Stereoselective synthesis of the C14-C26 fragment of the cytotoxic macrolide FD-891

A stereoselective synthesis of the C₁₄-C₂₆ fragment of the naturally occurring, cytotoxic macrolide FD-891, is described. Asymmetric Evans aldol reactions and aldehyde Brown allylations are key steps of the synthesis.     

Graphic sequences with a realization containing a generalized friendship graph

Gould, Jacobson and Lehel [R.J. Gould, M.S. Jacobson, J. Lehel, Potentially G-graphical degree sequences, in: Y. Alavi, et al. (Eds.), Combinatorics, Graph Theory and Algorithms, vol. I, New Issues Press, Kalamazoo, MI, 1999, pp. 451-460] considered a variation of the classical Turán-type extremal problems as follows: for any simple graph H, determine the smallest even integer σ(H,n) such that every n-term graphic sequence π=(d₁,d₂,…,d_n) with term sum σ(π)=d₁+d₂+?+d_n≥σ(H,n) has a realization G containing H as a subgraph. Let F_t,r,k denote the generalized friendship graph on kt−kr+r vertices, that is, the graph of k copies of K_t meeting in a common r set, where K_t is the complete graph on t vertices and 0≤r≤t. In this paper, we determine σ(F_t,r,k,n) for k≥2, t≥3, 1≤r≤t−2 and n sufficiently large.     

Abel's method on summation by parts and theta hypergeometric series

Abel's lemma on summation by parts is reformulated to investigate systematically terminating theta hypergeometric series. Most of the known identities are reviewed and several new transformation and summation formulae are established. The authors are convinced by the exhibited examples that the iterating machinery based on the modified Abel lemma is powerful and a natural choice for dealing with terminating theta hypergeometric series.     

Design,synthesis of novel N prenylated indole-3-carbazones and evaluation of in vitro cytotoxicity and 5-LOX inhibition activities

A series of novel N-1 and C-3 substituted indole derivatives (5a–f) were designed, synthesized and evaluated for their cytotoxic properties, viz Brine Shrimp Lethality Bioassay (BSLB) besides 5-Lipoxygenase (5-LOX) inhibitory activities through in vitro assays. Structure Activity Relation (SAR) studies showed that compound 5d with an LC₅₀ of 6.49 μM and 5c with an IC₅₀ of 33.69 μM were found to be interesting for cytotoxicity and 5-LOX inhibitory activity respectively.     

A divergent approach to apoptolidin and FD-891: asymmetric preparation of a common intermediate

Biologically active Apoptolidin and FD-891 have structural similarity in their macrocyclic cores. Asymmetric preparation of a common intermediate in the total synthesis of these two macrolides is presented. A modified Masuyama Sn-allylation was employed to control the relative stereochemistry in the synthesis of the intermediate.     

Applying numerical continuation to the parameter dependence of solutions of the Schrödinger equation

In molecular reactions at the microscopic level, the appearance of resonances has an important influence on the reactivity. It is important to predict when a bound state transitions into a resonance and how these transitions depend on various system parameters such as internuclear distances. The dynamics of such systems are described by the time-independent Schrödinger equation and the resonances are modeled by poles of the S-matrix.Using numerical continuation methods and bifurcation theory, techniques which find their roots in the study of dynamical systems, we are able to develop efficient and robust methods to study the transitions of bound states into resonances. By applying Keller’s Pseudo-Arclength continuation, we can minimize the numerical complexity of our algorithm. As continuation methods generally assume smooth and well-behaving functions and the S-matrix is neither, special care has been taken to ensure accurate results.We have successfully applied our approach in a number of model problems involving the radial Schrödinger equation.     

Simultaneous determination of TUG-891 and its metabolites in rat plasma using LC–HRMS with application to preclinical pharmacokinetic study

In this study, a simple and reliable LC–MS/MS method was first proposed for the simultaneous determination of TUG-891 and its metabolites TUG-891-alcohol, TUG-891-aldehyde, and TUG-891-acid in rat plasma. The analytes and fasiglifam (internal standard) were extracted from plasma samples with acetonitrile and separated using an Acquity BEH C₁₈ column (1.7 μm, 2.1 × 50 mm) with water containing 0.05% ammonium hydroxide and acetonitrile containing 0.05% ammonium hydroxide as the mobile phase. A Q-Exactive Orbitrap mass spectrometer in full-scan mode was used for mass detection, and the data analysis was obtained using a mass extraction window of 5 ppm. The calibration curves exhibited excellent linearity (correlation coefficient > 0.9981) in the concentration range of 0.5–1000 ng/mL. The lower limit of quantification was 0.5 ng/mL for all analytes. The intra- and inter-day precision was less than 11.31%, and the accuracy ranged from −11.50 to 9.50%. The extraction recovery of the analytes from rat plasma was greater than 82.31%, and no obvious matrix effect was found. The established method was further applied to the pharmacokinetic study of TUG-891, TUG-891-alcohol, TUG-891-aldehyde, and TUG-891-acid in rat after a single dose of 5-mg/kg treatment of TUG-891. The results demonstrated that TUG-891 was rapidly metabolized into its metabolites and the systemic exposures of the metabolites were much higher than those of TUG-891.