Solution-phase parallel synthesis of a pharmacophore library of HUN-7293 analogues: a general chemical mutagenesis approach to defining structure-function properties of naturally occurring cyclic (depsi)peptides

HUN-7293 (1), a naturally occurring cyclic heptadepsipeptide, is a potent inhibitor of cell adhesion molecule expression (VCAM-1, ICAM-1, E-selectin), the overexpression of which is characteristic of chronic inflammatory diseases. Representative of a general approach to defining structure-function relationships of such cyclic (depsi)peptides, the parallel synthesis and evaluation of a complete library of key HUN-7293 analogues are detailed enlisting solution-phase techniques and simple acid-base liquid-liquid extractions for isolation and purification of intermediates and final products. Significant to the design of the studies and unique to solution-phase techniques, the library was assembled superimposing a divergent synthetic strategy onto a convergent total synthesis. An alanine scan and N-methyl deletion of each residue of the cyclic heptadepsipeptide identified key sites responsible for or contributing to the biological properties. The simultaneous preparation of a complete set of individual residue analogues further simplifying the structure allowed an assessment of each structural feature of 1, providing a detailed account of the structure-function relationships in a single study. Within this pharmacophore library prepared by systematic chemical mutagenesis of the natural product structure, simplified analogues possessing comparable potency and, in some instances, improved selectivity were identified. One potent member of this library proved to be an additional natural product in its own right, which we have come to refer to as HUN-7293B (8), being isolated from the microbial strain F/94-499709.     

An averaging method applied to a duffing equation

We approximate a Duffing equation by an averaged system. We solve the system explicitely and draw bifurcation diagrams in dependence of the forcing term. We discuss the goodness of the averaging method, relative to the behavior of the solutions in dependence of involved parameters, by comparing with results obtained in [6,10] for the original Duffing equation.     

Contributions of the different water sources to the Elqui river runoff (northern Chile) evaluated by H/O isotopes

We present the results of an isotope (2H and 18O) and hydrogeochemical study in order to constrain the origin, recharge, and evolution of the surface and groundwater in the arid Andean realm of the Elqui watershed. The results of 2H and18O analyses of water samples obtained during our summer and winter campaigns indicate a generally meteoric origin of the river and spring waters of the watershed. The isotope signature of water of the Elqui river and its tributaries as well as that of groundwater in the coastal region fits the 2H-18O relation of delta2H =7.61delta18O+6.1. A relatively fast discharge and a quasi-closed catchment area can be asserted for water along the river flow path. The tributaries from the more arid coastal area, north of the Elqui river, differ in their isotopic signature due to evaporation and hydrochemically due to interactions with the strongly altered and fractured volcanic rocks of the basement. In the Andean zone, the18O-enriched hydrothermal spring of Ba?os del Toro exhibits the influence of water-rock interaction processes. The chemistry of the river water changes from sulphate- to chloride-rich along the river course from the high Andean mountains to the coast. The sulphate-rich character of these Andean waters reflects their passage through sulphide-rich rock massifs that were subjected to strong oxidation processes in the near superficial environment. This sulphate signature is enforced by past and present mining of precious metal epithermal deposits (e.g. those of El Indio-Tambo Au-Cu-As district), in which mineralised zones were developed during a series of Miocene magmatic-hydrothermal episodes in the Andean realm. Owing to the proximity of the lower Elqui river waters and its tributaries to the Pacific coast, the chloride character may be induced by agricultural and marine (sea spray, fog) sources. Generally, the main source of the Elqui river water is mainly attributed to surface runoff and less to contributions from the basement fractured aquifer.     

On the number of solutions of a Duffing equation

Summary The exact number of solutions of a Duffing equation with small forcing term and homogeneous Neumann boundary conditions is given. Several bifurcation diagrams are shown.Departamento de Matemática, Facultad de Ciencias, Universidad de Concepción, Concepción, Chile.     

Synthesis and molecular recognition studies of the HNK-1 trisaccharide and related oligosaccharides. The specificity of monoclonal anti-HNK-1 antibodies as assessed by surface plasmon resonance and STD NMR

The human natural killer cell carbohydrate, HNK-1, plays function-conducive roles in peripheral nerve regeneration and synaptic plasticity. It is also the target of autoantibodies in polyneuropathies. It is thus important to synthesize structurally related HNK-1 carbohydrates for optimizing its function-conducive roles, and for diagnosis and neutralization of autoantibodies in the fatal Guillain-Barré syndrome. As a first step toward these goals, we have synthesized several HNK-1 carbohydrate derivatives to assess the specificity of monoclonal HNK-1 antibodies from rodents: 2-aminoethyl glycosides of selectively O-sulfated trisaccharide corresponding to the HNK-1 antigen, its nonsulfated analogue, and modified structures containing 3-O-fucosyl or 6-O-sulfo substituents in the N-acetylglucosamine residues. These were converted, together with several related oligosaccharides, into biotin-tagged probes to analyze the precise carbohydrate specificity of two anti-HNK-1 antibodies by surface plasmon resonance that revealed a crucial role of the glucuronic acid in antibody binding. The contribution of the different oligosaccharide moieties in the interaction was shown by saturation transfer difference (STD) NMR of the complex consisting of the HNK-1 pentasaccharide and the HNK-1 412 antibody.     

Tridiagonal preconditioning for Poisson-like difference equations with flat grids: Application to incompressible atmospheric flow

The convergence of many iterative procedures, in particular that of the conjugate gradient method, strongly depends on the condition number of the linear system to be solved. In cases with a large condition number, therefore, preconditioning is often used to transform the system into an equivalent one, with a smaller condition number and therefore faster convergence. For Poisson-like difference equations with flat grids, the vertical part of the difference operator is dominant and tridiagonal and can be used for preconditioning. Such a procedure has been applied to incompressible atmospheric flows to preserve incompressibility, where a system of Poisson-like difference equations is to be solved for the dynamic pressure part. In the mesoscale atmospheric model KAMM, convergence has been speeded up considerably by tridiagonal preconditioning, even though the system matrix is not symmetric and, hence, the biconjugate gradient method must be used.