19 research outputs found
Palladium-Catalyzed Coupling of Alkynes with Unactivated Alkenes in Ionic Liquids: A Regio- and Stereoselective Synthesis of Functionalized 1,6-Dienes and Their Analogues
No full textA palladium-catalyzed
regio- and stereoselective intermolecular
tandem reaction of alkynes and unactivated 1,6-enols in ionic liquids
is described, providing a practical, efficient, and versatile method
for the synthesis of functionalized 1,6-dienes in moderate to good
yields. The present reaction has high functional-group tolerance and
gives products on a gram scale. Mechanistic studies indicate that
the reaction might proceed via a chain-walking mechanism
Choice of rice production technique in Thailand, 1890-1940
No full textThis study analyzes the choice of rice production technique in Thailand during 1890-1940. It focuses on two techniques: transplanting and broadcasting. Although transplanting has been the traditional rice growing method in Thailand at least since the seventeenth century, most cultivators in the newly developed areas of the commercialized Central Plain during the period adopted broadcasting. The two conventional explanations for choice of rice production technique--Iocal water conditions and factor prices--cannot consistently explain this choice. The water conditions necessary for transplanting rice did exist in the area, and factor prices during the period moved in favor of transplanting. Because the two techniques differ both in terms of variable input per unit of land and fixed capital input, a choice of technique model is formulated using the theory of production and the theory of investment to explain the choice of broadcasting. The model is a neoclassical production relation modified to incorporate fixed capital input and the firm's planning horizon. In this regard, the model allows a simultaneous analysis of the firm's short-run production decision and long-run capital investment. Empirical evidence regarding rice farming during the period is consistent with theoretical constructs. The main findings reveal that the choice of broadcasting during the period is a rational decision. The outcome was caused by uncertainty in land ownership and prices, which were consequences of increased external demand for rice and economic changes in Thailand at the time. Under uncertainty in land ownership, a short planning horizon and consequently a technique such as broadcasting which requires less fixed capital input minimizes expected losses. Under price uncertainty, broadcasting provides greater production flexibility and, consequently, higher profits for large landholding firms. This study contributes to conventional knowledge regarding factors affecting choice of rice production technique and, thus, improves the understanding of a firm's choice of technique. Although the model is simple and empirically oriented, it is adequate to analyze a firm's decision making process. The findings also illuminate relationships between external trade, internal institutions, and agricultural development. While the empirical results presented are specific to Thailand, the process employed here can be applied elsewhere.Ph.D
Evaluating the role of p38 MAPK in the accelerated cell senescence of Werner syndrome fibroblasts
No full textProgeroid syndromes show features of accelerated ageing and are used as models for human ageing, of which Werner syndrome (WS) is one of the most widely studied. WS fibroblasts show accelerated senescence that may result from p38 MAP kinase activation since it is prevented by the p38 inhibitor SB203580. Thus, small molecule inhibition of p38-signalling may be a therapeutic strategy for WS. To develop this approach issues such as the in vivo toxicity and kinase selectivity of existing p38 inhibitors need to be addressed, so as to strengthen the evidence that p38 itself plays a critical role in mediating the effect of SB203580, and to find an inhibitor suitable for in vivo use. In this work we used a panel of different p38 inhibitors selected for: (1) having been used successfully in vivo in either animal models or human clinical trials; (2) different modes of binding to p38; and (3) different off-target kinase specificity profiles, in order to critically address the role of p38 in the premature senescence seen in WS cells. Our findings confirmed the involvement of p38 in accelerated cell senescence and identified p38 inhibitors suitable for in vivo use in WS, with BIRB 796 the most effective
Microwave-assisted synthesis of a MK2 inhibitor by Suzuki-Miyaura coupling for study in Werner syndrome cells
