Investigating flavonoids as molecular templates for the design of small-molecule inhibitors of cell signaling

Epidemiological and clinical trials reveal compelling evidence for the ability of dietary flavonoids to lower cardiovascular disease risk. The mechanisms of action of these polyphenolic compounds are diverse, and of particular interest is their ability to function as protein and lipid kinase inhibitors. We have previously described structure-activity studies that reinforce the possibility for using flavonoid structures as templates for drug design. In the present study, we aim to begin constructing rational screening strategies for exploiting these compounds as templates for the design of clinically relevant, antiplatelet agents. We used the platelet as a model system to dissect the structural influence of flavonoids, stilbenes, anthocyanidins, and phenolic acids on inhibition of cell signaling and function. Functional groups identified as relevant for potent inhibition of platelet function included at least 2 benzene rings, a hydroxylated B ring, a planar C ring, a C ring ketone group, and a C-2 positioned B ring. Hydroxylation of the B ring with either a catechol group or a single C-4' hydroxyl may be required for efficient inhibition of collagen-stimulated tyrosine phosphorylated proteins of 125 to 130 kDa, but may not be necessary for that of phosphotyrosine proteins at approximately 29 kDa. The removal of the C ring C-3 hydroxyl together with a hydroxylated B ring (apigenin) may confer selectivity for 37 to 38 kDa phosphotyrosine proteins. We conclude that this study may form the basis for construction of maps of flavonoid inhibitory activity on kinase targets that may allow a multitargeted therapeutic approach with analogue counterparts and parent compounds.

Climate change impacts in the design of drainage systems: case study of Portugal

This paper aims to assess the necessity of updating the intensity-duration-frequency (IDF) curves used in Portugal to design building storm-water drainage systems. A comparative analysis of the design was performed for the three predefined rainfall regions in Portugal using the IDF curves currently in use and estimated for future decades. Data for recent and future climate conditions simulated by a global and regional climate model chain are used to estimate possible changes of rainfall extremes and its implications for the drainage systems. The methodology includes the disaggregation of precipitation up to subhourly scales, the robust development of IDF curves, and the correction of model bias. Obtained results indicate that projected changes are largest for the plains in southern Portugal (5–33%) than for mountainous regions (3–9%) and that these trends are consistent with projected changes in the long-term 95th percentile of the daily precipitation throughout the 21st century. The authors conclude there is a need to review the current precipitation regime classification and change the new drainage systems towards larger dimensions to mitigate the projected changes in extreme precipitation.

Design of delay-tolerant space–time codes with limited feedback

In cooperative communication networks, owing to the nodes' arbitrary geographical locations and individual oscillators, the system is fundamentally asynchronous. Such a timing mismatch may cause rank deficiency of the conventional space-time codes and, thus, performance degradation. One efficient way to overcome such an issue is the delay-tolerant space-time codes (DT-STCs). The existing DT-STCs are designed assuming that the transmitter has no knowledge about the channels. In this paper, we show how the performance of DT-STCs can be improved by utilizing some feedback information. A general framework for designing DT-STC with limited feedback is first proposed, allowing for flexible system parameters such as the number of transmit/receive antennas, modulated symbols, and the length of codewords. Then, a new design method is proposed by combining Lloyd's algorithm and the stochastic gradient-descent algorithm to obtain optimal codebook of STCs, particularly for systems with linear minimum-mean-square-error receiver. Finally, simulation results confirm the performance of the newly designed DT-STCs with limited feedback.

Molecular design of a discrete chain-folding polyimide for controlled inkjet deposition of supramolecular polymers

A supramolecular polymer based upon two complementary polymer components is formed by sequential deposition from solution in THF, using a piezoelectric drop-on-demand inkjet printer. Highly efficient cycloaddition or ‘click’ chemistry afforded a well-defined poly(ethylene glycol) featuring chain-folding diimide end groups, which possesses greatly enhanced solubility in THF relative to earlier materials featuring random diimide sequences. Blending the new polyimide with a complementary poly(ethylene glycol) system bearing pyrene end groups (which bind to the chain-folding diimide units) overcomes the limited solubility encountered previously with chain-folding polyimides in inkjet printing applications. The solution state properties of the resulting polymer blend were assessed via viscometry to confirm the presence of a supramolecular polymer before depositing the two electronically complementary polymers by inkjet printing techniques. The novel materials so produced offer an insight into ways of controlling the properties of printed materials through tuning the structure of the polymer at the (supra)molecular level.

