Synthesis and biological evaluation of (-)-dictyostatin and stereoisomers

Total syntheses of (−)-dictyostatin, 6,16-bis-epi-dictyostatin, 6,14,19-tris-epi-dictyostatin, and a number of other isomers and analogs are reported. Three main fragments—top, middle, and bottom—were first assembled and then joined by olefination or anionic addition reactions. After appending the two dienes at either end of the molecule, macrolactonization and deprotection completed the syntheses. The work proves both the relative and absolute configurations of (−)-dictyostatin. The compounds were evaluated by cell-based measurements of increased microtubule mass and antiproliferative activity, and in vitro tubulin polymerization assays as well as competitive assays with paclitaxel for its binding site on microtubules. These assays showed dictyostatin to be the most potent of the agents and further showed that the structural alterations caused from 20- to >1000-fold decreases in activity.     

Macro and microchemistry of trace metals in vitrified domestic wastes by laser ablation ICP-MS and scanning electron microprobe X-ray energy dispersive spectroscopy

Management of domestic wastes often relies on incineration, a process that eliminates large amount of wastes but also produces toxic residues that concentrate heavy metals. Those hazardous secondary wastes require specific treatment. Vitrification is seen as a powerful way to stabilise them. However, concern exists about the long term behaviour of these glass wastes and the potential release of toxic species into the environment. The answers will come with further investigation into the physico-chemical evolution of the vitrified wastes and the mobility of hazardous elements within the matrix with appropriate analytical methods. Laser ablation coupled with inductively coupled mass spectrometry (LA-ICP-MS) is a challenging technique for the chemical analysis of trace elements in solid materials. This paper presents an evaluation of the potential of LA- ICP-MS for macro and microanalysis of trace metals in domestic vitrified wastes with regards to other physical analytical techniques of solids such as scanning electronprobe X-ray energy dispersive spectroscopy (SEM-EDXS). Two typical samples, vitreous and crystallised, are used to compare the analytical performances of the two techniques. SEM-EDXS was used for mineralogical characterisation and chemical analysis of the mineralogical phases. Relative micro-analysis and bulk quantitative analysis of 30 major, minor and trace elements was performed by LA-ICP-MS: precision was between 10 and 20% for most elements and quantitative analysis proved possible with an accuracy of 20% and relative detection limits of 0.1 mg kg(-1).     

Modelisation of the Association Mechanism of a Series of Huperzine Derivatives Used for Alzheimer Disease with Human Serum Albumin: Effect of the Magnesium Cation

The role of the Mg²⁺ cation on huperzine molecule binding (drugs used for Alzheimer disease) on human serum albumin (HSA) was studied by affinity chromatography. The thermodynamic data corresponding to this binding were determined for a wide range of Mg²⁺ concentrations (x). For each solute, the huperzine binding on HSA was divided into two Mg²⁺ concentration regions. For a low x value, below x_c (1.2 mM), the binding decrease with x. For x above x_c the hydrophobic effect and van der Waals interactions between the huperzine molecule and the HSA implied a decrease in its binding. These results showed that for patients with Alzheimer disease, an Mg²⁺ supplementation during treatment with these huperzine molecules can increase the active pharmacological molecule concentration.     

A chromatographic approach to analyze dansyl amino acid-HP-beta-CD association using macrocyclic antibiotic as the stationary phase

The retention mechanism for a series of D,L-dansyl amino acids in high-performance liquid chromatography is investigated using a teicoplanin stationary phase and hydroxypropyl-beta-cyclodextrin (HP-beta-CD) as the mobile phase additive (0-16mM). A theoretical treatment is developed to determine the HP-beta-CD influence on the equilibrium between the teicoplanin phase and the aqueous medium, respectively. From the experimental data, the association constants of the D,L-dansyl amino acids-HP-beta-CD inclusion complexes are determined and discussed in relation to the enantiomer structure. A thermodynamic study confirms that both the retention and complexation mechanisms are independent of the dansyl amino acid molecular structure and its absolute carbon configuration.     

Comparison of optimization methods in planar chromatography

Summary The optimisation of chromatographic parameters is studied. The Window Diagram and Overlapping Resolution Map (ORM) methods are compared. The latter is developed to take into account the spot diameter and the average plate height variations with the development distance, in order to improve the reliability of the method.     

Preparative isolation of huperzines A and B from Huperzia serrata by displacement centrifugal partition chromatography

The pH-zone refining centrifugal partition chromatography technique was used to separate the two acetylcholinesterase inhibitors huperzines A and B from a crude alkaloid extract of the club moss Huperzia serrata. Complete co-elution of huperzines A and B was initially observed with the well-known methyl tert-butyl ether-acetonitrile-water (4:1:5, v/v/v) solvent system with triethylamine (8mM) as the displacer and methane sulfonic acid (6mM) as the retainer. An efficient biphasic system was designed on the basis of solvent association that provided selectivity in the elution mode: n-heptane/ethyl acetate/n-propanol/water (5:15:35:45, v/v/v/v). Lowering the bridge solvent content (n-propanol) of this system increased the polarity difference between the two phases thus adapting it to the pH-zone refining mode. Thus, the purification of these compounds was achieved using the biphasic system n-heptane/ethyl acetate/n-propanol/water (10:30:15:45, v/v/v/v) with triethylamine (8mM) as the displacer and methane sulfonic acid (6mM) as the retainer.     

Enantioselective aptameric molecular recognition material: Design of a novel chiral stationary phase for enantioseparation of a series of chiral herbicides by capillary electrochromatography

A chiral stationary phase derived from an L-RNA aptamer is evaluated for the enantiomer separation of a series of herbicide molecules (aryloxypropionic, aryloxyphenoxypropionic, and aminopropionic acid) by CEC after binding to biotin and grafting upon streptavidin-modified porous glass beads. We demonstrated that the aptamer capillary was stable in term of efficiency and retention during a long period. The influences of the mobile phase constitution and its flow-velocity on the enantioseparation were also investigated. The results suggest that the interactions of the enantiomer during CEC are solely based on chromatographic mechanisms and that the electrophoresis plays only a minor role. The separation efficiency and peak shape could be improved by Mg2+ divalent cation that stabilized the aptamer secondary structure and thus enhanced the mass transfer kinetics during the ligand-aptamer binding process. In addition, it was demonstrated that the determination of the enantiomerization barrier of flamprop was possible using this chiral stationary phase.     

Multiple dual-mode centrifugal partition chromatography, a semi-continuous development mode for routine laboratory-scale purifications

Nowadays, centrifugal partition chromatography (CPC) separations can be routinely achieved at the laboratory scale. The solvent system selection has been made easy, as generic sets of solvent systems are described in publications and books. This approach, however, generally reduces the scope of optimization strategies for two important parameters: selectivity and sample solubility. This can be very limiting for the preparative separation of structurally similar compounds. Multiple dual-mode (MDM) CPC has been developed to provide an easy-to-use alternative technique to circumvent this problem. A MDM separation consists of a succession of dual-mode runs (i.e. multiple inversion of stationary and mobile phase) that can only be achieved because both chromatographic phases are liquids. This original elution mode is thus a semi-continuous process with a classical sample injection and which only requires a single CPC column. Underlying mechanisms of MDM were studied using a model mixture of acenaphthylene and naphthalene. A mixture of two synthetic pairs of diastereomers was then successfully submitted to MDM CPC, in the framework of the synthesis of biologically active compounds.