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Central neural tumor destruction by controlled release of a synthetic glycoside dispersed in a biodegradable polymeric matrix.

An octyl N-acetylglucosaminide derivative with a pentaerythritol chain at position 6 has been synthesized and evaluated as an inhibitor of neural tumor growth. The glycoside inhibited the growth of a neuroectodermic tumor implanted in rats and, when loaded on a slow-delivery polymer disk, caused the destruction of cultured human astroblastoma obtained after surgical biopsy.

Acetylglucosamine↗

Design and synthesis of glycoside inhibitors of glioma and melanoma growth.

An N-acetylglucosaminide derivative with a pentaerythritol substituent at position C-6 was previously synthesized and shown to inhibit neural tumor growth. Now, we report the preparation of a series of new synthetic compounds introducing systematic changes in the nature, polarity, and size of the sugar substituents. The antimitotic activity of the new compounds was tested on cultured rat (C6) and human (U-373) glioma lines and on a human melanoma line (A-375). The antimitotic and antitumoral activity of the new compounds on glioma cell lines increased up to 2 orders of magnitude with respect to the parent compound or was abolished, permitting a detailed structure-function analysis of the new antitumorals. One of the glycosides inhibited melanoma division with an ID50 below the micromolar range.

Animals↗

Novel disaccharide inhibitors of human glioma cell division.

Several alpha-L-Fuc-(1-->3)-alpha-D-GlcNAcOC8H17 disaccharide derivatives bearing different hydroxylated alkyl chains, with or without sulfate groups at C-4 and/or C-6 positions of the GlcNAc unit, have been synthesized and tested as inhibitors of human astrocytoma lines U-373 and U-118. The antimitotic activity was dependent on the structure and position of the hydroxylated chain linked to the disaccharide. The compounds with a pentaerythritol or L-glyceryl chain at the C-6 position showed the best inhibitory properties, with an ID50 value of ca. 200 microM. On the contrary, sulfated disaccharide derivatives were inactive. The antimitotic activities of the compounds tested were essentially independent of the mitogen used to stimulate cell division.

Antineoplastic Agents↗

Improved synthesis of an ethereal tetraamine core for dendrimer construction.

A new route to a pentaerythritol-based tetraamine is delineated and subsequently contrasted to a previous report. Access to the pure tetraamine is facilitated by the smooth reduction of its tetraazide precusor. Characterization includes the preparation of a 4:1 Zn-tetraphenylporphyrin/tetraamine complex.

Journal Article↗

Synthesis and Properties of Multiarmed Geminis.

Three families of multiarmed and multicationic gemini surfactants, having pentaerythritol, dipentaerythritol, or adamantane cores, were synthesized and examined for their colloidal properties in water. Geminis with four or six six-carbon chains are highly water-soluble and do not self-assemble. But surface tension and conductivity measurements show that the geminis with four or six eight-carbon chains form micelles in the 3-6 mM range (compared to 0.5 M for a corresponding surfactant with a single chain). According to dynamic light scattering, these micelles are small (<30 Å diameter); no evidence of dendritic growth below 25 mM is evident. Geminis with four or six 12-carbon chains are too water-insoluble to examine for micelle formation. It is concluded the outward projection of the hydrocarbon chains in water greatly enhances the propensity of the surfactants to self-assemble. Micellar growth is seemingly restricted by chain pairing, chain looping, and associative ring formation. Since the aggregates have, despite these effects, greater residual water-hydrocarbon contact than found in typical micelles, water solubility of surfactants having longer chains is impaired.

Journal Article↗

Temperature-dependent far-infrared spectra of single crystals of high explosives using terahertz time-domain spectroscopy.

Survey spectra of single-crystal HMX (octahydro-1,3,5,7-tetranitro-1,3,5,7-tetrazocine), RDX (hexahydro-1,3,5-trinitro-1,3,5-triazine), and PETN (pentaerythritol tetranitrate) were acquired in the region from 10 to 80 cm(-1) using terahertz time-domain spectroscopy. The spectra were taken at temperatures ranging from 8.4 to 300 K. Generally, the spectra show multiple absorption peaks in the range 50-80 cm(-1), with PETN (110) showing strong absorption features at room temperature. RDX (210) is the most notable in the region 10-40 cm(-1), showing multiple spectral features, while HMX (010) shows a very broad absorption at 47.8 cm(-1) with a fwhm of 37.3 cm(-1). Future plans include polarization-dependent investigations for multiple crystallographic orientations over an increased spectral range and higher-level theoretical calculations.

Crystallization↗

Anharmonic vibrational properties of explosives from temperature-dependent Raman.

