10 research outputs found
Analysis of ergonomics problems contact-centers
The analysis of the ergonomic problems
of the contact center. It allocates main factors of
influence on man- operator
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Synthesis and Structural Analyses of Phenylethynyl-Substituted Tris(2-Pyridylmethyl)Amines and their Copper(II) Complexes
Three new tris(2-pyridylmethyl) amine-based ligands possessing phenylethynyl units have been prepared using Sonogashira couplings and substitution reactions. Copper(II) complexes of those tetradentate ligands have also been synthesized. Solid-state structures of the six new compounds have been determined by single-crystal X-ray diffraction analyses. Examination of the molecular structures of the ligands revealed the expected triangular geometries with virtually undeformed carbon-carbon triple bonds. While the tertiary nitrogen of the free ligands seem to be prevented from participation in supramolecular non-covalent interactions by the pyridyl hydrogen at the 3-position, the pyridyl nitrogens play a crucial role in the packing mode of the crystal structure. The nitrogens form weak hydrogen bonds, varied in length between 2.32 and 2.66 angstrom, with the pyridyl hydrogen of its neighbouring molecule. The [N center dot center dot center dot H-C] contacts enforce one-dimensional columnar assemblies on ligands that organize into wall-like structures, which in turn assemble into three-dimensional structures through CH-pi interactions. Structural analyses of Cu(II) complexes of the ligands revealed propeller-like structures caused by steric crowding of three pyridine ligands. The copper complexes of the ligands having three phenylethynyl substituents showed a remarkably deformed carbon-carbon triple bond enforced by a steric effect of the three phenyl groups. Most significantly, a total of seventy non-covalent interactions, classified into twelve types of hydrogen-involving short contacts, were identified in this study. The phenylethynyl substituent participated in forty-two interactions as a hydrogen bond acceptor, and its role was more distinctive in the crystal structures of the Cu(II) complexes.National Science Foundation CHE-1212971Welch Foundation F-0046Chemistr
Mechanistic Studies on Covalent Assemblies of Metal-Mediated Hemi-Aminal Ethers
The use of reversible covalent bonding in a four-component assembly incorporating chiral alcohols was recently reported to give a method for determining the enantiomeric excess of the alcohols via CD spectroscopy. Experiments that probe the mechanism of this assembly, which consists of 2-formylpyridine (2-PA), dipicolylamine (DPA), Zn(II) and alcohols to yield zinc complexes of tren-like ligands, are presented. The studies focus upon the mechanism of conversion of a hemi-aminal (1) to a hemi-aminal ether (3), thereby incorporating the fourth component. It was found that molecular sieves along with 3 to 4 equivalents of alcohol are required to drive the conversion of 1 to 3. Attempts to isolate an intermediate in this reaction via addition of strong Lewis acids led to the discovery of a five-membered ring pyridinium salt (5), but upon exposure to Zn(II) and alcohols gave different products to the assembly. This was interpreted to support the intermediacy of an iminium species. Kinetic studies reveal that the conversion of 1 to 3 is zero-order in alcohol in large excesses of alcohol, supporting rate-determining formation of an intermediate prior to reaction with alcohol. Further, the magnitudes of the rate constants for interconversion of 1 and 3 are similar, supporting the notion that there are similar rate-determining steps (rds) for the forward and reverse reactions. Hammett plots show that the rds involves creation of a negative charge (interpreted as the loss of positive charge), supporting the notion that the decomplexation of Zn(II) from the assemblies to generate apo-forms of 1 and 3 is rate-determining. The individual mechanistic conclusions are combined to create a qualitative reaction coordinate diagram for the interconversion of 1 and 3.National Institutes of Health R01GM077437Welch Foundation F-1151, F-1390National Science Foundation CHE-1212971NIH GM059802Chemistr
Synthesis of 5-Fluoro- and 5-Hydroxymethanoprolines via Lithiation of <i>N</i>-BOC-methanopyrrolidines. Constrained C<sup>γ</sup>-Exo and C<sup>γ</sup>-Endo Flp and Hyp Conformer Mimics
Proline derivatives with a C<sup>γ</sup>-exo pucker
typically
display a high amide bond trans/cis (<i>K</i><sub>T/C</sub>) ratio. This pucker enhances n→π* overlap of the amide
oxygen and ester carbonyl carbon, which favors a trans amide bond.
If there were no difference in n→π* interaction between
the ring puckers, then the correlation between ring pucker and <i>K</i><sub>T/C</sub> might be broken. To explore this possibility,
proline conformations were constrained using a methylene bridge. We
synthesized discrete gauche and anti 5-fluoro- and 5-hydroxy-<i>N</i>-acetylmethanoproline methyl esters from 3-syn and 3-anti
fluoro- and hydroxymethanopyrrolidines using directed α-metalation
to introduce the α-ester group. NBO calculations reveal minimal
n→π* orbital interactions, so contributions from other
forces might be of greater importance in determining <i>K</i><sub>T/C</sub> for the methanoprolines. Consistent with this hypothesis,
greater trans amide preferences were found in CDCl<sub>3</sub> for
anti isomers en-MetFlp and en-MetHyp (72–78% trans) than for
the syn stereoisomers ex-MetFlp and ex-MetHyp (54–67% trans).
These, and other, <i>K</i><sub>T/C</sub> results that we
report here indicate how substituents on proline analogues can affect
amide preferences by pathways other than ring puckering and n→π*
overlap and suggest that caution should be exercised in assigning
enhanced pyrrolidine C<sup>γ</sup>-exo ring puckering based
solely on enhanced trans amide preference
Definition of a Novel Feed-Forward Mechanism for Glycolysis-HIF1α Signaling in Hypoxic Tumors Highlights Aldolase A as a Therapeutic Target
Quantification of a Pharmacodynamic ERK End Point in Melanoma Cell Lysates: Toward Personalized Precision Medicine
Protein kinases are mutated or otherwise
rendered constitutively
active in numerous cancers where they are attractive therapeutic targets
with well over a dozen kinase inhibitors now being used in therapy.
While fluorescent sensors have capacity to measure changes in kinase
activity, surprisingly they have not been utilized for biomarker studies.
A first-generation peptide sensor for ERK based on the Sox fluorophore
is described. This sensor called ERK-sensor-D1 possesses high activity
toward ERK and more than 10-fold discrimination over other MAPKs.
The sensor can rapidly quantify ERK activity in cell lysates and monitor
ERK pathway engagement by BRAF and MEK inhibitors in cultured melanoma
cell lines. The dynamic range of the sensor assay allows ERK activities
that have potential for profound clinical consequences to be rapidly
distinguished