Betulin,a Newly Characterized Compound in Acacia auriculiformis Bark,Is a Multi-Target Protein Kinase Inhibitor

The purpose of this work is to investigate the protein kinase inhibitory activity of constituents from Acacia auriculiformis stem bark. Column chromatography and NMR spectroscopy were used to purify and characterize betulin from an ethyl acetate soluble fraction of acacia bark. Betulin, a known inducer of apoptosis, was screened against a panel of 16 disease-related protein kinases. Betulin was shown to inhibit Abelson murine leukemia viral oncogene homolog 1 (ABL1) kinase, casein kinase 1ε (CK1ε), glycogen synthase kinase 3α/β (GSK-3 α/β), Janus kinase 3 (JAK3), NIMA Related Kinase 6 (NEK6), and vascular endothelial growth factor receptor 2 kinase (VEGFR2) with activities in the micromolar range for each. The effect of betulin on the cell viability of doxorubicin-resistant K562R chronic myelogenous leukemia cells was then verified to investigate its putative use as an anti-cancer compound. Betulin was shown to modulate the mitogen-activated protein (MAP) kinase pathway, with activity similar to that of imatinib mesylate, a known ABL1 kinase inhibitor. The interaction of betulin and ABL1 was studied by molecular docking, revealing an interaction of the inhibitor with the ABL1 ATP binding pocket. Together, these data demonstrate that betulin is a multi-target inhibitor of protein kinases, an activity that can contribute to the anticancer properties of the natural compound and to potential treatments for leukemia.     

A stereoselective and short total synthesis of the polyhydroxylated gamma-amino acid (-)-detoxinine,based on stereoselective preparation of dihydropyrrole derivatives from lithiated alkoxyallenes

Based on our earlier results employing lithiated methoxyallene 2 as C(3) building block and imines 3 for the synthesis of dihydropyrrole derivatives 5, we have investigated chiral imines 6, 10, and 15 as electrophilic components. Combined with lithiated alkoxyallenes, these imines provide the corresponding primary adducts and finally the dihydropyrrole derivatives 8, 12, 17, 20, and 22 in good yields and with high to excellent syn selectivities. This stereochemical outcome is interpreted as a result of alpha-chelate control. Treatment with hydrochloric acid converted syn-8 and syn-12 into bicyclic compounds 9 and 13, whereas under more mildly acidic conditions adduct syn-17 was transformed into diol syn-18. The total synthesis of the uncommon gamma-amino acid (-)-detoxinine could be achieved by starting from (S)-malic acid, which was converted into imine 15 in four steps. Lithiated benzyloxyallene added to imine 15 and efficiently furnished the crucial dihydropyrrole derivative syn-22. The hydrogenolysis of this compound did not directly provide the protected triol 29 as anticipated, but a stepwise protocol made the triol available in a fairly satisfactory manner. A second crucial step of the synthesis was the selective oxidation of 29, which could be achieved by employing platinum dioxide and oxygen. The resulting bicyclic lactone 30 was smoothly transformed into enantiopure (-)-detoxinine. Thus, a fairly short synthesis of this natural product based on a lithiated alkoxyallene could be performed, demonstrating the potential of these intermediates for syntheses of interesting functionalized heterocyclic compounds.     

Characterizations of classical orthogonal polynomials on quadratic lattices

This paper is devoted to characterizations of classical orthogonal polynomials on quadratic lattices by using a matrix approach. In this form we recover the Hahn, Geronimus, Tricomi and Bochner type characterizations of classical orthogonal polynomials on quadratic lattices. Moreover a new matrix characterization of classical ortho-gonal polynomials in quadratic lattices is presented. From the Bochner type characterization we derive the three-term recurrence relation coefficients for these polynomials.     

Texture analysis of brain MRI evidences the amygdala activation by nociceptive stimuli under deep anesthesia in the propofol-formalin rat model

Magnetic resonance images of rat brain were analyzed by texture analysis in order to study the effects of a nociceptive stimulation (formalin test) under propofol deep anesthesia. Changes of the texture in different cerebral brain areas acquired before and after stimulation were checked. Our statistical analysis of texture shows that these changes were present only in the amygdala, in agreement with the facts already known about the unconscious memorization of nociceptive stimuli.     

New mechanistic aspects and structure activity relationships in the allyl nickel complex catalysed butadiene polymerization

The present state of knowledge of the mechanism of the allyl nickel complex catalysed stereoselective butadiene polymerization is outlined. On the basis of the reaction model, which has been worked out more thoroughly and comprehensively by our systematic experimental investigations during the last years, the thermodynamic and kinetic control of the catalytic activity and selectivity in dependence on the structure of the allylnickel complexes will be discussed. Finally, it will be shown how the structure of the technical nickel catalyst could be elucidated for the first time and how its catalytic properties can be explained in the framework of the derived structure-activity relationships.     

Self-assembly of amphiphilic liquid crystal polymers obtained from a cyclopropane-1,1-dicarboxylate bearing a cholesteryl mesogen

We study the self-assembly of a new family of amphiphilic liquid crystal (LC) copolymers synthesized by the anionic ring-opening polymerization of a new cholesterol-based LC monomer, 4-(cholesteryl)butyl ethyl cyclopropane-1,1-dicarboxylate. Using the t-BuP(4) phosphazene base and thiophenol or a poly(ethylene glycol) (PEG) functionalized with thiol group to generate in situ the initiator during the polymerization, LC homopolymer and amphiphilic copolymers with narrow molecular weight distributions were obtained. The self-assemblies of the LC monomer, homopolymer, and block copolymers in bulk and in solution were studied by small-angle X-ray scattering (SAXS), differential scanning calorimetry (DSC), polarizing optical microscopy (POM), and transmission electron microscopy (TEM). All polymers exhibit in bulk an interdigitated smectic A (SmA(d)) phase with a lamellar period of 4.6 nm. The amphiphilic copolymers self-organize in solution into vesicles with wavy membrane and nanoribbons with twisted and folded structures, depending on concentration and size of LC hydrophobic block. These new morphologies will help the comprehension of the fascinating organization of thermotropic mesophase in lyotropic structures.     

A direct route to polythiophenes displaying lateral substituents: Easy one‐step synthesis and polymerization of thiophene monomers substituted by a dimethylenecarboxylate (CH2CH2COOR) appendage on the 3‐position

Thiophene monomers displaying a dimethylenecarboxylate (CH₂CH₂COOR) substituent on the 3‐position of the aromatic ring can be easily obtained and in one step from the electrochemically induced reaction of 3‐bromothiophene with the corresponding acrylate (CH₂?CHCOOR). The synthesis of the ethyl ester monomer, of related 2,5‐dihalogenothiophenes, and their polymerization are reported. Despite the surprisingly low solubilities displayed by the polymers, a full spectroscopic characterization could be performed and the data fully analyzed. Oxidative polymerizations (FeCl₃ or electropolymerization) yield a regioirregular polythiophene, with 60–70% of head‐to‐tail diads. Both experimental and theoretical results suggest that the nonconjugated ester plays a very minor role—if any—in the polymerizations under oxidative conditions, but has a significant influence on the polymer properties. Preliminary attempts to polymerize the dihalogenothiophenes under reductive conditions were hampered by the even lower solubilities exhibited by the regioregular oligomers. © 2011 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2012