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P Geerlings

Publications and source records attributed to P Geerlings.

At least 19 recordsLinked to original sources
PubMed2003

Amide analogues of TSA: synthesis, binding mode analysis and HDAC inhibition.

The synthesis of new amide type histone deacetylase inhibitors is described, having an (R)-methyl substituent and a diene or saturated structure of the chain linking the hydroxamic acid and dimethylaminobenzoyl groups. The saturated compound shows stronger HDAC inhibition than the unsaturated analogue. Molecular modeling suggests that the flexibility of the linker chain is important for an optimal orientation of the dimethylaminobenzoyl group in the enzyme.

Amides↗
PubMed2003

Hirshfeld partitioning of the electron density: atomic dipoles and their relation with functional group properties.

Atomic dipole moments, derived within the Hirshfeld partitioning of the molecular electron density, have been studied for compounds of the type H-X and Cl-X, for a series of functional groups X frequently encountered in organic molecules. In the case of the H-X compounds, the component of the atomic dipole moment on H along the axis connecting H with the central atom in X is found to be linearly correlated with the electronegativity of X, the hardness of X playing no significant role. In the case of the Cl-X compounds, the situation is less clear. However, evidence seems to point to the conclusion that for these compounds, also the group hardness plays an important role.

Journal Article↗
PubMed2002

Atomic charges, dipole moments, and Fukui functions using the Hirshfeld partitioning of the electron density.

In the Hirshfeld partitioning of the electron density, the molecular electron density is decomposed in atomic contributions, proportional to the weight of the isolated atom density in the promolecule density, constructed by superimposing the isolated atom electron densities placed on the positions the atoms have in the molecule. A maximal conservation of the information of the isolated atoms in the atoms-in-molecules is thereby secured. Atomic charges, atomic dipole moments, and Fukui functions resulting from the Hirshfeld partitioning of the electron density are computed for a large series of molecules. In a representative set of organic and hypervalent molecules, they are compared with other commonly used population analysis methods. The expected bond polarities are recovered, but the charges are much smaller compared to other methods. Condensed Fukui functions for a large number of molecules, undergoing an electrophilic or a nucleophilic attack, are computed and compared with the HOMO and LUMO densities, integrated over the Hirshfeld atoms in molecules.

Journal Article↗
PubMed2002

Case study of the clinical usefulness of bioelectrical impedance spectroscopy in evaluating nutritional status.

Bioelectrical impedance spectroscopy (BIS) can be a valuable tool in assessing changes in body composition. Although the validity of BIS in healthy subjects is relatively good, in patients considerably larger measurement errors have been reported. In this article the clinical usefulness of BIS in assessing nutritional status of one case study will be discussed. Interpretation of the predictions of BIS in this unstable patient was difficult. This is in agreement with the consensus that BIS does not give accurate prediction of body composition in individual patients. It is recommended that validation studies of BIS should focus on clinical aspects which can influence BIS measurements.

Adult↗
PubMed2001

Nitrous oxide as a 1,3-dipole: a theoretical study of its cycloaddition mechanism.

The 1,3-dipolar cycloadditions of nitrous oxide and substituted alkynes have been studied at the B3LYP/6-31G(d,p) level. The reaction is controlled by LUMO (dipole)--HOMO (dipolarofile) and involves aromatic transition structures. The shape of the potential energy surface and the regioselectivity are not affected by the polarity of the solvents, except in the case of N2O + HC triple bond CSiH3. Different reactivity criteria including FMO coefficients product C, local softness differences Delta, magnetic susceptibility anisotropy chi(anis), and nucleus-independent chemical shifts NICS were used to predict the regioselectivity in all studied cases; the C, Delta criteria turn out to give the best results among them. The aromaticity of the transition structure is not a factor in determining the regiochemistry of the cycloaddtition reactions.

Alkynes↗
PubMed2001

Theoretical Study of [2 + 1] cycloaddition of CO and CS to acetylenes forming cyclopropenones and cyclopropenethiones.

