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61.
Dr. Sankar Mohan Dr. Philip S. Kerry Nicole Bance Prof. Dr. Masahiro Niikura Prof. Dr. B. Mario Pinto 《Angewandte Chemie (International ed. in English)》2014,53(4):1076-1080
We have previously reported a potent neuraminidase inhibitor that comprises a carbocyclic analogue of zanamivir in which the hydrophilic glycerol side chain is replaced by the hydrophobic 3‐pentyloxy group of oseltamivir. This hybrid inhibitor showed excellent inhibitory properties in the neuraminidase inhibition assay (Ki=0.46 nM ; Ki (zanamivir)=0.16 nM ) and in the viral replication inhibition assay in cell culture at 10?8 M . As part of this lead optimization, we now report a novel spirolactam that shows comparable inhibitory activity in the cell culture assay to that of our lead compound at 10?7 M . The compound was discovered serendipitously during the attempted synthesis of the isothiourea derivative of the original candidate. The X‐ray crystal structure of the spirolactam in complex with the N8 subtype neuraminidase offers insight into the mode of inhibition. 相似文献
62.
Isabel V. L. Wilkinson Kelly J. Perkins Hannah Dugdale Lee Moir Aini Vuorinen Maria Chatzopoulou Sarah E. Squire Sebastian Monecke Alexander Lomow Marcus Geese Philip D. Charles Peter Burch Jonathan M. Tinsley Graham M. Wynne Stephen G. Davies Francis X. Wilson Fraydoon Rastinejad Shabaz Mohammed Kay E. Davies Angela J. Russell 《Angewandte Chemie (International ed. in English)》2020,59(6):2420-2428
Duchenne muscular dystrophy (DMD) is a fatal muscle‐wasting disease arising from mutations in the dystrophin gene. Upregulation of utrophin to compensate for the missing dystrophin offers a potential therapy independent of patient genotype. The first‐in‐class utrophin modulator ezutromid/SMT C1100 was developed from a phenotypic screen through to a Phase 2 clinical trial. Promising efficacy and evidence of target engagement was observed in DMD patients after 24 weeks of treatment, however trial endpoints were not met after 48 weeks. The objective of this study was to understand the mechanism of action of ezutromid which could explain the lack of sustained efficacy and help development of new generations of utrophin modulators. Using chemical proteomics and phenotypic profiling we show that the aryl hydrocarbon receptor (AhR) is a target of ezutromid. Several lines of evidence demonstrate that ezutromid binds AhR with an apparent KD of 50 nm and behaves as an AhR antagonist. Furthermore, other reported AhR antagonists also upregulate utrophin, showing that this pathway, which is currently being explored in other clinical applications including oncology and rheumatoid arthritis, could also be exploited in future DMD therapies. 相似文献
63.
64.
Kuehn K Mehta S Fu H Genio E Murphy D Liu F Liu Y Ahlers G 《Physical review letters》2002,88(9):095702
We report new measurements in four cells of the thermal boundary resistance R between copper and (4)He below but near the superfluid-transition temperature T(lambda). For 10(-7)< or =t identical to 1-T/T(lambda))< or =10(-4) fits of R = R(0)t(-x(b))+R(B) to the data yielded x(b) approximately equal to 0.18, whereas a fit to theoretical values based on the renormalization-group theory yielded x(b) = 0.23. Alternatively, a good fit of the theory to the data could be obtained if the amplitude of the prediction was reduced by a factor close to 2. The results raise the question whether the boundary conditions used in the theory should be modified. 相似文献
65.
If an ex situ programme for the conservation of rare and threatened bryophytes is to succeed, a method of long-term, basal storage is required. The aim of this study was to determine the effectiveness of sucrose, ABA and sucrose/ABA combined, as cryoprotectant pretreatments, for the long-term storage of protonemata of the endangered Cornish path moss, Ditrichum cornubicum. This work is a prelude to the in vitro conservation of rare and endangered UK bryophytes. The addition of sucrose and/or ABA in the pre-culture medium, reduced protonemal growth rate. However, pretreatment afforded a high level of protection against tissue damage during dehydration and freezing, with 100 % regeneration of pretreated plants after thawing, compared to 53 % regeneration of controls. Sucrose combined with ABA in the pre-culture medium gave the most effective cryoprotection, with protonemata having fewer necrotic tissues and rapid recovery of growth. 相似文献
66.
Kwok W. Chiu David Lyons Geoffrey Wilkinson Mark Thornton-Pett Michael B. Hursthouse 《Polyhedron》1983,2(8):803-810
The reduction of WCl4(PMe3)3 by sodium amalgam in presence of phenylacetylene gives W(PMe3)(PhCCH)3 (A). Reduction in presence of methylisocyanide gives W(PMe3)2(MeNC)4 (B), while in presence of excess PMe3 in tetrahydrofuran under hydrogen, WH2Cl2(PMe3)4 (C) is formed. The reaction of WCl2(PMe3)4 with methanol in tetrahydrofuran gives mixtures of WH2Cl2(PMe3)4 and WOC12(PMe3)3 (D).The structures of A, B, and D have been determined by X-ray diffraction. 相似文献
67.
A numerical solution of the developing non-isothermal flow of a generalised power-law fluid in a slightly converging slit is presented, a problem which is relevance to some polymer processing operations.The results are presented in graphical form. They indicate that inertia forces and kinetic energy increases along the slit and these factors affect the development of the velocity and stress distributions. The effect of other parameters on the process is also brought out. 相似文献
68.
69.
Kerry A. Landman 《Studies in Applied Mathematics》1980,62(3):217-248
This paper is concerned with a nonlinear integrodifferential equation (the delay logistic equation) governing the growth dynamics of a single species N(t) for time t > 0. This equation contains a positive parameter λ. Suppose that there exists a positive equilibrium solution N = c which is stable for all small values of λ. Assume also that this solution loses stability as λ is increased past a critical value λ*. This will correspond to a simple pure imaginary conjugate pair of roots of a characteristic equation associated with the linearized stability of N = c at λ = λ*. Then we will construct a unique bifurcating time periodic solution of the equation as a Taylor series in a parameter ε. Furthermore this solution exists either for supercritical values of the parameter (λ > λ*) or for subcritical values (λ < λ*). The stability behavior of this small periodic solution can be characterized according to whether the bifurcation is supercritical or subcritical-supercritical solutions are stable, but subcritical solutions are unstable. Therefore these results are analogous to Hoprs bifurcation theorem for autonomous systems of differential equations. 相似文献
70.