Synthesis of novel 7-aryl and 7-spiropyrazolo[4′,3′:5,6]pyrido[2,3-<Emphasis Type="BoldItalic">d</Emphasis>]pyrimidine derivatives and their study as AChE inhibitors

An efficient route for the synthesis of novel 7-aryl and 7-spiropyrazolo[4\(^{\prime }\),3\(^{\prime }\):5,6]pyrido[2,3-d]pyrimidine derivatives is described. These compounds were obtained by a cyclocondensation reaction between pyrazolopyridinediamines 4 and aldehydes 5 or cyclic ketones 6 in the presence of acetic acid as catalyst. This procedure provides the desired compounds in good yields under a simple two-step methodology. The obtained compounds were evaluated as AChE inhibitors and showed weak AChe inhibition with \(\hbox {IC}_{50} = 115{-}470 \, \upmu \hbox {M}\).     

<Emphasis Type="Italic">Z</Emphasis><Superscript>′</Superscript> boson signal at Fermilab-Tevatron and CERN-LHC in a 331 model

We analyse the possibilities to detect a new Z ^′ boson in di-electron events at Tevatron and LHC in the framework of the 331 model with right-handed neutrinos. We also study other fermions and Higgs events as final state at LHC. Using collision data collected by the CDF II detector at Fermilab Tevatron, we find that the 331 Z ^′ boson is excluded with masses below 920 GeV. For an integrated luminosity of 100 fb⁻¹ at LHC, and considering a central value GeV, we obtain the invariant-mass distribution in the process pp→Z ^′→e ⁺ e ⁻, where a huge peak, corresponding to 800 signal events/(20 GeV), is found above the SM background. The number of di-electron events vary from 50000 to 2400 in the mass range of –2000 GeV. We also obtain branching ratios and cross sections in other fermion and Higgs channels at LHC, where a heavy top quark T exhibits the biggest ratio with m _T =300 GeV.     

An inhibitor of human asparagine synthetase suppresses proliferation of an L-asparaginase-resistant leukemia cell line

Drug resistance in lymphoblastic and myeloblastic leukemia cells is poorly understood, with several lines of evidence suggesting that resistance can be correlated with upregulation of human asparagine synthetase (hASNS) expression, although this hypothesis is controversial. New tools are needed to investigate this clinically important question, including potent hASNS inhibitors. In vitro experiments show an adenylated sulfoximine to be a slow-onset, tight-binding inhibitor of hASNS with nanomolar affinity. This binding affinity represents a 10-fold improvement over that reported for the only other well-characterized hASNS inhibitor. The adenylated sulfoximine has a cytostatic effect on L-asparaginase-resistant MOLT-4 cells cultured in the presence of L-asparaginase, an enzyme that depletes L-asparagine in the growth medium. These observations represent direct evidence that potent hASNS inhibitors may prove to be effective agents for the clinical treatment of acute lymphoblastic leukemia.     

Re-examining the Mechanisms of Competing Pericyclic Reactions of 1,3,7-Octatriene

DFT (both B3LYP and M06-2X), CASSCF, and CASPT2 calculations were used to investigate competing [3,?3] and [3,?5] sigmatropic shifts and intramolecular [4+2] cycloaddition of 1,3,7-octatriene. In accord with previous results on 1,5-hexadiene, CASSCF calculations found both stepwise and concerted pathways for the [3,?3] rearrangement. For the competing [3,?5] sigmatropic rearrangement, CASSCF and CASPT2 calculations revealed three stepwise pathways with similar barriers. UB3LYP and UM06-2X calculations predicted a different potential energy landscape: no stepwise [3,?3] pathway, only two competing [3,?5] sigmatropic shifts, and an intramolecular Diels-Alder cycloaddition/homolytic ring-opening pathway. Significant lowering of barriers for all rearrangements was predicted for some 1,3,7-octatrienes with substituents at the 4- and 7-positions.     