The [2 + 1] cycloadditions of carbon monoxide and carbon monothioxide CX (X = O, S) to acetylenes (R1C triple bond CR2 with R1 = H, OH and R2 = CH3, OH, NH2, C6H5) have been studied at the B3LYP/6-311G(d,p) level. It has been shown that the reaction proceeds in two steps forming first an intermediate having the properties of both a carbene and a zwitterion followed by a ring closure leading to cyclopropenones or cyclopropenethiones. The solvent effect does not play an important role in the course of the cycloaddition. The estimation of the first vertical excitation energies by CIS and TD-B3LYP methods shows that the reactions likely take place in the ground state rather than in an excited state. All the studied cyclopropenones and cyclopropenethiones are aromatic as shown by their NICS values and confirmed by calculated and experimental NMR chemical shifts. Different reactivity criteria including HOMO coefficient, local softness, hardness, polarizability, and NICS are used to predict the site selectivity in all studied cases, and the NICS criterion seems to yield the best results among them.

Journal Article↗
PubMed2000

Enhanced aromaticity of the transition structures for the diels-alder reactions of quinodimethanes: evidence from ab initio and DFT computations

The Diels-Alder reactions of various quinodimethanes with ethylene are studied by means of ab initio molecular orbital and density functional theory (DFT) to show the effect of aromaticity on the reaction path. The calculations reveal that these reactions are both kinetically and thermodynamically much more favored than the prototype butadiene-ethylene Diels-Alder reaction due to the aromatization process in the transition state (TS) and product. A progressive aromaticity gain is noticed during the reaction, and hence the partial pi-delocalized peripheral diene ring function is coupled with the six-electron sigma,pi-delocalized cyclic unit resulting in an enhanced aromaticity of the TS. The magnetic criteria such as magnetic susceptibility exaltation and nucleus independent chemical shift provide definitive evidence for and fully support the aromatization process and the aromaticity of the TS. The extent of sigma-pi delocalization and the bond make-break at the TS are consistent with each other, and this is strongly influenced by the adjacent pi-aromatization process. Moreover, the aromaticity trends in the resulting TSs and products parallel the activation and reaction energies; the extent of aromatization increases with increasing reaction rate and exothermicity. This confirms that aromaticity is the driving factor governing cycloadditions involving quinodimethanes.

Journal Article↗
PubMed2000

Aromaticity interplay between quinodimethanes and C(60) in diels-alder reactions: insights from a theoretical study

A theoretical study is performed of the Diels-Alder reactions of various o-quinodimethanes (QDM) with C(60) by the AM1 model and limited ab initio and DFT techniques. All reactions are shown to proceed through a concerted transition state possessing a considerable net aromaticity as evidenced from bond orders and magnetic criteria such as the magnetic susceptibility exhaltations (MSE) and nucleus independent chemical shifts (NICS) and produce different kinds of aromatic stabilized fullerene cycloadducts. Computations show that a strong LUMO-dienophile control of C(60) is realized by the influence of pyramidalization, but its high reactivity over alkene appears to be governed by the global aromaticity on fullerene rather than its strain. The aromatic functionalization occurring in QDM upon cycloaddition drastically increases the reaction rate and exothermicity of all QDM-C(60) reactions as compared to the butadiene-C(60) reaction. In fact, the simultaneously existing aromatic destabilization in fullerene indicates its opposite effect to the resonance stabilization in diene; it is thus fully restricted when the gained aromaticity is transmitted from the nucleophilic QDM to the fullerene electrophile in a push-pull manner. However, the overall aromaticity effect shown by the aromatization as well as the aromaticity of C(60) seems to accelerate these reactions at an increased rate.

Journal Article↗
PubMed1998

Quantumchemical study of the catalytic triad in subtilisin: the influence of amino acid substitutions on enzymatic activity.

