aqueous and micellar phases and apparent excited state acidity constant (pK(a)(*)) values are calculated. The probes show formation of different species on changing pH. Various species present in water, CTAB and SDS have been identified and the equilibrium constants have been determined by Fluorimetric Titration method. The fluorescence spectral data suggest the formation of oxonium ion through the excited state proton transfer reaction in highly acidic media and formation of photoproducts due to the base catalyzed auto-oxidative reaction in basic aqueous solutions. Variations in the apparent pK(a)(*) value have been observed in different media. The change in the apparent pK(a) values depends upon the solubilising power of the micelles, as well as on the location of the protonating site in the molecule. The observation about increase in pK(a)(*) values in SDS and decrease in CTAB compared to pure water for various equilibria is consistent with the pseudophase ion-exchange (PIE) model.
Spectrochim Acta A Mol Biomol Spectrosc 2007 Nov
PMID:Effect of CTAB and SDS micelles on the excited state equilibria of some indole probes. 1736 22

Resistance to anticancer drugs and consequent failure of chemotherapy is a complex problem severely limiting therapeutic options in metastatic cancer. Many studies have shown a role for drug efflux pumps of the ATP-binding cassette transporters family in the development of drug resistance. ClC-3, a member of the CLC family of chloride channels and transporters, is expressed in intracellular compartments of neuronal cells and involved in vesicular acidification. It has previously been suggested that acidification of intracellular organelles can promote drug resistance by increasing drug sequestration. Therefore, we hypothesized a role for ClC-3 in drug resistance. Here, we show that ClC-3 is expressed in neuroendocrine tumor cell lines, such as BON, LCC-18, and QGP-1, and localized in intracellular vesicles co-labeled with the late endosomal/lysosomal marker LAMP-1. ClC-3 overexpression increased the acidity of intracellular vesicles, as assessed by acridine orange staining, and enhanced resistance to the chemotherapeutic drug etoposide by almost doubling the IC(50) in either BON or HEK293 cell lines. Prevention of organellar acidification, by inhibition of the vacuolar H(+)-ATPase, reduced etoposide resistance. No expression of common multidrug resistance transporters, such as P-glycoprotein or multidrug-related protein-1, was detected in either the BON parental cell line or the derivative clone overexpressing ClC-3. The probable mechanism of enhanced etoposide resistance can be attributed to the increase of vesicular acidification as consequence of ClC-3 overexpression. This study therefore provides first evidence for a role of intracellular CLC proteins in the modulation of cancer drug resistance.
Mol Cancer Ther 2007 Mar
PMID:ClC-3 expression enhances etoposide resistance by increasing acidification of the late endocytic compartment. 1736 91

The geometries of 12 multi-halogenated pyridine derivatives were optimized using theoretical methods. The Hartree-Fock (HF) method with the 6-31G(d) and B3LYP method with 6-31G(d) basis sets were found to be adequate in calculation of absolute acidity constants, pK(a) values. A perfect correlation between the computed and experimentally obtained acidity constants, pK(a) values, was observed.
J Mol Graph Model 2007 Nov
PMID:A theoretical study on protonation of some halogen substituted pyridine derivatives. 1754 May 91


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