Synthesis and evaluation of caged Garcinia xanthones

Inspired by the combination of unique structure and potent bioactivities exhibited by several family members of the caged Garcinia xanthones, we developed a synthesis of simplified analogues that maintain the overall caged motif. The caged structure of these compounds was constructed via a site-selective Claisen/Diels-Alder reaction cascade. We found that the fully substituted caged structure, in which are included the C18 and C23 geminal methyl groups, is necessary to maintain bioactivity. Analogue had comparable activity to the natural products of this family, such as gambogic acid. These compounds exhibit cytotoxicity in a variety of tumor cell lines at low micromolar concentrations and were found to induce apoptosis in HUVE cells. In addition, studies with HL-60 and HL-60/ADR cells indicate that these compounds are not affected by the mechanisms of multidrug resistance, conferred by P glycoprotein expression, typical of relapsed cancers and thus represent a new and potent pharmacophore.     

Cellular covers of groups

In this paper we discuss the concept of cellular cover for groups, especially nilpotent and finite groups. A cellular cover is a group homomorphism c:G→M such that composition with c induces an isomorphism of sets between and . An interesting example is when G is the universal central extension of the perfect group M. This concept originates in algebraic topology and homological algebra, where it is related to the study of localizations of spaces and other objects. As explained below, it is closely related to the concept of cellular approximation of any group by a given fixed group. We are particularly interested in properties of M that are inherited by G, and in some cases by properties of the kernel of the map c.     

Error expansion for the discretization of backward stochastic differential equations

We study the error induced by the time discretization of decoupled forward–backward stochastic differential equations (X,Y,Z)$(X,Y,Z)$. The forward component X$X$ is the solution of a Brownian stochastic differential equation and is approximated by a Euler scheme X^N$X^N$ with N$N$ time steps. The backward component is approximated by a backward scheme. Firstly, we prove that the errors (Y^N−Y,Z^N−Z)$(Y^N-Y,Z^N-Z)$ measured in the strong _Lp$L_p$-sense (p≥1$p\ge 1$) are of order N^−1/2$N^{-1/2}$ (this generalizes the results by Zhang [J. Zhang, A numerical scheme for BSDEs, The Annals of Applied Probability 14 (1) (2004) 459–488]). Secondly, an error expansion is derived: surprisingly, the first term is proportional to X^N−X$X^N-X$ while residual terms are of order N⁻¹$N^{-1}$.     

Benzodiazepine biosynthesis in Streptomyces refuineus

Anthramycin is a benzodiazepine alkaloid with potent antitumor and antibiotic activity produced by the thermophilic actinomycete Streptomyces refuineus sbsp. thermotolerans. In this study, the complete 32.5 kb gene cluster for the biosynthesis of anthramycin was identified by using a genome-scanning approach, and cluster boundaries were estimated via comparative genomics. A lambda-RED-mediated gene-replacement system was developed to provide supporting evidence for critical biosynthetic genes and to validate the boundaries of the proposed anthramycin gene cluster. Sequence analysis reveals that the 25 open reading frame anthramycin cluster contains genes consistent with the biosynthesis of the two halves of anthramycin: 4 methyl-3-hydroxyanthranilic acid and a "dehydroproline acrylamide" moiety. These nonproteinogenic amino acid precursors are condensed by a two-module nonribosomal peptide synthetase (NRPS) terminated by a reductase domain, consistent with the final hemiaminal oxidation state of anthramycin.     

Determining protein adducts of fipexide: mass spectrometry based assay for confirming the involvement of its reactive metabolite in covalent binding

Fipexide is a nootropic drug, withdrawn from the market due to its idiosyncratic drug reactions causing adverse effects in man. Previous work on its metabolites has identified several potential reactive metabolites which could be implicated in protein binding. Here, we investigated the formation of these metabolites in rat and human hepatocytes. Based on these results, the o-quinone of fipexide (FIP), formed via the demethylenation reaction through a catechol intermediate, was chosen for further investigation. Studies were then pursued in order to relate this metabolite to protein binding, and thus better understand potential mechanisms for the toxicity of the parent compound. An assay was developed for determining the fipexide catechol-cysteine adduct in the microsomal protein fractions following in vitro incubations. This method digests the entire protein fraction into amino acids, followed by the detection of the Cys-metabolite adduct by liquid chromatography/mass spectrometry (LC/MS). We have designed a strategy where drug metabolism taking place in microsomal incubations and involved in protein binding can be assessed after the proteins have been digested, with the detection of the specific amino acid adduct. In this study, the structure of the fipexide adduct was hypothesized using knowledge previously gained in glutathione and N-acetylcysteine trapping experiments. Acetaminophen was used as a positive control for detecting a drug metabolite-cysteine adduct by LC/MS. This approach has the potential to be applicable as a protein-binding assay in early drug discovery without the need for radioactive compounds.     