In the catalytic reaction of serine proteases the basicity of a histidine and the nucleophilicity of a serine, both residues together with an aspartate residue belonging to the catalytic triad, are of great importance. The influence of amino acid substitution on the basicity and the fast nucleophilicity of these important amino acids was investigated using a very simple and fast procedure. The amino acids of the triad were calculated at an ab initio level with the environment residues represented by point charges obtained with the CHelpG population analysis. Basicity trends were found to be reflected by the charge on the basic nitrogen and the "protonation energy", calculated for the triad. The serine nucleophilicity was found to correlate with the charge on the hydroxyl atom and with the minimum of the Molecular Electrostatic Potential in the vicinity of this oxygen.

Amino Acid Substitution↗
PubMed1998

In vitro mutagenicity and genotoxicity study of a number of short-chain chlorinated hydrocarbons using the micronucleus test and the alkaline single cell gel electrophoresis technique (Comet assay) in human lymphocytes: a structure-activity relationship (QSAR) analysis of the genotoxic and cytotoxic potential.

Using the micronucleus (MN) test and the alkaline single cell gel electrophoresis (Comet) assay, potential mutagenicity (MN formation), genotoxicity (DNA breakage capacity) and cytotoxicity (cell proliferation reduction) of five chlorinated hydrocarbons (carbon tetrachloride, hexachloroethane, 1,2-dichloroethane, 1-chlorohexane and 2,3-dichlorobutane) have been evaluated in isolated human lymphocytes. With the MN test a low but statistically significant mutagenic activity was detected for all tested substances (except 2,3-dichlorobutane) with one out of the two donors and in the presence or absence of an exogenous metabolic activation system (S9 mix). However, at the concentration ranges tested none of the positive compounds induced a clear dose-dependent mutagenic effect. The Comet assay detected a strong DNA damaging effect for 1-chlorohexane, 2,3-dichlorobutane and 1,2-dichloroethane, but not for carbon tetrachloride and hexachloroethane. The influence of metabolism on the genotoxic activity of the chemicals was more clear in the Comet assay than in the MN test. The experimental genotoxicity and cytotoxicity data obtained in this study, together with data on five more related chemicals previously investigated, and their physico-chemical descriptors or electronic parameters have been used for QSAR analysis. The QSAR analysis high-lighted that the toxicity of the tested compounds was influenced by different parameters, like lipophilicity (logP), electron donor ability (charge) and longest carbon-chlorine (LBC-Cl) bond length. In addition, steric parameters, like molar refractivity (MR) and LBC-Cl, and electronic parameters, like ELUMO (energy of the lowest unoccupied molecular orbital, indicating electrophilicity), were predominant factors discriminating genotoxins from non-genotoxins in the presence but not in the absence of S9 mix. Although a limited number of compounds have been examined and cytotoxicity and genotoxicity were identified in two different bioassay tests, the data set was obtained by the same experimentor, strengthening the reliability of the QSAR.

Adult↗
PubMed1997

Molecular structure and gas chromatographic retention behavior of the components of Ylang-Ylang oil.

Using quantitative structure-retention relationships (QSRR) methodologies the Kovats gas chromatographic retention indices for both apolar (DB-1) and polar (DB-Wax) columns for 48 compounds from Ylang-Ylang essential oil were empirically predicted from calculated and experimental data on molecular structure. Topological, geometric, and electronic descriptors were obtained for model generation. Relationships between descriptors and the retention data reported were established by linear multiple regression, giving equations that can be used to predict the Kovats indices for compounds present in essential oils, both in DB-1 and DB-Wax columns. Factor analysis was performed to interpret the meaning of the descriptors included in the models. The prediction model for the DB-1 column includes descriptors such as Randic's first-order connectivity index (1X), the molecular surface (MSA), the sum of the atomic charge on all the hydrogens (QH), Randic's third-order connectivity index (3X) and the molecular electronegativity (chi). The prediction model for the DB-Wax column includes the first three descriptors mentioned for the DB-1 column (1X, MSA and QH) and the most negative charge (MNC), the global softness (S), and the difference between Randic's and Kier and Hall's third-order connectivity indexes (3X-3XV).