Raman spectra from 50 to 3500 cm(-1) and 4-296 K are analyzed for molecular crystal powders of the explosives pentaerythritol tetranitrate (PETN), beta-octahydro-1,3,5,7-tetranitro-1,3,5,7-tetrazocine (HMX), and 1,3,5-triamino-2,4,6-trinitrobenzene (TATB) and the inert naphthalene. Temperature-dependent Raman spectroscopy is utilized for its sensitivity to anharmonic couplings between thermally populated phonons and higher frequency vibrations relevant to shock up-pumping. The data are analyzed with anharmonic perturbation theory, which is shown to have significant fundamental limitations in application to real data. Fitting to perturbation theory revealed no significant differences in averaged anharmonicities among the three explosives, all of which exhibited larger averaged anharmonicities than naphthalene by a factor of 3. Calculations estimating the multiphonon densities of states also failed to correlate clearly with shock sensitivity. However, striking differences in temperature-dependent lifetimes were obvious: PETN has long lived phonons and vibrons, HMX has long lived phonons but short lived vibrons, while TATB has short lived phonons and vibrons at low temperature. Naphthalene, widely used as a model system, has significantly different anharmonicities and density of states from any of the explosives. The data presented suggest the further hypothesis that hindered vibrational energy transfer in the molecular crystals is a significant factor in shock sensitivity.

Journal Article↗

Hydrophilic elastomers for microcontact printing of polar inks.

A moderately hydrophilic, thermoplastic elastomer (poly(ether-ester)) was investigated as a stamp material for microcontact printing of a polar ink: pentaerythritol-tetrakis-(3-mercaptopropionate). Stamps with a relief structure were produced from this polymer by hot embossing, and a comparison was made with conventional poly(dimethylsiloxane) (PDMS) and oxygen-plasma-treated PDMS. It is shown that the hydrophilic stamps can be used for the repetitive printing (without re-inking) of at least 10 consecutive patterns, which preserve their etch resistance, and this in rather sharp contrast to conventional and oxygen plasma-treated PDMS stamps. It is argued that these enhanced printing characteristics of the hydrophilic stamps originate from an improved wetting and solubility of polar inks in the hydrophilic stamp.

Journal Article↗

Porous thin films based on photo-cross-linked star-shaped poly(D,L-lactide)s.

Self-assembly processes and subsequent photo-cross-linking were used to generate cross-linked, ordered microporous structures on the surfaces of well defined four-arm star-shaped poly(D,L-lactide) (PDLLA) thin films. The four-arm star-shaped PDLLAs were synthesized using an ethoxylated pentaerythritol initiator. Solutions of the PDLLAs were cast in a humid environment, and upon solvent evaporation, ordered honeycomb structures (or breath figures) were obtained. Correlations between molar mass, polymer solution viscosity, and pore dimensions were established. The average pore dimension decreased with increasing polymer solution concentration, and a linear relationship was observed between relative humidity and average pore dimensions. Highly ordered microporous structures were also developed on four-arm star-shaped methacrylate-modified PDLLA (PDLLA-UM) thin films. Subsequent photo-cross-linking resulted in more stable PDLLA porous films. The photo-cross-linked films were insoluble, and the honeycomb structures were retained despite solvent exposure. Free-standing, structured PDLLA-UM thin films were obtained upon drying for 24 h. Ordered microporous films based on biocompatible and biodegradable polymers, such as PDLLA, offer potential applications in biosensing and biomedical applications.

Cross-Linking Reagents↗

Heavyweight dendritic inks for positive microcontact printing.

Poly(propylene imine) dendrimers with dialkyl sulfide end groups were prepared and developed as inks for positive microcontact printing ((+)muCP) on gold. Long (C10H21-S-C10H20-), medium (C3H7-S-C4H8-), and short (CH3-S-CH2-) dialkyl sulfide end groups were attached to second- and third-generation PPI dendrimers to create a family of dendritic sulfides. The dendritic inks flatten upon adsorption and form monolayers on gold. (+)muCP was performed on gold using commercially available poly(dimethylsiloxane) as stamp material and n-octadecanethiol as etch resist. The gold beneath the dendrimers was selectively etched away with an acidic Fe(NO3)3/thiourea solution to give the positive copy of the original master pattern. The multivalent sulfide attachment and the relatively high molecular mass of these dendrimers ensured minimal lateral ink spreading and thus optimal feature reproducibility. Contact times were varied to analyze the spreading rates of the dendritic inks. The spreading rates of the dendritic inks were found to be much lower than that of pentaerythritol tetrakis(3-mercaptopropionate). (+)muCP with the new inks was extended to submicrometer features. Optical microscopy, scanning electron microscopy, and atomic force microscopy were used to characterize the etched samples. Lines with a width of 100 nm were faithfully replicated with the third-generation dendrimers bearing medium (C3-S-C4-) end groups.

