Pyrolysis-gas chromatography-mass spectrometry of a series of bile acid sequestrants.

Pyrolysis of a series of polymers based on polystyrene and used as bile acid sequestrants produced characteristic mixtures of compounds which were analysed by gas chromatography-mass spectrometry. The nature of the substituent groups was clearly apparent while the polymer backbone gave rise to representative styrenes. The reproducibility of the results was examined by experimenting with the temperature of pyrolysis. It was found that at low temperatures very little fragmentation of the polystyrene backbone occurred but the substituents were still released in high yield. The orientation of the various substituted styrenes generated by pyrolysis was confirmed by the use of gas chromatography with infrared and mass spectrometric detection.     

Capillary gas chromatography of hydroxylated bile acid stereoisomers of the allo and normal series

Relative retention times and methylene unit (MU) values were determined for 56 bile acids of the allo (5 alpha, A/B-trans) and normal (5 beta, A/B-cis) series, which differ from one another in the number, position and configuration of the hydroxyl groups at positions C-3, C-6, C-7 and/or C-12. The bile acids were derivatized to their methyl ester O-trimethylsilyl ethers (Me-TMS) and methyl ester O-dimethylethylsilyl ethers (Me-DMES), and chromatographed on fused-silica capillary columns, chemically bonded with non-selective OV-1 and selective PEG-20M liquid phases. Of the four possible combinations of derivatives and columns examined, Me-DMES on OV-1 and Me-TMS on PEG-20M were most suitable. The differences in the MU values between the 5 alpha- and 5 beta-series, and between the Me-DMES and Me-TMS ether derivatives, are also summarized. These retention data would be helpful in the identification of closely related bile acid stereoisomers or for estimation of their structures. photolysis.     

Acidity in bile acid systems

The acidity parameter in bile acid systems was re-examined in an attempt to unify the many contrasting results reported in the literature. Discrepancies originate not only through differences in experimental approaches but mainly through the peculiar behaviour of bile acids and their salts, which can be present in aqueous solution as monomers, or simple and/or mixed aggregates. The acidity (and the pK_a values) of bile acid could also be affected by parameters which do not usually play a major role (e.g. hydroxy groups, far from the reaction centre). The microenvironment, where the bile acid is partitioned (e.g. inside a mixed micelle), also makes the carboxyl group less acidic than it would commonly be, considering only structural factors. When the system is made simpler, avoiding problems of solubility and self-aggregation (e.g. in mixed solvents), unconjugated and glycine-conjugated bile acids display acidity behaviour which matches their molecular structure.     

Infrared and Raman group frequency correlations: Substituted oxamides

Infrared and Raman spectra of N,N′-dialkyl oxamides and N,N′-diaryl oxamides or (N,N′-oxanilides) were recorded, and characteristic group frequencies useful in spectra-structure identification are presented.The i.r. and Raman data recorded for N,N′-dialkyl or N,N′-diaryl oxamides in the solid phase can be explained on the basis that they exist in an intermolecularly hydrogen bonded trans configuration where each oxamide group can be viewed as having C_2h symmetry. In the vapor phase, N,N′-dimethyloxamide also exists in the trans configuration. Evidence is presented that suggest N,N,N′,N′-tetraethyloxamide exists as rotational isomers in solution, and that these are the trans and gauche structures.     

HMO correlations with the electronic spectra of a large non-homogeneous series

A basic set of electronic spectra for 46 compounds of widely divergent structures have been used to form a correlation with HMO transition energies for p-bands, and β-bands. Regression equations have been used to predict the location of these bands in a varied series of 88 additional compounds. The results serve to extend the applicability of the Hückel method as a simple tool for the qualitative and approximate quantitative prediction of the basic elements of singlet transitions.     

Spectra-structure correlations in the isomorphous series of metal (II) saccharinates hexahydrates

The observed infrared frequencies were correlated with the values of the Ow…O distances in manganese and cadmium saccharinate hexahydrate and the derived correlation equation was used to estimate the corresponding distances in the rest of the metal(II) saccharinates monohydrates.     

