Chiral separation of the four stereoisomers of a novel antianginal agent using a dual cyclodextrin system in capillary electrophoresis

Reported here is an analytical method enabling the stereochemical resolution of a new antianginal compound possessing two stereogenic centers, leading to four stereoisomers. Only one of these isomers is currently under development as a novel antianginal agent and consequently, the other three isomers are considered as unwanted chiral impurities. Therefore, an enantioselective method is required in order to check its enantiomeric purity. This paper presents a method exploiting the high efficiency of capillary electrophoresis and the complexing properties of cyclodextrins to achieve the separation of the four stereoisomers of this weakly basic compound (pKa = 7.4). For this purpose, the combination of a neutral cyclodextrin, hydroxypropyl-gamma-cyclodextrin (HP-gamma-CD), and an anionic cyclodextrin, carboxymethyl-beta-cyclodextrin (CM-beta-CD), was added to the separation buffer running in an uncoated silica capillary. After selection of the suitable cyclodextrin system, satisfactorily separation conditions were as follows: 30 mM phosphate buffer (pH 6.4) containing 10 mM of HP-gamma-CD and 10 mM of CM-beta-CD, running voltage +30 kV. The resulting run time and resolutions were respectively about 17 min and between 1.95 and 2.84. Linearity curves (0.993 < r2 < 0.998) are also shown.     

A systematic formula for the asymptotic expansion of singular integrals

Asymptotic theories like the lifting-line, the slender body or the slender ship lead to lineintegrals with singular kernels. Sometimes these integrals are improper, that is to say that they are defined only by their Finite Part. To find asymptotic expansions of these integrals, the Matched Asymptotic Expansion Method is widely used along with other more specific methods depending on the kernel type. The first method is laborious and not systematic, and the other methods are sometimes too much specific to treat general cases. Moreover, all of them are not well adapted to deal with Finite Part integrals.Here, a new method is proposed to avoid the previous difficulties. This method is systematic for homogeneous kernels and gives approximations up to any order, as long as the derivative of the weight function exists at this given order. Moreover the occurrence of logarithmic terms in the expansion is explained and easily predictable. An elliptic integral and the classical lifting-line theory are treated to illustrate the ease of this method.

---

Résumé Les théories asymptotiques telles que la ligne portante, le corps élancé ou le navire de grand allongement conduisent à des intégrales curvilignes à noyaux singuliers. Parfois, ces intégrales sont impropres c'est à dire qu'elles sont définies en Parties Finies. Différentes méthodes ont été mises au point pour trouver les développements asymptotiques de ces intégrales. Généralement elles dépendent fortement de la nature du noyau, et c'est finalement la méthode des développements raccordés qui est utilisées quand le noyau est trop compliqué. Cependant, cette méthode est laborieuse et comme les précèdentes non adaptée aux intégrales défines par leur Partie Finie.Une nouvelle méthode est proposée pour surmonter ces difficultés. Cette méthode est systématique pour les noyaux homogènes et donne les approximations à tout ordre pourvu que les dérivées de la fonction poids existent jusqu'à cet ordre. De plus la présence de termes logarithmiques dans le développement est expliquée et aisément prédictible.Une intégrale elliptique, ainsi que la fameuse théorie de la ligne portante sont traités pour illustrer les possibilités de la méthode.

---

Nomenclature D domain of integration - f(x) weight function - FP Finite Part - h(x) weight function - I ,I _o bounded intervals - j, J integers - K(x, ) singular kernel - L, L integers - M integer defining the approximation order - P _k (x) Legendre polynomial - R set of real numbers - R(ß) equals 1 if is an integer and 0 if not - R _{f, J} ,R _{K, L} remainders of Taylor developments - S () equals either 1 or the sign function:sgn() - t, u, v, x variable of integration - , real numbers - homogeneity order of the kernel - F () Euler's integral (gamma function) - small parameter - [.] integer part of     

Percolation in strongly correlated systems: The massless Gaussian field

We derive a number of new results for correlated nearest neighbor site percolation onZ ^d. We show in particular that in three dimensions the strongly correlated massless harmonic crystal, i.e., the Gaussian random field with mean zero and covariance –, has a nontrivial percolation behavior: sites on whichS _x h percolate if and only ifh _c . with0 _c < . This provides the first rigorous example of a percolation transition in a system with infinite susceptibility.     