Une infinité de structures de contact tendues sur une infinité de variétés

V de dimension trois, tout champ de plans tangents est homotope à une structure de contact, c'est-à-dire – dans le cas d'un champ orientable – au noyau ξ d'une 1-forme α dont le produit extérieur avec dα ne s'annule pas. Plus tard, les travaux de D.Bennequin [Be] puis de Y. Eliashberg [El1] ont conduit à ne retenir comme géométriquement intéressantes que les structures de contact dites tendues, c'est-à-dire telles qu'aucun disque plongé dans V ne soit tangent àξ en tous les points de son bord. En outre, Y. Eliashberg [El2, El3] a prouvé qu'un certain nombre de variétés –à savoir D ³, R ³, S ³, S ²×S ¹ et S ²×R– portent une seule structure de contact tendue, ce qui l'a amenéà conjecturer qu'une variété close orientable ne pouvait admettre qu'un nombre fini de structures tendues à isotopie près [El2, Conjecture 8.6.1]. Cependant, cette conjecture s'est vite révélée fausse sur le tore T ³ [Gi2, Gi3, Ka, Th] et le but du présent article est de montrer que toutes les variétés orientables fibrées en tores au-dessus du cercle (donc une infinité de variétés de dimension trois) portent une infinité de structures de contact tendues deux à deux non conjuguées. Oblatum 14-V-1998 & 11-lX-1998 / Published online: 28 January 1999     

Development of an electrochemical flow injection immunoassay (FIIA) for the real-time monitoring of biospecific interactions

Not only are sensors a revolution in analysis; they themselves are also experiencing a revolution brought about by parallel developments in sensor fabrication techniques and materials, polymer chemistry, signal processing methodologies, the increased use of biomolecular processes as a means of analyte detection, and the coupling of sensors to other techniques such as flow injection analysis. Many of these developments have been incorporated into the present study, which we are undertaking in the development of our immunosensor technology. The system described here utilises screen-printed electrodes which are low-cost, disposable devices that are simple to fabricate. Incorporated into our sensor is the electroactive polymer, polyaniline, which brings about mediatorless redox coupling between the electrode and biomolecular components attached to the polymer surface. This system also utilises enzyme-labelled antibodies as the biomolecular recognition component for the analysis of the test analyte, biotin. The system has also been integrated into a flow injection system. This has led to the monitoring of real-time antibody-antigen interactions using electrochemical methods and foreshadows the development of single-step immunosensors.     

Brownmillerites CaFeO2.5 and SrFeO2.5 as Catalyst Support for CO Oxidation

The support material can play an important role in oxidation catalysis, notably for CO oxidation. Here, we study two materials of the Brownmillerite family, CaFeO_2.5 and SrFeO_2.5, as one example of a stoichiometric phase (CaFeO_2.5, CFO) and one existing in different modifications (SrFeO_2.75, SrFeO_2.875 and SrFeO₃, SFO). The two materials are synthesized using two synthesis methods, one bottom-up approach via a complexation route and one top-down method (electric arc fusion), allowing to study the impact of the specific surface area on the oxygen mobility and catalytic performance. CO oxidation on ¹⁸O-exchanged materials shows that oxygen from SFO participates in the reaction as soon as the reaction starts, while for CFO, this onset takes place 185 °C after reaction onset. This indicates that the structure of the support material has an impact on the catalytic performance. We report here on significant differences in the catalytic activity linked to long-term stability of CFO and SFO, which is an important parameter not only for possible applications, but equally to better understand the mechanism of the catalytic activity itself.     

Absolute Configuration of Two New 6‐Alkylated α‐Pyrones (=2H‐Pyran‐2‐ones) from Ravensara crassifolia

The stem bark CH₂Cl₂ extract of Ravensara crassifolia showed antifungal activity against the phytopathogenic fungus Cladosporium cucumerinum in a bioautographic TLC assay. Activity‐guided fractionation afforded two new α‐pyrones : (6S)‐5,6‐dihydro‐6‐[(2R)‐2‐hydroxy‐6‐phenylhexyl]‐2H‐pyran‐2‐one ( 1 ) and (6R)‐6‐[(4R,6R)‐4,6‐dihydroxy‐10‐phenyldec‐1‐enyl]‐5,6‐dihydro‐2H‐pyran‐2‐one ( 2 ). Their structures and absolute configurations were established by NMR spectroscopy, chemical methods, and CD spectroscopy. The antifungal activity against C. cucumerinum was determined for both compounds.