Chromatography, Gas↗
PubMed1996

Interleukin-12 gene-expression of macrophages is regulated by nitric oxide.

Interleukin-12 is a heterodimeric cytokine, mainly produced by macrophages. In our present study we demonstrate that interleukin-12 expression is regulated by nitric oxide. Incubation of the macrophage cell line IC 21 with interferon-gamma gave rise to both interleukin-12 p40 mRNA and nitric oxide production. The concurrent addition of the nitric oxide synthase inhibitor N(G)-monomethyl-L-arginine inhibited nitrite production and in parallel completely suppressed interleukin-12 p40 mRNA formation. This indicated that endogenous nitric oxide synthase activity was required for IL-12 p40 gene expression. Exposure of the cells towards the nitric oxide generating compounds nitroprusside or S-nitroso-N-acetyl-penicillamine induced interleukin-12 p40 mRNA. Maximal mRNA levels were induced with nitric oxide donors at 1 microM concentration. We conclude that nitric oxide may exert an autoregulatory and paracrine control of interleukin-12 gene expression.

Animals↗
PubMed1996

Effects of calcisorb on fecal bile acids and fatty acids in human volunteers.

The intake of calcium (Ca) is negatively associated with colorectal cancer (crc) risk. The aim of this study was to investigate in a double-blind, placebo-controlled trial, the effects of the Ca-binder Calcisorb, which is given to kidney stone patients with hypercalciuria type I, on risk factors for crc risk, bile acids (BA), and long-chain fatty acids (LCFA) in fecal water. Results show that the concentration of BA and LCFA in fecal water did not change, although the urinary excretion of Ca and magnesium (Mg) and the concentration of Ca and magnesium in fecal water decreased. The daily excretion of BA and LCFA acids decreased significantly (p < 0.05) during the Calcisorb period. In conclusion, binding dietary Ca and Mg with Calcisorb from a diet with a relatively low amount of fat does not enhance the solubility of BA and LCFA in fecal water.

Adult↗
PubMed1989

The Addiction Severity Index: reliability and validity in a Dutch addict population.

In order to meet the need for a multidimensional diagnostic instrument in the field of drug addiction in The Netherlands, the Addiction Severity Index (ASI) has been applied to a sample of Dutch drug addicts. In this article the usefulness and psychometric characteristics of the Dutch version of the ASI are discussed. Overall, there was no evidence of a general relationship between the ASI ratings of problem severity. The severity ratings showed good concurrent validity, and subscales of selected items in each problem area of the ASI were demonstrated to have good internal consistency reliability. Regression analysis indicated that the ASI items accounted for a considerable proportion of the variance in the severity ratings, indicating a strong relationship between "subjective" rating and "objective" data. On the basis of the general concept of the ASI and the satisfactory psychometric characteristics, implementation of the instrument in The Netherlands is advocated.

Adult↗
PubMed1985

Relationship between gas chromatographic behaviour and topological, physicochemical, and quantum chemically calculated charge parameters for neuroleptica.

Gas chromatographic retention indices for a number of neuroleptic drugs on an apolar phase, OV-101, and a polar phase, OV-17, are correlated with parameters describing various properties of the separated molecules. The gas chromatographic behaviour is related to the same parameters as those used in quantitative structure activity relationships. The molecular connectivity indices and log k' in a reversed-phase HPLC system were chosen as parameters describing the apolar interactions of the molecules with the stationary phase. As properties involved in more specific interactions, and related to the presence of overall or local polarity, the molecular dipole moment and the charge on the N-atom were selected and quantum chemically calculated. It is found that the retention indices on the apolar phase, OV-101, can be successfully correlated with molecular connectivity indices, which are also used in QSAR studies. The retention indices on OV-17 show a high correlation with the charge on the N-atom. Evidence of the importance of this N-atom in pharmacological activity is known.

Antipsychotic Agents↗