Journal Article↗

Toward novel polyacetals by transacetalation techniques: dendrimeric diacetals.

[structure: see text] A new approach to polyacetal systems using sequential transacetalation and protection-deprotection techniques was developed for the preparation of macromolecular polyacetals and applied to secure new dendrimers with 2,4,8,10-tetraoxaspiro[5,5]undecane dendrons from pentaerythritol and polyaldehydes. These novel dendrimers, featuring a 1,3,5-benzene-tricarbaldehyde core, viz., the dodecaol (18) and its hexaacetal (19), were prepared, and molecular modeling revealed peculiar dendron convergent structures above the core, due to intramolecular pi-stacking interactions, reinforced by H-bonding of multifunctional termini.

Acetals↗

Impaired vasodilator response to organic nitrates in isolated basilar arteries.

1. The differential responsiveness of various sections and regions in the vascular system to the vasodilator activity of organic nitrates is important for the beneficial antiischaemic effects of these drugs. In this study we examined the vasodilator activity of organic nitrates in cerebral arteries, where vasodilation causes substantial nitrate induced headache. 2. Isolated porcine basilar and coronary arteries were subjected to increasing concentrations of glyceryl trinitrate (GTN), isosorbide-5-nitrate (ISMN) and pentaerythritol tetranitrate (PETN). S-nitroso-N-acetyl-D,L-penicillamine (SNAP) and endothelium-dependent vasodilation was investigated for comparison purpose. 3. The vasodilator potency (halfmaximal effective concentration in -logM) of GTN (4.33+/-0.1, n=8), ISMN (1.61+/-0.07, n=7) and PETN (>10 microM, n=7) in basilar arteries was more than 100 fold lower than that of GTN (6.52+/-0.06, n=12), ISMN (3.66+/-0.08, n=10) and PETN (6.3+/-0.13, n=8) observed in coronary arteries. 4. In striking contrast, the vasodilator potency of SNAP (halfmaximal effective concentration in -logM) was almost similar in basilar (7.76+/-0.05, n=7) and coronary arteries (7.59+/-0.05, n=9). Likewise, no difference in endothelium dependent relaxation was observed. 5. Denudation of the endothelium resulted in a small increase of the vasodilator potency (halfmaximal effective concentration in -logM) of GTN (4.84+/-0.09, n=7, P<0.03) in basilar arteries and similar results were obtained in the presence of the NO-synthase inhibitor N(omega)-nitro-L-arginine (4.59+/-0.05, n=9, P<0.03). 6. These results suggest that cerebral conductance blood vessels such as porcine basilar arteries seems to have a reduced expression and/or activity of certain cellular enzymatic electron transport systems such as cytochrome P450 enzymes, which are necessary to bioconvert organic nitrates to NO.

Animals↗

Olefin self-metathesis as a new entry into xenotransplantation antagonists bearing the Galili antigen.

A hexameric disaccharide cluster bearing the terminal Gal alpha related xenotransplantation antigen was constructed using a sequence of ruthenium carbenoid catalyzed olefin self-metathesis of monoallylated tribenzyl pentaerythritol followed, after interconversion of benzyl ethers into para-iodobenzyl ethers, by a single step Sonogashira cross-coupling of six prop-2-ynyl glycosides onto a hexameric aryl iodide scaffold.

Alkenes↗

Separation of ephedrine stereoisomers by molecularly imprinted polymers--influence of synthetic conditions and mobile phase compositions on the chromatographic performance.

Separation of ephedrine stereoisomers by molecularly imprinted polymers was performed to study the factors that affect the selectivity and column efficiency. The polymer synthesized with pentaerythritol triacrylate as the cross-linker and chloroform as the porogen was found to have the best overall separation performance. Investigation of the recognition mechanism by NMR and chromatographic analysis revealed that the major binding forces between the polymer stationary phase and ephedrine are the ionic and hydrogen bonding interactions. Studies of the influence of mobile phase compositions on the HPLC analysis have shown that a methanol-aqueous buffer was the suitable mobile phase for the separation in which pH, ionic strength and water content can be adjusted to optimize the chromatographic analysis.

Adrenergic Agents↗

First demonstration of differential inhibition of lectin binding by synthetic tri- and tetravalent glycoclusters from cross-coupling of rigidified 2-propynyl lactoside.