No full textMicrowave-assisted Suzuki-Miyaura cross-coupling reactions have been employed towards the synthesis of three different MAPKAPK2 (MK2) inhibitors to study accelerated aging in Werner syndrome (WS) cells, including the cross-coupling of a 2-chloroquinoline with a 3-pyridinylboronic acid, the coupling of an aryl bromide with an indolylboronic acid and the reaction of a 3-amino-4-bromopyrazole with 4-carbamoylphenylboronic acid. In all of these processes, the Suzuki-Miyaura reaction was fast and relatively efficient using a palladium catalyst under microwave irradiation. The process was incorporated into a rapid 3-step microwave-assisted method for the synthesis of a MK2 inhibitor involving 3-aminopyrazole formation, pyrazole C-4 bromination using N-bromosuccinimide (NBS), and Suzuki-Miyaura cross-coupling of the pyrazolyl bromide with 4-carbamoylphenylboronic acid to give the target 4-arylpyrazole in 35% overall yield, suitable for study in WS cells
Microwave-Assisted Ullmann C−S Bond Formation: Synthesis of the P38α MAPK Clinical Candidate VX-745
No full textMicrowave irradiation promotes the rapid and efficient reaction of a thiophenol and aryl or heteroaryl halide using a copper or palladium catalyst and a range of ligands, depending upon substrate. Of particular utility is the use of copper(I) iodide (5 mol %) and trans-cyclohexane-1,2-diol as ligand under basic conditions and microwave irradiation to give the corresponding sulfide in high yield. This method for C−S bond formation is applied in the four-step synthesis of the clinical candidate VX-745 in 38% overall yield. The inhibitory activity of VX-745 against p38α MAPK is confirmed in Werner syndrome dermal fibroblasts at 1.0 μM concentration by immunoblot assay
Regiocontrolled synthesis of 3- and 5-aminopyrazoles, pyrazolo[3,4-d]pyrimidines, pyrazolo[3,4-b]pyridines and pyrazolo[3,4-b]quinolinones as MAPK inhibitors
No full textMicrowave irradiation of a hydrazine and 3-methoxyacrylonitrile, ethoxymethylenemalononitrile or ethyl acetoacetate provides rapid access to 3- or 5-substituted pyrazoles in excellent yield and with total regiocontrol in a process that can be switched from one regioisomer to the other by choice of conditions. Subsequent reaction, either by microwave-assisted hydrolysis and cyclocondensation with formamide, Hantzsch-type three-component reaction with an aldehyde and ketone, or by cyclocondensation with 2-nitrobenzaldehyde, provides the pyrazolo[3,4-d]pyrimidine, pyrazolo[3,4-b]pyridine or pyrazolo[3,4-b] quinolin-4-one framework, respectively, of inhibitors of mitogen-activated protein kinases
CD1d-mediated lipid presentation by CD11c+ cells regulates intestinal homeostasis
No full textIntestinal homeostasis relies on a continuous dialogue between the commensal bacteria and the immune system. Natural killer T (NKT) cells, which recognize CD1d-restricted microbial lipids and self-lipids, contribute to the regulation of mucosal immunity, yet the mechanisms underlying their functions remain poorly understood. Here, we demonstrate that NKT cells respond to intestinal lipids and CD11c+ cells (including dendritic cells (DCs) and macrophages) are essential to mediate lipid presentation within the gut ultimately controlling intestinal NKT cell homeostasis and activation. Conversely, CD1d and NKT cells participate in the control of the intestinal bacteria composition and compartmentalization, in the regulation of the IgA repertoire and in the induction of regulatory T cells within the gut. These changes in intestinal homeostasis require CD1d expression on DC/macrophage populations as mice with conditional deletion of CD1d on CD11c+ cells exhibit dysbiosis and altered immune homeostasis. These results unveil the importance of CD11c+ cells in controlling lipid-dependent immunity in the intestinal compartment and reveal an NKT cell-DC crosstalk as a key mechanism for the regulation of gut homeostasis
Microwave-assisted synthesis of a pyrazolyl ketone library for evaluation as p38 MAPK inhibitors in Werner syndrome cells
No full textBackground: The pyrazolyl ketone motif of RO3201195, which exhibits good oral bioavailability and high selectivity for p38 MAPK over other kinases, is a key pharmacophore that could find application in the treatment of Werner syndrome. Results and discussion: Microwave irradiation promotes Knoevenagel condensation of a β-ketonitrile and formamidine, to give β-aminovinyl ketones, and their subsequent cyclocondensation with a subset of hydrazines to provide rapid access to a 24-membered library of pyrazolyl ketones. The library was evaluated in human hTERT-immortalized HCA2 dermal cells and Werner syndrome cells. Conclusion: Four compounds display comparable, if not slightly improved, potency over RO3201195
The effect of RO3201195 and a pyrazolyl ketone P38 MAPK inhibitor library on the proliferation of Werner syndrome cells
No full textNo description supplie
Supplementary Data from Doxorubicin Resistance in a Novel <i>In vitro</i> Model of Human Pleomorphic Liposarcoma Associated with Alternative Lengthening of Telomeres
No full textSupplementary Data from Doxorubicin Resistance in a Novel In vitro Model of Human Pleomorphic Liposarcoma Associated with Alternative Lengthening of Telomere