Quantitative structure-activity relationships for a series of inhibitors of cruzain from Trypanosoma cruzi: Molecular modeling, CoMFA and CoMSIA studies

Human parasitic diseases are the foremost threat to human health and welfare around the world. Trypanosomiasis is a very serious infectious disease against which the currently available drugs are limited and not effective. Therefore, there is an urgent need for new chemotherapeutic agents. One attractive drug target is the major cysteine protease from Trypanosoma cruzi, cruzain. In the present work, comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) studies were conducted on a series of thiosemicarbazone and semicarbazone derivatives as inhibitors of cruzain. Molecular modeling studies were performed in order to identify the preferred binding mode of the inhibitors into the enzyme active site, and to generate structural alignments for the three-dimensional quantitative structure-activity relationship (3D QSAR) investigations. Statistically significant models were obtained (CoMFA. r(2) = 0.96 and q(2) = 0.78; CoMSIA, r(2) = 0.91 and q(2) = 0.73), indicating their predictive ability for untested compounds. The models were externally validated employing a test set, and the predicted values were in good agreement with the experimental results. The final QSAR models and the information gathered from the 3D CoMFA and CoMSIA contour maps provided important insights into the chemical and structural basis involved in the molecular recognition process of this family of cruzain inhibitors, and should be useful for the design of new structurally related analogs with improved potency. (C) 2009 Elsevier Inc. All rights reserved.

The mer-[RuCl(3)(dppb)(H(2)O)] complex: A versatile tool for synthesis of Ru(II) compounds

The complex mer-[RuCl(3)(dppb)(H(2)O)] [dppb = 1,4-bis(diphenylphosphino)butane] was used as a precursor in the synthesis of the complexes tc-[RuCl(2)(CO)(2)(dppb)], ct-[RuCl(2)(CO)(2)(dppb)]. cis-[RuCl(2)(dppb)(Cl-bipy)], [RuCl(2Ac4mT)(dppb)] (2Ac4mT = N(4)-meta-tolyl-2-acetylpyridine thiosemicarbazone ion) and trans-[RuCl(2)(dppb)(mang)] (mang = mangiferin or 1,3,6,7-tetrahydroxyxanthone-C2-beta-D-glucoside) complexes. For the synthesis of Run complexes, the Ru(III) atom in mer-[RuCl(3)(dppb)(H(2)O)] may be reduced by H(2)(g), forming the intermediate [Ru(2)Cl(4)(dppb)(2)], or by a ligand (such as H2Ac4mT or mangiferin). The X-ray structures of the cis-[RuCl(2)(dppb)(Cl-bipy)], tc-[RuCl(2)(CO)(2)(dppb)] and [RuCl(2Ac4mT)(dPpb)] complexes were determined. (C) 2010 Elsevier Ltd. All rights reserved.

Design of a Modern Liposome and Bee Venom Formulation for the Traditional VIT-Venom Immunotherapy