Stereocontrol in a combined allylic azide rearrangement and intramolecular Schmidt reaction

Pre-equilibration of an interconverting set of isomeric allylic azides is coupled with an intramolecular Schmidt reaction to afford substituted lactams stereoselectively. The effect of substitution and a preliminary mechanistic study are reported. The synthetic potential of this method is demonstrated in the context of an enantioselective synthesis of an advanced intermediate leading toward pinnaic acid.     

Re‐examining the Mechanisms of Competing Pericyclic Reactions of 1,3,7‐Octatriene

DFT (both B3LYP and M06‐2X), CASSCF, and CASPT2 calculations were used to investigate competing [3, 3] and [3, 5] sigmatropic shifts and intramolecular [4+2] cycloaddition of 1,3,7‐octatriene. In accord with previous results on 1,5‐hexadiene, CASSCF calculations found both stepwise and concerted pathways for the [3, 3] rearrangement. For the competing [3, 5] sigmatropic rearrangement, CASSCF and CASPT2 calculations revealed three stepwise pathways with similar barriers. UB3LYP and UM06‐2X calculations predicted a different potential energy landscape: no stepwise [3, 3] pathway, only two competing [3, 5] sigmatropic shifts, and an intramolecular Diels–Alder cycloaddition/homolytic ring‐opening pathway. Significant lowering of barriers for all rearrangements was predicted for some 1,3,7‐octatrienes with substituents at the 4‐ and 7‐positions.     

Method for measuring waveguide propagation losses by means of a Mach–Zehnder Interferometer structure

In this paper, a method for measuring waveguide propagation losses by means of a Mach–Zehnder Interferometer (MZI) structure is reported. The method, based on the analysis of the transmission spectra of asymmetric MZIs, enables the propagation losses of the optical waveguides to be calculated without the requirement of identical coupling conditions for each measurement. In addition, the power imbalance of the branching structure in the MZI can also be obtained. Our theoretical analysis is supported by experimental measurements.     

Solving Delay Differential Equations Through RBF Collocation

A general and easy-to-code numerical method based on radial basis functions (RBFs) collocation is proposed for the solution of delay differential equations (DDEs). It relies on the interpolation properties of infinitely smooth RBFs, which allow for a large accuracy over a scattered and relatively small discretization support. Hardy's multiquadric is chosen as RBF and combined with the Residual Subsampling Algorithm of Driscoll and Heryudono for support adaptivity. The performance of the method is very satisfactory, as demonstrated over a cross-section of benchmark DDEs, and by comparison with existing general-purpose and specialized numerical schemes for DDEs.     

Combining classification and regression approaches for the quantification of highly overlapping capillary electrophoresis peaks by using evolutionary sigmoidal and product unit neural networks

This is a study of the potential of neural networks built by using different transfer functions (sigmoidal, product and sigmoidal–product units) designed by an evolutionary algorithm to quantify highly overlapping electrophoretic peaks. To test this approach, two aminoglycoside antibiotics, amikacin and paramomycin, were quantified from samples containing either only one component or mixtures of them though capillary zone electrophoresis (CZE) with laser‐induced fluorescence (LIF) detection. The three models assayed used as input data the four‐parameter Weibull curve associated with the profile of the electrophoretic peak and in some cases the class label for each sample estimated by cluster analysis. The combination of classification and regression approaches allowed the establishment of straightforward network topologies enabling the analytes to be quantified with great accuracy and precision. The best models for mixture samples were provided by product unit neural networks (PUNNs), 4:4:1 (14 weights) for both analytes, after discrimination by cluster analysis, allowing the analytes to be quantified with great accuracy: 8.2% for amikacin and 5.6% for paromomycin within the standard error of prediction for the generalization test, SEP_G. For comparison, partial least square regression was also used for the resolution of these mixtures; it provided a minor accuracy: SEP_G 11.8 and 15.7% for amikacin and paramomycin, respectively. The reduced dimensions of the neural networks models selected enabled the derivation of simple quantification equations to transform the input variables into the output variable. These equations can be more easily interpreted from a chemical point of view than those provided by other ANN models. Copyright © 2007 John Wiley & Sons, Ltd.