The interplay of mammalian lectins such as galectins with cellular glycoconjugates is intimately involved in crucial reaction pathways including tumor cell adhesion, migration or growth regulation. These clinically relevant functions explain the interest in designing glycoclusters with potent activity to interfere with lectin binding. In view of the perspective for medical applications the following objective arises: to correlate topological factors of ligand display most favorably to reactivity against endogenous lectins. To date, plant agglutinins have commonly been used as models. Properly addressing this issue we first prepared di- to tetravalent clusters from 2-propynyl lactoside under mild oxidative homocoupling conditions and using the Sonogashira palladium-catalyzed cross-coupling reaction with triiodobenzene or pentaerythritol cores. These products were tested for bioactivity in a competitive solid-phase assay using different labeled sugar receptors as probes, i,e. the beta-trefoil mistletoe lectin, the natural lactoside-binding immunoglobulin G fraction from human serum and three mammalian galectins from two subgroups. The lactose headgroups in the derivatives retained ligand properties. Differences in inhibitory capacity were marked between the galectins. In contrast to homodimeric proto-type galectins-1 and -7 significant inhibition of galectin-3 binding with a 7-fold increase in relative potency was observed for the trivalent compound. In comparison, the binding of the beta-trefoil mistletoe agglutinin was reduced best by tetravalent substances The result for galectin-3 was independently confirmed by haemagglutination and cytofluorometric cell binding assays. These data underline the feasibility of galectin-type target selectivity by compound design despite using an identical headgroup (lactose) in synthesis.

Agglutinins↗

Organotin and organogermanium linkers for simple, direct functionalization of polyoxotungstates.

Fifteen Keggin-anion-derived polytungstates [TW11O39[MCH2CH2X]]n- (T = Si, Ge, Ga; M = Sn, Ge; X = COOH, COOCH3, CONH2, CN; n = 5, 6) were prepared in aqueous or aqueous-organic solution from the corresponding lacunary polytungstates and trichlorotin and -germanium precursors, and were isolated as caesium salts. The derivatized polytungstates were characterized by elemental analysis, multinuclear NMR spectroscopy, and cyclic voltammetry; they are stable in aqueous solution to pH 6-7. NMR spectroscopy revealed the presence of a second (beta1 or beta3) isomer in the tungstogallate derivatives. Acid hydrolysis of the ester and nitrile derivatives could be achieved without decomposition of the polytungstate moieties, and esterification and amidation of the carboxylate functions was straightforward using standard coupling techniques, e.g. the formation, isolation and characterization of [SiW11O39[Ge(CH2)2CONHCH2COOCH3]]5- from glycine methyl ester. Since the Cl3MCH2CH2X precursors are readily accessible by hydrostannation/germanation reactions with the corresponding alkenes, novel coupled polytungstates, such as [(SiW11O39GeCH2CH2COOCH2)4C]20- from pentaerythritol tetraacrylate, can also be prepared.

Journal Article↗

Studies on mammalian glucoamylases with special reference to monkey intestinal glucoamylase.

1. Highly purified preparations of glucoamylase were obtained from liver, spleen and intestine of the monkey. The enrichment factor was lower for intestine (60-fold) compared with that of liver (1200-fold) and of spleen (2000-fold) but the final specific activities were of a similar magnitude. 2. The liver and spleen enzymes had maximum activity at pH4.8 whereas the intestinal enzyme showed an optimum at pH5.8. The K(m) values for both starch and maltose with spleen and liver enzymes were higher than for the intestinal enzyme. With the intestinal enzyme, the V(max.) values were higher for both starch and maltose than those of the spleen and liver enzymes. 3. Gel filtration on Sephadex G-200 under identical conditions revealed that liver and spleen enzymes emerge from the columns much later than the intestinal enzyme. 4. Evidence is presented that the glucoamylase activity of the intestinal mucosa is exhibited by the maltase II fraction. 5. Tris, pentaerythritol and turanose inhibited glucoamylase from all the three tissues, but turanose inhibited the spleen and liver enzymes to a higher degree than the intestinal enzyme.

Animals↗

The effect of reactor geometry on frontal polymerization spin modes.

Using reactors of different sizes and geometries the dynamics of the frontal polymerization of 1,6-hexanediol diacrylate (HDDA) and pentaerythritol tetraacrylate (PETAC), with ammonium persulfate as the initiator were studied. For this system, the frontal polymerization exhibits complex behavior that depends on the ratio of the monomers. For a particular range of monomers concentration, the polymerization front becomes nonplanar, and spin modes appear. By varying the reactor diameter, we experimentally confirmed the expected shift of the system to a greater number of "hot spots" for larger diameters. For square test tubes a "zig-zag" mode was observed for the first time in frontal polymerization. We confirmed the viscosity-dependence of the spin mode instabilities. We also observed novel modes in cylinder-inside-cylinder reactors. Lastly, using a conical reactor with a continuously varying diameter, we observed what may be evidence for bistability depending on the direction of propagation. We discuss these finding in terms of the standard linear stability analysis for propagating fronts. (c) 2002 American Institute of Physics.

Journal Article↗