Structure-property correlations of a series of antimalarial chloroquine derivatives

Summary As part of the development of our in-house molecular modelling package, COSMIC, the structure-property relationships of a series of 13 antimalarial chloroquine derivatives have been investigated using physicochemical properties calculated from molecular models. This has involved the use of various statistical techniques. The compounds were analysed using three different modelling approximations concerning assumptions about the invariant amino alkyl side chain. The first two sets of data were obtained from models with and without the side shain using a formal charge of 0.0. Analysis of these data using principal components resulted in plots of principal component scores in which activity categories were separated. In the third data set, the side chain was modelled with a charge of +1 and an examination of the molecular properties showed poorer clustering of activity categories. We have also investigated relationships between biological activity and physicochemical properties using multiple linear regression. Although significant equations were developed, the correlation coefficients were low and it was not felt that they would be useful for quantitative prediction. The identification of important variables, however, may give some clues to the mechanism of action of these compounds.

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Beziehungen zwischen Strukturen und Eigenschaften einer Reihe von Chloroquinderivaten mit Antimalariawirkung

Zusammenfassung Die physikalisch-chemischen Eigenschaften von 13 Chloroquinderivaten mit Antimalariawirkung wurden mittels Molekülmodellrechnungen bestimmt und unter Anwendung verschiedener statistischer Analysenmethoden ausgewertet. Die Untersuchungen sind Teil der firmeneigenen Entwicklung eines Software-Paketes für Molecular Modelling mit Namen COSMIC. Die konstante Aminoalkylseitenkette der Verbindungen wurde in den Modellierungen mit drei verschiedenen Näherungsannahmen berücksichtigt. Für die beiden ersten Datensätze wurde mit ungeladener Seitenkette und ohne Seitenkette gerechnet. Hauptkomponentenzerlegung der Daten ergab in beiden Fällen klare Trennungen hinsichtlich der Aktivitätskategorien. Bei der Berechnung des dritten Datensatzes wurde die Seitenkette mit einer Ladung von +1 modelliert. Die Clusterung der molekularen Daten in Aktivitätskategorien war in diesem Fall wesentlich schwächer ausgeprägt als in den beiden anderen Fällen. Außerdem wurde die Beziehung zwischen der biologischen Aktivität und den physikalisch-chemischen Eigenschaften durch multiple lineare Regressionsanalyse untersucht. Ungeachtet der Möglichkeit einer Herleitung von signifikanten Gleichungen waren die Korrelationskoeffizienten so gering, daß man die Beziehungen als ungeeignet für eine quantitative Vorhersage ansehen muß. Die ldentifikation der wichtigen Variablen kann aber dessenungeachtet nützliche Hinweise auf die Wirkmechanismen dieser Substanzklasse geben.

     

A general statistical test for correlations in a finite-length time series

The statistical properties of the autocorrelation function from a time series composed of independently and identically distributed stochastic variables has been studied. Analytical expressions for the autocorrelation function's variance have been derived. It has been found that two common ways of calculating the autocorrelation, moving-average and Fourier transform, exhibit different uncertainty characteristics. For periodic time series, the Fourier transform method is preferred because it gives smaller uncertainties that are uniform through all time lags. Based on these analytical results, a statistically robust method has been proposed to test the existence of correlations in a time series. The statistical test is verified by computer simulations and an application to single-molecule fluorescence spectroscopy is discussed.     

Potential bile acid metabolites. XV. Synthesis of 4 beta-hydroxylated bile acids; unique bile acids in human fetal bile

The 4 beta-hydroxylated derivatives of lithocholic, deoxycholic, chenodeoxycholic, and cholic acids were synthesized from their respective parent compounds. The principal reactions employed were 1) beta-face cis-dihydroxylation of delta 3 intermediates with osmium tetroxide-N-methylmorpholine N-oxide, 2) selective cathylation of vicinal 3 beta,4 beta-diols followed by oxidation of the resulting 4 beta-monocathylates, or direct selective oxidation at C-3 of 3 beta,4 beta-diols with pyridinium chlorochromate, and 3) stereoselective reduction of the 3-oxo compounds with tert-butylamine-borane complex. The results of analysis of the prepared 4 beta-hydroxylated bile acids with a diequatorial trans-glycol structure and their 3 beta-epimers by proton and carbon-13 nuclear magnetic resonance spectroscopies are briefly discussed along with the mass spectrometric properties.     

