Synthesis, Biological Evaluation and Mechanism Studies of Deoxytylophorinine and Its Derivatives as Potential Anticancer Agents

Previous studies indicated that (+)-13a-(S)-Deoxytylophorinine (1) showed profound anti-cancer activities both in vitro and in vivo and could penetrate the blood brain barrier to distribute well in brain tissues. CNS toxicity, one of the main factors to hinder the development of phenanthroindolizidines, was not obviously found in 1. Based on its fascinating activities, thirty-four derivatives were designed, synthesized; their cytotoxic activities in vitro were tested to discover more excellent anticancer agents. Considering the distinctive mechanism of 1 and interesting SAR of deoxytylophorinine and its derivatives, the specific impacts of these compounds on cellular progress as cell signaling transduction pathways and cell cycle were proceeded with seven representative compounds. 1 as well as three most potent compounds, 9, 32, 33, and three less active compounds, 12, 16, 35, were selected to proform this study to have a relatively deep view of cancer cell growth-inhibitory characteristics. It was found that the expressions of phospho-Akt, Akt, phospho-ERK, and ERK in A549 cells were greater down-regulated by the potent compounds than by the less active compounds in the Western blot analysis. To the best of our knowledge, this is the first report describing phenanthroindolizidines alkaloids display influence on the crucial cell signaling proteins, ERK. Moreover, the expressions of cyclin A, cyclin D1 and CDK2 proteins depressed more dramatically when the cells were treated with 1, 9, 32, and 33. Then, these four excellent compounds were subjected to flow cytometric analysis, and an increase in S-phase was observed in A549 cells. Since the molecular level assay results of Western blot for phospho-Akt, Akt, phospho-ERK, ERK, and cyclins were relevant to the potency of compounds in cellular level, we speculated that this series of compounds exhibit anticancer activities through blocking PI3K and MAPK signaling transduction pathways and interfering with the cell cycle progression

H{\mathcal {H}} H -matrix Accelerated Second Moment Analysis for Potentials with Rough Correlation

We consider the efficient solution of partial differential equations for strongly elliptic operators with constant coefficients and stochastic Dirichlet data by the boundary integral equation method. The computation of the solution's two-point correlation is well understood if the two-point correlation of the Dirichlet data is known and sufficiently smooth. Unfortunately, the problem becomes much more involved in case of roughly correlated data. We will show that the concept of the $${\mathcal {H}}$$ H -matrix arithmetic provides a powerful tool to cope with this problem. By employing a parametric surface representation, we end up with an $${\mathcal {H}}$$ H -matrix arithmetic based on balanced cluster trees. This considerably simplifies the implementation and improves the performance of the $${\mathcal {H}}$$ H -matrix arithmetic. Numerical experiments are provided to validate and quantify the presented methods and algorithms

Bembel: The fast isogeometric boundary element C++ library for Laplace, Helmholtz, and electric wave equation

In this article, we present Bembel, the C++ library featuring higher order isogeometric Galerkinboundary element methods for Laplace, Helmholtz, and Maxwell problems. Bembel is compatible withgeometriesfromtheOctaveNURBSpackage,andprovidesaninterfacetotheEigentemplatelibraryforlinear algebra operations. For computational efficiency, it applies an embedded fast multipole methodtailored to the isogeometric analysis framework and a parallel matrix assembly based on OpenMP

The structure of cell adhesion molecule uvomorulin. Insights into the molecular mechanism of Ca2+-dependent cell adhesion.

We have determined the amino acid sequence of the Ca2+-dependent cell adhesion molecule uvomorulin as it appears on the cell surface. The extracellular part of the molecule exhibits three internally repeated domains of 112 residues which are most likely generated by gene duplication. Each of the repeated domains contains two highly conserved units which could represent putative Ca2+-binding sites. Secondary structure predictions suggest that the putative Ca2+-binding units are located in external loops at the surface of the protein. The protein sequence exhibits a single membrane-spanning region and a cytoplasmic domain. Sequence comparison reveals extensive homology to the chicken L-CAM. Both uvomorulin and L-CAM are identical in 65% of their entire amino acid sequence suggesting a common origin for both CAMs