Catalytic Nitrene Transfer by an FeIV-Imido Complex Generated by a Comproportionation Process

Nitrene transfer reactions have emerged as one of the most powerful and versatile ways to insert an amine function to various kinds of hydrocarbon substrates. However, the mechanisms of nitrene generation have not been studied in depth albeit their formation is taken for granted in most cases without definitive evidence of their occurrence. In the present work, we compare the generation of tosylimido iron species and NTs transfer from Fe^II and Fe^III precursors where the metal is embedded in a tetracarbene macrocycle. Catalytic nitrene transfer to reference substrates (thioanisole, styrene, ethylbenzene and cyclohexane) revealed that the same active species was at play, irrespective of the ferrous versus ferric nature of the precursor. Through combination of spectroscopic (UV-visible, Mössbauer), ESI-MS and DFT studies, an Fe^IV tosylimido species was identified as the catalytically active species and was characterized spectroscopically and computationally. Whereas its formation from the Fe^II precursor was expected by a two-electron oxidative addition, its formation from an Fe^III precursor was unprecedented. Thanks to a combination of spectroscopic (UV-visible, EPR, Hyscore and Mössbauer), ESI-MS and DFT studies, we found that, when starting from the Fe^III precursor, an Fe^III tosyliodinane adduct was formed and decomposed into an Fe^V tosylimido species which generated the catalytically active Fe^IV tosylimide through a comproportionation process with the Fe^III precursor.     

Identifying aspirin polymorphs from combined DFT-based crystal structure prediction and solid-state NMR

A combined experimental and computational approach was used to distinguish between different polymorphs of the pharmaceutical drug aspirin. This method involves the use of ab initio random structure searching (AIRSS), a density functional theory (DFT)-based crystal structure prediction method for the high-accuracy prediction of polymorphic structures, with DFT calculations of nuclear magnetic resonance (NMR) parameters and solid-state NMR experiments at natural abundance. AIRSS was used to predict the crystal structures of form-I and form-II of aspirin. The root-mean-square deviation between experimental and calculated ¹H chemical shifts was used to identify form-I as the polymorph present in the experimental sample, the selection being successful despite the large similarities between the molecular environments in the crystals of the two polymorphs.     

Azasugar inhibitors as pharmacological chaperones for Krabbe disease

Krabbe disease is a devastating neurodegenerative disorder characterized by rapid demyelination of nerve fibers. This disease is caused by defects in the lysosomal enzyme β-galactocerebrosidase (GALC), which hydrolyzes the terminal galactose from glycosphingolipids. These lipids are essential components of eukaryotic cell membranes: substrates of GALC include galactocerebroside, the primary lipid component of myelin, and psychosine, a cytotoxic metabolite. Mutations of GALC that cause misfolding of the protein may be responsive to pharmacological chaperone therapy (PCT), whereby small molecules are used to stabilize these mutant proteins, thus correcting trafficking defects and increasing residual catabolic activity in cells. Here we describe a new approach for the synthesis of galacto-configured azasugars and the characterization of their interaction with GALC using biophysical, biochemical and crystallographic methods. We identify that the global stabilization of GALC conferred by azasugar derivatives, measured by fluorescence-based thermal shift assays, is directly related to their binding affinity, measured by enzyme inhibition. X-ray crystal structures of these molecules bound in the GALC active site reveal which residues participate in stabilizing interactions, show how potency is achieved and illustrate the penalties of aza/iminosugar ring distortion. The structure–activity relationships described here identify the key physical properties required of pharmacological chaperones for Krabbe disease and highlight the potential of azasugars as stabilizing agents for future enzyme replacement therapies. This work lays the foundation for new drug-based treatments of Krabbe disease.     

Evolved gas analysis (EGA) of brick clays

Using a system based on non-dispersive infrared (NDIR) detectors, evolved gas analysis (EGA) was able to identify and quantify the principal volatiles produced by heating powdered samples of UK brick clays. From these results, atmospheric emissions likely to result from brick production can be predicted. In addition, EGA results for extruded brick clay test pieces are significantly different from those of powdered samples. Within an extruded brick clay body, evolved gases are contained within a pore system and evolved gas-solid phase reactions also occur. This EGA study provides further evidence on the nature of firing reactions within brick clay bodies. The qualitative and quantitative influence of heating rate — a key process condition in brick manufacture — on gas release is also outlined.Dedicated to Dr. Robert Mackenzie on the occasion of his 75th birthday     

When should you sack a football manager? Results from a simple model applied to the English Premiership

What strategy should a football (soccer, in American parlance) club adopt when deciding whether to sack its manager? This paper introduces a simple model assuming that a club's objective is to maximize the number of league points that it scores per season. The club's strategy consists of three choices: the length of the honeymoon period during which it will not consider sacking a new manager, the level of the performance trapdoor below which the manager get the sack, and the weight that it will give to more recent games compared to earlier ones. Some data from the last six seasons of the English Premiership are used to calibrate the model. At this early stage of the research, the best strategy appears to have only a short honeymoon period of eight games (much less than the actual shortest period of 12 games), to set the trapdoor at 0.74 points per game, and to put 47% of the weight on the last five games. A club adopting this strategy would obtain on average 56.8 points per season, compared to a Premiership average of 51.8 points.     

On the bounded version of Hilbert's tenth problem

 The paper establishes lower bounds on the provability of 𝒟=NP and the MRDP theorem in weak fragments of arithmetic. The theory I ⁵ E ₁ is shown to be unable to prove 𝒟=NP. This non-provability result is used to show that I ⁵ E ₁ cannot prove the MRDP theorem. On the other hand it is shown that I ¹ E ₁ proves 𝒟 contains all predicates of the form (∀i≤|b|)P(i,x)^Q(i,x) where ^ is =, <, or ≤, and I ⁰ E ₁ proves 𝒟 contains all predicates of the form (∀i≤b)P(i,x)=Q(i,x). Here P and Q are polynomials. A conjecture is made that 𝒟 contains NLOGTIME. However, it is shown that this conjecture would not be sufficient to imply 𝒟=N P. Weak reductions to equality are then considered as a way of showing 𝒟=NP. It is shown that the bit-wise less than predicate, ≤₂, and equality are both co-NLOGTIME complete under FDLOGTIME reductions. This is used to show that if the FDLOGTIME functions are definable in 𝒟 then 𝒟=N P. Received: 13 July 2001 / Revised version: 9 April 2002 / Published online: 19 December 2002 Key words or phrases: Bounded Arithmetic – Bounded Diophantine Complexity     

Global expression analysis of CESA and CSL genes in Arabidopsis

We have used Affymetrix gene chips to measure the expression of 10 CESA and 29 CSL genes of Arabidopsis in different developmental stages or organs. These measurements reveal that many of the genes exhibit different levels of expression in the various organs. While several CESA genes are highly expressed in all the tissues examined, very few CSL genes approach such high levels of expression. This suggests that the CSL genes either encode enzymes for the synthesis of minor components of cell walls or are expressed only in specific cell types. The expression data also highlights the potential importance of the CESA genes for primary and secondary cell wall formation during different developmental stages and in the different organs examined.