Traditional venom immunotherapy uses injections of whole bee venom in buffer or adsorbed in Al (OH)(3) in an expensive, time-consuming way. New strategies to improve the safety and efficacy of this treatment with a reduction of injections would, therefore, be of general interest. It would improve patient compliance and provide socio-economic benefits. Liposomes have a long tradition in drug delivery because they increase the therapeutic index and avoid drug degradation and secondary effects. However, bee venom melittin (Mel) and phospholipase (PLA(2)) destroy the phospholipid membranes. Our central idea was to inhibit the PLA(2) and Mel activities through histidine alkylation and or tryptophan oxidation (with pbb, para-bromo-phenacyl bromide, and/or NBSN-bromosuccinimide, respectively) to make their encapsulations possible within stabilized liposomes. We strongly believe that this formulation will be nontoxic but immunogenic. In this paper, we present the whole bee venom conformation characterization during and after chemical modification and after interaction with liposome by ultraviolet, circular dichroism, and fluorescence spectroscopies. The PLA(2) and Mel activities were, measured indirectly by changes in turbidity at 400(nm), rhodamine leak-out, and hemolysis. The native whole bee venom (BV) presented 78.06% of alpha-helical content. The alkylation (A-BV) and succynilation (S-BV) of BV increased 0.44 and 0.20% of its alpha-helical content. The double-modified venom (S-A-BV) had a 0.74% increase of alpha-helical content. The BV chemical modification induced another change on protein conformations observed by Trp that became buried with respect to the native whole BV. It was demonstrated that the liposomal membranes must contain pbb (SPC:Cho:pbb, 26:7:1) as a component to protect them from aggregation and/or fusion. The membranes containing pbb maintained the same turbidity (100%) after incubation with modified venom, in contrast with pbb-free membranes that showed a 15% size decrease. This size decrease was interpreted as membrane degradation and was corroborated by a 50% rhodamine leak-out. Another fact that confirmed our interpretation was the observed 100% inhibition of the hemolytic activity after venom modification with pbb and NBS (S-A-BV). When S-A-BV interacted with liposomes, other protein conformational changes were observed and characterized by the increase of 1.93% on S-A-BV alpha-helical content and the presence of tryptophan residues in a more hydrophobic environment. In other words, the S-A-BV interacted with liposomal membranes, but this interaction was not effective to cause aggregation, leak-out, or fusion. A stable formulation composed by S-A-BV encapsulated within liposomes composed by SPC:Cho:pbb, at a ratio of 26:7:1, was devised. Large unilamellar vesicles of 202.5 nm with a negative surface charge (-24.29 mV) encapsulated 95% of S-A-BV. This formulation can, now, be assayed on VIT.

Photoluminescence study of new lanthanide complexes with benzeneseleninic acids

New lanthanide complexes with benzeneseleninic (ABSe) and 4-chloro-benzeneseleninic (ABSeCl) acids have been synthesized and characterized by elemental analysis, infrared and UV-visible spectroscopies. The emission spectra of the trivalent europium complexes presented the typical electronic (5)D(0) -> (7)F(j) transitions of the ion (J = 0-4). The ground-state geometries of the europium complexes have been calculated by using the Sparkle/AM1 model. From these results, the 4f-4f intensity parameters and energies of the ligand singlet and triplet excited states have been obtained. The lower emission quantum yield for the [Eu(ABSe)(3)(H(2)O)(2)](H(2)O)(2) compound, as compared to the [Eu(Al(3)SeCl)(3)(H(2)O)(2)] one, can be associated to the higher numbers of water molecules, in the first and second coordination spheres, that contribute to the luminescence quenching. The [Eu(Al(3)Se)(3)(H(2)O)(2)](H(2)O)(2) complex presents an intermediate state whose energy difference with respect to the first excited singlet state is resonant with three phonons from the water molecules, favouring a multiphonon relaxation process from the singlet state followed by a fast internal conversion process; this effect is less pronounced in the complex with the ABSeCl ligand. The luminescence decay curves of the gadolinium complexes indicate that the level responsible for the intramolecular energy transfer process has a triplet character for both compounds. The nephelauxetic effect in these compounds was investigated under the light of a recently proposed covalency scale based on the concept of overlap polarizability of the chemical bond. (C) 2009 Elsevier B.V. All rights reserved.

Kinetic resolution of iodophenylethanols by Candida antarctica lipase and their application for the synthesis of chiral biphenyl compounds

The kinetic resolution of (+/-)-iodophenylethanols was carried out using lipase from Candida antarctica and in some cases the enantiomeric excesses were high (up to >98%). Enantiomerically enriched (S)-iodophenylethanols produced by the enzymatic resolution process were used in the synthesis of chiral biphenyl compounds by the Suzuki reaction with good yields (63-65%). (C) 2010 Elsevier Ltd. All rights reserved.

