A set of azoheteroarenes have been synthesized with Buchwald–Hartwig coupling and microwave-assisted O2 oxidation as the key steps. Several compounds exhibit good to excellent photoswitching ...properties (high switching efficiency, good fatigue resistance, and thermal stability of Z-isomer) relevant for photocontrolled applications, which pave the way for use in photopharmacology.
An approach using water as a solvent (coupling and deprotection) was developed for the solid-phase synthesis of peptides using the most common Boc-amino acid derivatives. Key aspects of this ...methodology are the use of a PEG-based resin, EDC-HONB as a coupling method, and microwave irradiation as an energy source.
The underlying role that many kinases play in complex cellular pathways as well as disease remains unclear. To better understand the role that kinases play in both health and disease states, the use ...of light as an external stimulus to modulate kinase activity with high spatiotemporal resolution has gained increasing interest over the years. Herein we highlight the progress made towards the development of light‐responsive kinase enzymes and small molecule inhibitors. In these examples, photolabile caging groups and photoswitchable entities have been utilised to modulate either kinase activation or inhibition in a light‐controlled manner.
Moving on up: To better understand the relationship between kinase activity and cellular behaviour, the use of light as an external stimulus to modulate kinase activity with high spatiotemporal resolution has gained increasing interest of late. Herein we highlight the progress made towards the development of light‐responsive kinase enzymes and small molecule inhibitors.
Mutations in the rearranged during transfection (RET) tyrosine kinase gene leading to gain or loss of function have been associated with the development of several human cancers and Hirschsprung's ...disease (HSCR). However, to what extent these mutations affect individual bio-molecular functions remains unclear. In this article, the functionally significant mutations in the RET CLD1-4 calcium-binding site which lead to HSCR, and depletion of calcium ions in the RET CLD1-4 calcium binding site, were investigated by molecular dynamics simulations--to understand the mechanistic action of the mutations or loss of calcium ions in altering the protein kinase structure, dynamics, and stability. The mutations or loss of calcium ions change the local conformation and change the free energy landscape. Specifically, the mutations and loss of calcium ions decrease the radius of gyration of the whole structure, leading to improper protein folding and GFL-GFRα contact site reduction. Furthermore, based on the most populated conformation in the wildtype MD simulations, a pharmacophore was generated by fragment docking to identify key features of the possible inhibitors targeting the calcium binding site. Overall, the findings may provide useful structural insights into the molecular mechanism underlying RET calcium-binding site mutations and assist in development of novel drugs targeting the extracellular ligand contact site of wildtype RET.
In this study a general, efficient and environmentally benign solution phase synthesis of 2,5-diketopiperazines (DKPs) using microwave assisted heating in water is described. A series of 11 ...structurally different DKPs have been synthesized from dipeptide methyl esters. A range of common laboratory solvents have been tested as well as different reaction times and temperatures. Both classic thermal and microwave assisted heating have been investigated. Microwave assisted heating for 10
min using water as solvent proved, by far, to be the most efficient method of cyclization giving moderate to excellent yields (63–97%) of DKPs. In contrast to other published procedures, this method seems independent of the amino acid sequence.
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Photochromic molecules from the spiropyran family are known to undergo light-induced interconversion between the colorless spiro- and the colored merocyanine forms. Here, we show for the first time ...that small structural modifications open up for an additional photoisomerization mode: reversible cis–trans isomerization of the merocyanine. Moreover, the introduction of a photocage allows for light-activated switching between the two modes.
Herein, we report a tri‐component photochromic molecular cocktail that can be used to encrypt and decrypt information. The time‐dependent fluorescent response of this cocktail is highly non‐linear ...with respect to the set of inputs used (concentrations of the three photochromic components, excitation‐ and emission wavelengths), a property required for the generation of so‐called encryption keys. The all‐optical system can generate more than 80 million unique fluorescence responses by applying different input combinations and is operated using a conventional fluorimeter.
A molecular cocktail consisting of three fluorescent photochromic compounds is demonstrated as a molecular encryption key. It is operated by all‐photonic means and the function relies on highly non‐linear time‐based fluorescence in response to excitation and emission readout at different wavelengths.
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2,6,9-Trisubstituted purines are brominated in high yields using pyridinium tribromide as the brominating reagent. This procedure works excellently for electron-rich purines having ...electron-donating substituents at the 2- and 6-positions. The use of pyridinium tribromide, a crystalline alternative to elemental bromine, improves the bromination procedure for this type of substrate as the reagent is easy to handle and the work-up and purification procedures are simplified.
Small molecules are routinely used to inhibit protein kinases, but modulators capable of enhancing kinase activity are rare. We have previously shown that the small molecule INR119, designed as an ...inhibitor of MEK1/2, will enhance the activity of its fission yeast homologue, Wis1, under oxidative stress. To investigate the generality of these findings, we now study the effect of INR119 in human cells under similar conditions. Cells of the established breast cancer line MCF-7 were exposed to H
O
or phenothiazines, alone or combined with INR119. In line with the previous results in fission yeast, the phosphorylation of the MAPKs ERK and p38 increased substantially more with the combination treatment than by H
O
or phenothiazines, whereas INR119 alone did not affect phosphorylation. We also measured the mRNA levels of
and
, known to be affected by ERK and p38 activity. Similarly, the combination of INR119 and phenothiazines increased both mRNAs to higher levels than for phenothiazines alone. In conclusion, the mechanism of action of INR119 on its target protein kinase may be conserved between yeast and humans.
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