Synthesis of novel piperazine-linked anthranilic acids as potential small molecule kinase inhibitors

Please cite as follows: Chakravorty, S. et al. 2014. Synthesis of novel piperazine-linked anthranilic acids as potential small molecule kinase inhibitors. South African Journal of Chemistry, 67:71–79.The original publication is available at http://www.journals.co.za/sajchemSubstituted anthranilic acid and piperazines were used as building blocks to prepare two libraries of compounds, with the aim being that they would exhibit biochemical activity as small molecule kinase inhibitors. The synthesized anthranilamidepiperazine compounds were subsequently tested against a panel of kinases including EGFR, Abl, Akt and Aurora B.http://www.scielo.org.za/scielo.php?script=sci_abstract&pid=S0379-43502014000100012&lng=en&nrm=iso&tlng=enPublisher's versio

1-(3-Bromo-2-thien­yl)ethanone

In the title compound, C6H5BrOS, the non-H and aromatic H atoms lie on a crystallographic mirror plane. In the crystal, mol­ecules are linked into chains propagating along the c axis by inter­molecular C—H⋯O hydrogen bonds

Linking Northern Hemisphere blocking and storm track biases in the CMIP5 climate models

The relationship between biases in Northern Hemisphere (NH) atmospheric blocking frequency and extratropical cyclone track density is investigated in 12 CMIP5 climate models to identify mechanisms underlying climate model biases and inform future model development. Biases in the Greenland blocking and summer Pacific blocking frequencies are associated with biases in the storm track latitudes while biases in winter European blocking frequency are related to the North Atlantic storm track tilt and Mediterranean cyclone density. However, biases in summer European and winter Pacific blocking appear less related with cyclone track density. Furthermore, the models with smaller biases in winter European blocking frequency have smaller biases in the cyclone density in Europe, which suggests that they are different aspects of the same bias. This is not found elsewhere in the NH. The summer North Atlantic and the North Pacific mean CMIP5 track density and blocking biases might therefore have different origins

Covalent allosteric inhibitors of Akt generated using a click fragment approach

Akt is a protein kinase that has been implicated in the progression of cancerous tumours. A number of covalent allosteric Akt inhibitors are known, and based on these scaffolds, a small library of novel potential covalent allosteric imidazopyridine-based inhibitors was designed. The envisaged compounds were synthesised, with click chemistry enabling a modular approach to a number of the target compounds. The binding modes, potencies and antiproliferative activities of these synthesised compounds were explored, thereby furthering the structure activity relationship knowledge of this class of Akt inhibitors. Three novel covalent inhibitors were identified, exhibiting moderate activity against Akt1 and various cancer cell lines, potentially paving the way for future covalent allosteric inhibitors with improved properties

Synthesis of pyrrolocarbazoles with N-substituted alkynyl-, alkylcyano- and alkylhydroxyl-groups

CITATION: Van der Westhuyzen, A. E. et al. 2020. Synthesis of pyrrolocarbazoles with N-substituted alkynyl-, alkylcyano- and alkylhydroxyl-groups. Arkivoc, v:129-147, doi:10.24820/ark.5550190.p011.412.The original publication is available at https://www.arkat-usa.orgDue to their involvement in almost all stages of cellular life, kinase biomolecular catalysts have been linked to cancer development and, thus, remain attractive drug targets for cancer therapeutics. 6-(3ꞌ-Hydroxypropyl)-, 6-(2ꞌ-hydroxyethyl)-, 6-(2ꞌ-propynyl)- and 6-(3ꞌ-propanenitrile)-pyrrolo[3,4-c]carbazole-1,3(2H,6H)-diones were synthesized as potential small molecule EGFR kinase inhibitors. The pyrrolocarbazole compounds were synthesized by way of a Diels-Alder approach involving N-alkylated 2-vinyl-1H-indole and maleimide as starting materials followed by aromatization with MnO2.Publisher's versio

Atmospheric blocking and upper-level Rossby wave forecast skill dependence on model configuration