A propos de conjectures de Serre et Sullivan

Summary We first give a new proof of a conjecture of J.-P. Serre on the homotopy of finite complexes, which was recently proved by C. McGibbon and J. Neisendorfer. The emphasis is on a property of the mod. 2 homology of certain spaces: their quasi-boundedness as right modules over the Steenrod algebra. This property is preserved when one goes from a simply connected space to its loop space and also when one takes a covering of anH-space. Then we show that this notion of quasi-boundedness simplifies H. Miller's proof of D. Sullivan's conjecture on the contractibility of the space of pointed maps from the classifying space of the groupe /2 into a finite complex.     

The synthesis of imidazole-2-thione nucleosides

Ribosylation of the trimethylsilyl derivative ( 1b ) of imidazole-2-thione ( 1a ) using either stannic chloride or silver perchlorate as catalyst resulted in the formation of the acylated derivatives of 1-(β-D-ribofuranosyl)imidazole-2-thione ( 3c ) and 1,3-di-(β-D-ribofuranosyl)imidazole-2-thione ( 4c ) with the latter predominating ( 4c:3c , ca. 2:1 ). The diribosylated nucleoside 4c was shown to be the N,N-disubstituted product rather than the N,S-disubstituted product by ¹H nmr and ¹³C nmr spectroscopy. Employment of the iodine-catalyzed fusion procedure reversed the aforementioned product ratios and provided the monoriboside 3c in excellent yield. When the trimethylsilyl derivative ( 5b ) of 2-methylthioimidazole ( 5a ) was reacted with 2,3,5-tri-O-benzoyl-D-ribofuranosyl bromide ( 2d ) in acetonitrile, the major product was 1,3-di-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)-imidazole-2-thione ( 4b ). The formation of 4b in this reaction is thought to arise via the Hilbert-Johnson mechanism.     

Efficient solid-phase synthesis of 4,5-dihydro-1,2,4-triazin-6(1H)-ones

A new and easy protocol for the formation of substituted 4,5-dihydro-1,2,4-triazin-6(1H)-ones was developed on solid support. The heterocyclic compounds were formed by nucleophilic reaction of hydrazine on thioamide esters. As cyclization was concomitant with cleavage from the support, substituted 4,5-dihydrotriazinones were obtained in high purity.     

Synthesis of pyridone and pyridine rings by [4+2] hetero-cyclocondensation

Substituted pyridones and pyridines have been synthesised efficiently by employing iminium salt as a key precursor. These compounds were prepared using tandem [4+2] cycloaddition/deamination between azabutadiene and dienophiles.     

Modelling and mutation studies on the histamine H1-receptor agonist binding site reveal different binding modes for H1-agonists: Asp116 (TM3) has a constitutive role in receptor stimulation

Summary A modelling study has been carried out, investigating the binding of histamine (Hist), 2-methylhistamine (2-MeHist) and 2-phenylhistamine (2-PhHist) at two postulated agonistic binding sites on transmembrane domain 5 (TM5) of the histamine H₁-receptor. For this purpose a conformational analysis study was performed on three particular residues of TM5, i.e., Lys²⁰⁰, Thr²⁰³ and Asn²⁰⁷, for which a functional role in binding has been proposed. The most favourable results were obtained for the interaction between Hist and the Lys²⁰⁰/Asn²⁰⁷ pair. Therefore, Lys²⁰⁰ was subsequently mutated and converted to an alanine, resulting in a 50-fold decrease of H₁-receptor stimulation by histamine. Altogether, the data suggest that the Lys²⁰⁰/Asn²⁰⁷ pair is important for activation of the H₁-receptor by histamine. In contrast, analogues of 2-PhHist seem to belong to a distinct subclass of histamine agonists and an alternative mode of binding is proposed in which the 2-phenyl ring binds to the same receptor location as one of the aromatic rings of classical histamine H₁-antagonists. Subsequently, the binding modes of the agonists Hist, 2-MeHist and 2-PhHist and the H₁-antagonist cyproheptadine were evaluated in three different seven--helical models of the H₁-receptor built in homology with bacteriorhodopsin, but using three different alignments. Our findings suggest that the position of the carboxylate group of Asp¹¹⁶ (TM3) within the receptor pocket depends on whether an agonist or an antagonist binds to the protein; a conformational change of this aspartate residue upon agonist binding is expected to play an essential role in receptor stimulation.Abbreviations 2-MeHist 2-methylhistamine - 2-PEA 2-pyridyl-ethylamine - 2-PhHist 2-phenylhistamine - CHO Chinese hamster ovary - E_int interaction energy - E_str strain energy - GES global energy structure - gpH₁R guinea pig H₁-receptor - GPCR G-protein coupled receptor - Hist histamine - N proximal nitrogen - N tele nitrogen - TM transmembrane domain - WT wild type