Thermal and spectrophotometric studies of new crosslinking method for collagen matrix with glutaraldehyde acetals

Despite the many existing crosslinking procedures, glutaraldehyde (GA) is still the method of choice used in the manufacture of bioprosthesis. The major problems with GA are: (a) uncontrolled reactivity due to the chemical complexity or GA solutions; (b) toxicity due to the release of GA from polymeric crosslinks; and (c) tissue impermeabilization due to polymeric and heterogeneous crosslinks formation, partially responsible for the undesirable calcification of the bioprosthesis. A new method of crosslinking glutaraldehyde acetals has been developed with GA in acid ethanolic solution, and after the distribution inside de matrix, GA is released to crosslinking. Concentrations of hydrochloride acid in ethanolic solutions between 0.1 and 0.001 mol/L with GA concentration between 0.1 and 1.0% were measured in an ultraviolet spectrophotometer to verify the presence of free aldehyde groups and polymeric compounds of GA. After these measurements, the solutions were used to crosslink bovine pericardium. The spectrophotometric results showed that GA was better protected in acetal forms for acid ethanolic solution with HCl at 0.003 mol/L and GA 1.0%(v/v). The shrinkage temperature results of bovine pericardium crosslinked with acetal solutions showed values near 85 C after the exposure to triethylamine vapors.

Synthesis, Spectroscopic Studies and X-ray Crystal Structures of New Pyrazoline and Pyrazole Derivatives

The synthesis and characterization of some pyrazoline compounds of 1,3-diketones with hydrazine derivatives, namely, 1-(S-benzyldithiocarbazate)-3-methyl-5-phenyl-5-hydroxypyrazoline (1); 1-(2-thiophenecarboxylic)-3-methyl-5-phenyl-5-hydroxypyrazoline (2); 1-(2-thiophenecarboxylic)-3,5-dimethyl-5-hydroxypyrazoline (3); 1-(S-benzyldithiocarbazato)-3-methyl-5-phenylpyrazole (4); 1-(2-thiophenecarboxylic)-3-methyl-5-phenylpyrazole (5) and 1-(S-benzyldithiocarbazate)-3,5-dimethylpyrazole (6) are reported. Studies by IR, ((1)H, (13)C)-NMR spectroscopies and single crystal X-ray diffraction revealed that compounds (1)(,) (2) and (3) are formed as pyrazoline, whereas (4) and (5) are formed as pyrazole derivatives only under acidic conditions. Compound (1) crystallizes in orthorhombic P2(1)2(1)2(1), a = 6.38960(10) angstrom, b = 12.9176(3) angstrom, c = 21.2552(5) angstrom, (2) crystallizes in monoclinic, P2(1)/n, a = 11.3617(2) angstrom, b = 8.4988(2) angstrom, c = 92.8900(10)angstrom and beta = 92.8900(5)degrees, (3) crystallizes in monoclinic, C2/c, a = 15.9500(5) angstrom, b = 9.3766(3) angstrom, c = 16.6910(5)angstrom and beta = 113.825(2)degrees, (4) crystallizes in monoclinic, P2(1)/c, a = 15.228(4) angstrom, b = 5.5714(13) angstrom, c = 19.956(5)angstrom and beta = 91.575(7)degrees and (6) crystallizes in orthorhombic, P2(1)2(1)2(1), a = 5.3920(2) angstrom, b = 11.2074(5) angstrom, c = 21.885(1)angstrom . The (3) derivative represents the first pyrazoline compound prepared from 2,4-pentanedione and characterized crystallographically.

Assessing the Design of the Library's Discovery Interface and Online resources: A Case Study at the University of Maryland

This presentation was offered as part of the CUNY Library Assessment Conference, Reinventing Libraries: Reinventing Assessment, held at the City University of New York in June 2014.