Electron correlations in molecules. II. General trends derived for isoelectronic series

We investigate general features of electronic correlations in four series of small isoelectronic molecules (partially model systems) containing hydrogen and first-row atoms. The calculations are done by combining a semi-empirical INDO scheme for the SCF part with the local ansatz for the calculation of interatomic correlations and an atoms-in-molecule approach for the determination of intraatomic correlation energies. The latter ones turn out to depend in the simple way on the mean number of electrons and the hybridization of an atom, but only weakly on the nuclear charge. We discuss how the individual (intra- and inter-bond) contributions to the interatomic correlation energy depend on the bond polarity, type of bonding and different kinds of atoms involved. Furthermore we characterize the suppression of charge fluctuations by interatomic correlations by means of a correlation strength parameter.     

Dakin-west reaction in the 2-imino-3-thiazolinylacetic acid series

The reaction of 2-imino-3-benzothiazolinylacetic acid with acetic anhydride under the conditions of the Dakin-West reaction leads to 3-acetony1-2-acetimidobenzothiazoline. Under the same conditions 2-imino-3-thiazolinylacetic acid gives 5-acety1-6-hydroxyimidazo[2,1-b]thiazole. The structures of the compounds obtained were proved by means of their IR, PMR, and mass spectra.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 476–479, April, 1978.     

Liquid solubilization dynamics: Oleic acid in bile salt

The solubilization dynamics of oleic acid by aqueous sodium taurodeoxycholate solutions at 37°C does not conform to previous resistance in series models involving diffusion and interfacial steps. This is especially true as the ionic strength of the aqueous solution is increased by adding NaCl or by increasing the taurodeoxycholate concentration above 2%. Experiments conducted with a liquid/liquid stirred cell show that as the ionic strength is increased, the flux of oleic acid into the aqueous solution exceeds a reasonable value for the diffusion limit, assuming that oleic acid diffuses only in mixed micelles, and that the flux becomes independent of flow at these high ionic strengths. Two alternative models for the solubilization process are proposed. One involves a rapid exchange of oleic acid between mixed micelles and oleic acid free micelles in parallel with mixed micelle diffusion; and the second involves formation of a small emulsion droplet at the interface, which contains significantly more oleic acid than a mixed micelle, and which rapidly dissolves into micellar solution as the droplet leaves the interface.     

Exploitation of bile acid transport systems in prodrug design

The enterohepatic circulation of bile acids is one of the most efficient recycling routes in the human body. It is a complex process involving numerous transport proteins, which serve to transport bile acids from the small intestine into portal circulation, from the portal circulation into the hepatocyte, from the hepatocyte into the bile, and from the gall bladder to the small intestine. The tremendous transport capacity and organ specificity of enterohepatic circulation combined with versatile derivatization possibilities, rigid steroidal backbone, enantiomeric purity, availability, and low cost have made bile acids attractive tools in designing pharmacological hybrid molecules and prodrugs with the view of improving intestinal absorption, increasing the metabolic stability of pharmaceuticals, specifically targeting drugs to organs involved in enterohepatic circulation, as well as sustaining therapeutically reasonable systemic concentrations of active agents. This article briefly describes bile acid transport proteins involved in enterohepatic circulation, summarizes the key factors affecting on the transport by these proteins, and reviews the use of bile acids and their derivatives in designing prodrugs capable of exploiting the bile acid transport system.     

Infrared matrix-isolation spectra of monomeric oxalic acid

Infrared spectra of monomeric oxalic acid-h₂, -hd and -d₂ have been observed using neon matrix-isolation spectroscopy. In addition, spectra of oxalic acid-h₂, vapor were obtained using a heated absorption cell with a 10 m pathlength. All IR active fundamentals are assigned for oxalic acid-h₂, and -d₂, except the low frequency torsion. The spectra are interpreted in terms of the C_2h intramolecularly hydrogen bonded model. Two vibrational assignments are discussed; one involves a very large intensity for the v₈ + v₁₁ (COH torsion) combination band of oxalic acid-h₂. Tentative values for several Raman active fundamentals of oxalic acid-h₂ are suggested using possible combination bands. Few fundamentals of oxalic acid-hd correlating with the Raman modes of the symmetric monomers could be observed. A force constant analysis of the by secular block is presented.