Weather models differ in their ability to forecast, at medium range, atmospheric blocking and the associated structure of upper-level Rossby waves. Here, we evaluate the effect of a model's dynamical core on such forecasts. Operational forecasts from the ensemble prediction systems (EPSs) of the European Centre for Medium-range Weather Forecasts (ECMWF), the Met Office (MO) and the Korean Meteorological Administration (KMA) are used. Northern hemisphere model output is analysed from winters before and after a major upgrade to the dynamical core of the MO-EPS. The KMA-EPS acts as a control as it uses the same model as the MO-EPS, but used the older dynamical core throughout. The confounding factor of resolution differences between the MO-EPS and the KMA-EPS is assessed using a MO forecast model hindcast experiment with the more recent dynamical core, but the operational resolution of the KMA-EPS. The introduction of the new dynamical core in the MO-EPS has led to increased forecast blocking frequency, at lead times of five and seven days, counteracting the typically-observed reduction in blocking frequency with lead time. Hit rates of blocking activity, onset and decay are also increased in the main blocking regions (without a corresponding increase in false positive rate). The previously-found reduction of upper-level ridge area and tropopause sharpness (measured by isentropic potential vorticity gradient) with lead time is also reduced with the new dynamical core. This dynamical core improvement (associated with a reduction in implicit damping) is thus demonstrated to be at least as effective as operational resolution improvements in improving forecasts of upper-level Rossby waves and associated blocking

Revisiting the β-lactams for tuberculosis therapy with a compound-compound synthetic lethality approach

The suboptimal effectiveness of β-lactam antibiotics against Mycobacterium tuberculosis has hindered the utility of this compound class for tuberculosis treatment. However, the results of treatment with a second-line regimen containing meropenem plus a β-lactamase inhibitor were found to be encouraging in a case study of extensively drug-resistant tuberculosis (M. C. Payen, S. De Wit, C. Martin, R. Sergysels, et al., Int J Tuberc Lung Dis 16:558-560, 2012, https://doi.org/10.5588/ijtld.11.0414). We hypothesized that the innate resistance of M. tuberculosis to β-lactams is mediated in part by noncanonical accessory proteins that are not considered the classic targets of β-lactams and that small-molecule inhibitors of those accessory targets might sensitize M. tuberculosis to β-lactams. In this study, we screened an NIH small-molecule library for the ability to sensitize M. tuberculosis to meropenem. We identified six hit compounds, belonging to either the N-arylindole or benzothiophene chemotype. Verification studies confirmed the synthetic lethality phenotype for three of the N-arylindoles and one benzothiophene derivative. The latter was demonstrated to be partially bioavailable via oral administration in mice. Structure-activity relationship studies of both structural classes identified analogs with potent antitubercular activity, alone or in combination with meropenem. Transcriptional profiling revealed that oxidoreductases, MmpL family proteins, and a 27-kDa benzoquinone methyltransferase could be the targets of the N-arylindole potentiator. In conclusion, our compound-compound synthetic lethality screening revealed novel small molecules that were capable of potentiating the action of meropenem, presumably via inhibition of the innate resistance conferred by β-lactam accessory proteins. β-Lactam compound-compound synthetic lethality may be an alternative approach for drug-resistant tuberculosis

Transcriptomics identified a critical role for Th2 cell-intrinsic miR-155 in mediating allergy and antihelminth immunity

Allergic diseases, orchestrated by hyperactive CD4^(+) Th2 cells, are some of the most common global chronic diseases. Therapeutic intervention relies upon broad-scale corticosteroids with indiscriminate impact. To identify targets in pathogenic Th2 cells, we took a comprehensive approach to identify the microRNA (miRNA) and mRNA transcriptome of highly purified cytokine-expressing Th1, Th2, Th9, Th17, and Treg cells both generated in vitro and isolated ex vivo from allergy, infection, and autoimmune disease models. We report here that distinct regulatory miRNA networks operate to regulate Th2 cells in house dust mite-allergic or helminth-infected animals and in vitro Th2 cells, which are distinguishable from other T cells. We validated several miRNA (miR) candidates (miR-15a, miR-20b, miR-146a, miR-155, and miR-200c), which targeted a suite of dynamically regulated genes in Th2 cells. Through in-depth studies using miR-155^(−/−) or miR-146a^(−/−) T cells, we identified that T-cell–intrinsic miR-155 was required for type-2 immunity, in part through regulation of S1pr1, whereas T-cell–intrinsic miR-146a was required to prevent overt Th1/Th17 skewing. These data identify miR-155, but not miR-146a, as a potential therapeutic target to alleviate Th2-medited inflammation and allergy

Basic Atomic Physics

Contains reports on five research projects.National Science Foundation Grant PHY 89-19381National Science Foundation Grant PHY 92-21489U.S. Navy - Office of Naval Research Grant N00014-90-J-1322Joint Services Electronics Program Contract DAAL03-92-C-0001National Science Foundation Grant PHY 89-21769U.S. Army - Office of Scientific Research Grant DAAL03-92-G-0229U.S. Navy - Office of Naval Research Grant N00014-89-J-1207U.S. Navy - Office of Naval Research Grant N00014-90-J-164