Analysis of conformational equilibria in aplidine using selective excitation 2D NMR spectroscopy and molecular mechanics/dynamics calculations

Aplidine (dehydrodidemnin B), a natural product with potent antitumor activity currently in multicenter phase II clinical trials, exists in DMSO as a mixture of four slowly interconverting conformations in a ratio of 47:33:13:7. NMR spectroscopy shows that these arise as a consequence of cis/trans isomerization about the NMe-Leu(7)-Pro(8) and Pro(8)-Pyr amide bonds of the molecule's side chain. Two major conformations account for 47% and 33% of the total population, a ratio of 60:40 between the two. They correspond to the cis- and trans-isomers, respectively, about the Pro(8)-Pyr amide bond. Two minor conformers arise as a consequence of similar isomerism about the Pro(8)-Pyr amide bond, but in structures in which the NMe-Leu(7)-Pro(8) amide bond is cis rather than trans. These account for approximately 13% and 7% of the total population, corresponding to a ratio of 65:35 cis/trans, respectively. Molecular dynamics simulations show that the three-dimensional structures of all four conformational isomers are similar in the macrocycle and that all are essentially unchanged with respect to the macrocycle of didemnin B. Significant differences in the conformation of the molecule's side chain are, however, observed between major and minor pairs. Analysis of hydrogen-bonding patterns shows that each major conformer exhibits a beta-turn like structure and is stabilized by hydrogen bonding between a different carbonyl group of the pyruvyl unit of the molecule's side chain and the NH of the Thr(6) residue. The minor isomers have a cis-amide bond between the NMe-Leu(7) and Pro(8) residues that obliges the side chain to adopt an extended disposition where hydrogen bonding to the macrocycle is absent. These results suggest that the ability of the molecule's side chain to adopt a beta-turn-like conformation may not be a prerequisite for biological activity in the didemnins and that conformations having an extended side-chain may play a role in the biological activity of aplidine.     

A Review of: “Aquatic Chemistry (An Introduction Emphasizing Chemical Equilibria in Natural Waters)”

Abstract

2nd Edition, by Prof. Dr. Werner Stumm, Swiss Federal Institute of Technology, Zurich, and Prof. Dr. James J. Morgan, California Institute of Technology, Pasadena, 780 pages (including 97 tables, 167 figures, an appendix of 8 pages “Thermodynamic Properties of Common Chemical Species in Aquatic Systems”, an author index of 10 pages, and a subject index of 14 pages), stiff paper cover, format 234 ± 161 mm, ISBN 0-471-04831-3, John Wiley & Sons, New York (1981)     

Beyond the standard model: Working group report

This report summarises the activities of the working group on ‘Physics beyond the Standard Model’. The results of investigations in incorporatingR-parity in grand unification, the possibility of a light charged Higgs boson in extension of MSSM and radiative generation of neutral vector boson self-couplings within the MSSM are described. Also given is an account of activities in neutrino physics, namely a proposal for a study of the atmospheric muon anomaly in deep underground mines, a field theoretic study of neutrino oscillations and a mechanism to generate appropriate masses of three active plus one sterile neutrino species.     

Three-dimensional elastic wave scattering by a layer containing vertical periodic fractures

Elastic wave scattering off a layer containing a single set of vertical periodic fractures is examined using a numerical technique based on the work of Hennion et al. [J. Acoust. Soc. Am. 87, 1861-1870 (1990)]. This technique combines the finite element method and plane wave method to simulate three-dimensional scattering off a two-dimensional fractured layer structure. Each fracture is modeled explicitly, so that the model can simulate both discrete arrivals of scattered waves from individual fractures and multiply scattered waves between the fractures. Using this technique, we examine changes in scattering characteristics of plane elastic waves as a function of wave frequency, angle of incidence, and fracture properties such as fracture stiffness, height, and regular and irregular spacing.     

SR XRF and micro-PIXE studies on ancient metallurgy of thirteen Dacian gold bracelets

A thorough microscopic investigation by SR XRF and micro-PIXE brings insight into the probable techniques used in the manufacture of thirteen Dacian gold bracelets, one of the most spectacular archaeological finds ever on the territory of Romania.     

20-ISO-20-Deethylaspidospermidine

The two-step process of hydrogenation of l-alkyl-3-acylpyridinium salts and cyclization of the resultant 1, 4, 5, 6-tetrahydropyridines has been the foundation of a general scheme of alkaloid synthesis.¹ Its application in the indole alkaloid field has yielded ready access to tetrahydro-β-carboline systems, e.g. 1a → 2 → eburnamonine.² Since acid treatment of N_b -acyl derivatives of substances related to la has been shown to lead to products of indole β-cyclization³, it became of interest to test the cyclization behavior of the vinylogous imide lb, prepared by the dicyclohexylcarbodiimide-induced acylation of 3-acetyl-1, 4, 5, 6-tetrahydropyridine⁴ with indoleacetic acid. Treatment of lb with boron trifluoride gave a 62 yield of ketolactam 3a. Thus a two-step entry into the pentacyclic Aspidosperma alkaloid skeleton is on hand.     

Development of an Inhibition Enzyme-Linked Immunosorbent Assay (ELISA) Prototype for Detecting Cytotoxic Three-Finger Toxins (3FTxs) in African Spitting Cobra Venoms

The administration of toxin-specific therapy in snake envenoming is predicated on improved diagnostic techniques capable of detecting specific venom toxins. Various serological tests have been used in detecting snakebite envenoming. Comparatively, enzyme-linked immunosorbent assay (ELISA) has been shown to offer a wider practical application. We report an inhibition ELISA for detecting three-finger toxin (3FTx) proteins in venoms of African spitting cobras. The optimized assay detected 3FTxs in N. ashei (including other Naja sp.) venoms, spiked samples, and venom-challenged mice samples. In venoms of Naja sp., the assay showed inhibition, implying the detection of 3FTxs, but showed little or no inhibition in non-Naja sp. In mice-spiked samples, one-way ANOVA results showed that the observed inhibition was not statistically significant between spiked samples and negative control (p-value = 0.164). Similarly, the observed differences in inhibition between venom-challenged and negative control samples were not statistically significant (p-value = 0.9109). At an LOD of 0.01 µg/mL, the assay was able to confirm the presence of 3FTxs in the samples. Our results show a proof of concept for the use of an inhibition ELISA model as a tool for detecting 3FTxs in the venoms of African spitting cobra snakes.     

Ernest Julius Wilczynski (in Memoriam)

Ringrazio il collega dell'Università di Chicago di avermi permesso di pubblicare qui un breve sunto della commemorazione da lui scritta; e sono dolente che lo spazio concessomi non me ne abbia permesso la pubblicazione integrale.Guido Fubini     

A wider convergence area for the MSTMAOR iteration methods for LCP

In this paper, based on the Hermitian and skew-Hermitian splitting, we give a generalized modified Hermitian and skew-Hermitian splitting (GMHSS) method to solve singular complex symmetric linear systems, this method has two parameters. We give the semi-convergent conditions, and some numerical experiments are given to illustrate the efficiency of this method.