A unified and quantitative receptor model for the microtubule binding of paclitaxel and epothilone

[formula: see text] Paclitaxel and epothilone represent the two major classes of antimicrotubule agents that promote tubulin polymerization and, presumably, mitotic arrest during cell division. A common minireceptor binding site model at beta-tubulin has been constructed for these structurally divergent compounds. Utilizing 20 amino acids identified in photoaffinity labeling experiments, the 3-D model correlates measured and predicted Ki's with r = 0.99 and rms(delta Gcalc-delta Gexp) = 0.2 kcal/mol. In addition, the model predicts the affinity of compounds not used in the training set and explains much of the SAR for the paclitaxel and epothilone families.     

Construction of a 2,6-difunctionalized 2-methyl-2H-1-benzopyran library by using a solid-phase synthesis protocol

[reaction: see text] A library containing 1200 analogues of 2,6-difunctionalized 2-methyl-2H-1-benzopyran was constructed by using a solid-phase synthesis protocol. Polymer-bound 6-amido-, 6-sulfonamido-, and 6-uredo-functionalized 2-hydroxymethyl-2-methylbenzopyrans 10 were prepared as part of a first-generation diversification step by employing reactions of respective acid halides, sulfonyl chlorides, and isocyanates with the amine precursor 7. Transformations of the resin-bound intermediates 10 by reactions with alkyl and acid halides were then used to produce a diverse series of 2,6-difunctionalized 2-methyl-2H-1-benzopyran analogues 12 and 14.     

Field and flow programming in frit-inlet asymmetrical flow field-flow fractionation

The separation of wide molecular mass (Mr) ranges of macromolecules using frit inlet asymmetrical flow field-flow fractionation (FI-AFlFFF) has been improved by implementing a combination of field and flow programming. In this first implementation, field strength (governed by the cross flow-rate through the membrane-covered accumulation wall) is decreased with time to obtain faster elution and improved detection of the more strongly retained (high Mr) materials. The channel outlet flow-rate is optionally held constant, increased, or decreased with time. With circulation of the flow exiting the accumulation wall to the inlet frit, the dual programming of cross flow and channel outlet flow could be implemented using just two pumps. With this flow configuration, the channel outlet flow-rate is always equal to the channel inlet flow-rate, and these may be programmed independently of the cross flow-rate through the membrane. FI-AFlFFF retains its operational advantage over conventional asymmetrical flow FFF (AFlFFF). Unlike conventional AFlFFF, FI-AFlFFF does not require time consuming, and experimentally inconvenient, sample focusing and relaxation steps involving valve switching and interruption of sample migration. The advantages of employing dual programming with FI-AFlFFF are demonstrated for sets of polystyrene sulfonate standards in the molecular mass range of 4 to 1000 kDa. It is shown that programmed FI-AFlFFF successfully expands the dynamic separation range of molecular mass.     

Growth promotion of HepG2 hepatoma cells by antisense-mediated knockdown of glypican-3 is independent of insulin-like growth factor 2 signaling

Glypican-3 (GPC3) encodes a cell-surface heparan- sulfate proteoglycan and its expression is frequently silenced in ovarian cancer, mesotheliomas, and breast cancer cell lines and ectopic expression of GPC3 inhibited the growth of these cells, suggesting that GPC3 plays a negative role in cell proliferation. In contrast, up-regulation of GPC3 is often observed in hepatoma, neuroblastoma, and Wilms' tumor. Whether GPC3 plays the same growth inhibitory role in these tumors remains to be studied. Here we report that antisense-mediated knockdown of GPC3 in the HepG2 hepatoma cells significantly promotes the growth of hepatoma cells. In addition, we show that this growth promotion is independent of insulin-like growth factor 2 (IGF2) signaling. Our data suggest that GPC3 plays a growth-suppressing role in hepatoma and provide cell biological evidence inconsistent with the hypothesis that GPC3 acts as a growth suppressor by downregulating IGF2.     

Intermolecular Nuclear Relaxations and Molecular Site-Site Pair Correlation Functions in Liquids

Intermolecular nuclear relaxation studies of real liquids and the results of theoretical calculations for model potential functions have provided significant information on the role of molecular interactions in the structure of liquids. The intermolecular proton-proton paircorrelation function (pcf), obtained from the reference interaction site model (RISM) is used as the equilibrium distribution and is used to obtarn an effective force for the calculation of intermolecular proton relaxation rates in liquid benzene, 1,3,5-trideuterobenzene and ethane. For liquid ethane, better agreement with experiment is observed with the pcf obtained from the Monte Carlo simulation than with the RISM result.     

Novel fluorophores: efficient synthesis and photophysical study

[structure: see text] We have synthesized novel fluorophores by using Sonogashira reactions of 1,4-bis(dibromovinyl)benzene and 2,5-bis(dibromovinyl)thiophene with various aromatic bromides. The emission maxima of these fluorophores vary from the indigo blue to the reddish-orange region, depending on the structures of aromatic nuclei and peripheral moieties.     

Quantification of L-ascorbic acid and total ascorbic acid in fruits and spinach by capillary zone electrophoresis

A standard curve for the quantification of L-ascorbic acid (L-AA) by capillary zone electrophoresis (CZE) was established, and the quantification of ascorbic acid and total ascorbic acid in fruits (lemon, Sunkist, and pineapple) and spinach were performed using D-isoascorbic acid (D-IAA) as an internal standard. The minimum detection limits (MDLs) for L-AA and D-IAA were determined to be 1 and 2 microg/mL, respectively, at 265 nm. Dehydroascorbic acid (DHAA) in fruits and spinach was quantified in the presence of DL-homocysteine. The recoveries for L-AA in these juices were between 95 and 105%.     

Characterization of the Effects of Vanadium Traps in Cracking Catalysts by Imaging Secondary Ion Mass Spectrometry and Microactivity Test

The vanadium trapping effect of Mg and La containing additives in cracking catalyst contaminated with 2300 ppm Ni and 4700 ppm V has been analyzed by microactivity test (MAT) and imaging secondary ion mass spectrometry (SIMS). The results of SIMS imaging are consistent with cracking activity data and show that the La/spinel is a superior vanadium trap for the fluid catalytic cracking of hydrocarbons (FCC) operation. La/spinel serves as a dual function additive for both vanadium trap and SO_x removal. The optimum amount of La/spinel added to the cracking catalyst is about 15% by weight. This results in an increased catalytic activity, an increase in gasoline yield, and a decrease in coke and gas factors. The MgAl₂O₄ phase of Mg/Al₂O₃ additive is found capable of trapping vanadium while its MgO of Mg/Al₂O₃ phase can migrate to zeolite particles (the active component of the FCC catalyst) that, in turn, causes a decline in the activity of that catalyst.