Aminopyrazine Inhibitors Binding to an Unusual Inactive Conformation of the Mitotic Kinase Nek2: SAR and Structural Characterization†

We report herein the first systematic exploration of inhibitors of the mitotic kinase Nek2. Starting from HTS hit aminopyrazine 2, compounds with improved activity were identified using structure-based design. Our structural biology investigations reveal two notable observations. First, 2 and related compounds bind to an unusual, inactive conformation of the kinase which to the best of our knowledge has not been reported for other types of kinase inhibitors. Second, a phenylalanine residue at the center of the ATP pocket strongly affects the ability of the inhibitor to bind to the protein. The implications of these observations are discussed, and the work described here defines key features for potent and selective Nek2 inhibition, which will aid the identification of more advanced inhibitors of Nek2

The synthesis of pseudo-geminal, pseudo-ortho and ortho hydroxy-oxazolinyl[2.2]paracyclophanes for use as ligands in asymmetric catalysis

Synthetic routes to pseudo-geminal, pseudo-ortho and ortho hydroxy-oxazolinyl-[2.2]paracyclophanes (and the diastereoisomers of each) for use as N,O ligands in asymmetric catalysis have been devised. The substitution pattern was found to have a strong effect on the rate and enantioselectivity of the formed catalyst in the addition of diethylzinc to benzaldehyde

Influence of Headgroups in Ethylene-Tetrafluoroethylene-Based Radiation-Grafted Anion Exchange Membranes for CO₂ Electrolysis

The performance of zero-gap CO2 electrolysis (CO2E) is significantly influenced by the membrane’s chemical structure and physical properties due to its effects on the local reaction environment and water/ion transport. Radiation-grafted anion-exchange membranes (RG-AEM) have demonstrated high ionic conductivity and durability, making them a promising alternative for CO2E. These membranes were fabricated using two different thicknesses of ethylene-tetrafluoroethylene polymer substrates (25 and 50 μm) and three different headgroup chemistries: benzyl-trimethylammonium, benzyl-N-methylpyrrolidinium, and benzyl-N-methylpiperidinium (MPIP). Our membrane characterization and testing in zero-gap cells over Ag electrocatalysts under commercially relevant conditions showed correlations between the water uptake, ionic conductivity, hydration, and cationic-head groups with the CO2E efficiency. The thinner 25 μm-based AEM with the MPIP-headgroup (ion-exchange capacities of 2.1 ± 0.1 mmol g–1) provided balanced in situ test characteristics with lower cell potentials, high CO selectivity, reduced liquid product crossover, and enhanced water management while maintaining stable operation compared to the commercial AEMs. The CO2 electrolyzer with an MPIP-AEM operated for over 200 h at 150 mA cm–2 with CO selectivities up to 80% and low cell potentials (around 3.1 V) while also demonstrating high conductivities and chemical stability during performance at elevated temperatures (above 60 °C)

ETFE-based anion-exchange membrane ionomer powders for alkaline membrane fuel cells: A first performance comparison of head-group chemistry

In the last few years, the development of radiation-grafted powder-form anion-exchange ionomers (AEI), used in combination with anion-exchange membranes (AEM), has led to the assembly of AEM-based fuel cells (AEMFC) that routinely yield power densities ranging between 1-2 W cm-2 (with a variety of catalysts). However, to date, only benzyltrimethylammonium-type powder AEIs have been evaluated in AEMFCs. This study presents an initial evaluation of the relative AEMFC power outputs when using a combination of ETFE-based radiation-grafted AEMs and AEIs containing three different head-group chemistries: benzyltrimethylammonium (TMA), benzyl-N-methylpyrrolidinium (MPY), and benzyl-N-methylpiperidinium (MPRD). The results from this study strongly suggest that future research should focus on the development and operando long-term durability testing of AEMs and AEIs containing the MPRD head-group chemistryThe research was funded by the Engineering and Physical Sciences Research Council (EPSRC grants EP/M014371/1, EP/M022749/1, and EP/M005933/1). ALGB's exchange was funded by FAPESP grants 2016/13277-9 and 2015/09210-3, while EIS' exchange was funded by FAPESP grants 2015/23621-6, 2014/09087-4 and 2014/50279-4. DH's student-exchange was funded by a PDIF Short Stay Scholarship of the Autonomous University of Madrid. GS' 2015 exchange was funded by the ERASMUS+work placement schem

ETFE-based anion-exchange membrane ionomer powders for alkaline membrane fuel cells: a first performance comparison of head-group chemistry

In the last few years, the development of radiation-grafted powder-form anion-exchange ionomers (AEI), used in combination with anion-exchange membranes (AEM), have led to the assembly of AEM-based fuel cells (AEMFC) that routinely yield power densities ranging between 1 – 2 W cm-2 (with a variety of catalysts). However, to date, only benzyltrimethyammonium-type powder AEIs have been evaluated in AEMFCs. This study presents an initial evaluation of the relative AEMFC power outputs when using a combination of ETFE-based radiation-grafted AEMs and AEIs containing three different head-group chemistries: benzyltrimethylammonium (TMA), benzyl-N-methylpyrrolidinium (MPY), and benzyl-N-methylpiperidinum (MPRD). The results from this study strongly suggest that future research should focus on the development and operando long-term durability testing of AEMs and AEIs containing the MPRD head-group chemistry

An aza-nucleoside, fragment-like inhibitor of the DNA repair enzyme alkyladenine glycosylase (AAG)

The DNA repair enzyme AAG has been shown in mice to promote tissue necrosis in response to ischaemic reperfusion or treatment with alkylating agents. A chemical probe inhibitor is required for investigations of the biological mechanism causing this phenomenon and as a lead for drugs that are potentially protective against tissue damage from organ failure and transplantation, and alkylative chemotherapy. Herein, we describe the rationale behind the choice of arylmethylpyrrolidines as appropriate aza-nucleoside mimics for an inhibitor followed by their synthesis and the first use of a microplate-based assay for quantification of their inhibition of AAG. We finally report the discovery of an imidazol-4-ylmethylpyrrolidine as a fragment-sized, weak inhibitor of AAG

Structure of the Inhibited State of the Sec Translocon

Protein secretion in eukaryotes and prokaryotes involves a universally conserved protein translocation chan-nel formed by the Sec61 complex. Unrelated small-molecule natural products and synthetic compoundsinhibit Sec61 with differential effects for different substrates or for Sec61 from different organisms, makingthis a promising target for therapeutic intervention. To understand the mode of inhibition and provide insightinto the molecular mechanism of this dynamic translocon, we determined the structure of mammalian Sec61inhibited by theMycobacterium ulceransexotoxin mycolactone via electron cryo-microscopy. Unexpect-edly, the conformation of inhibited Sec61 is optimal for substrate engagement, with mycolactone wedgingopen the cytosolic side of the lateral gate. The inability of mycolactone-inhibited Sec61 to effectively trans-port substrate proteins implies that signal peptides and transmembrane domains pass through the site occu-pied by mycolactone. This provides a foundation for understanding the molecular mechanism of Sec61 inhib-itors and reveals novel features of translocon function and dynamics

An Optimised Synthesis of High Performance Radiation-Grafted Anion-Exchange Membranes

High performance benzyltrimethylammonium-type alkaline anion-exchange membranes (AEM), for application in electrochemical devices such as anion-exchange membrane fuel cells (AEMFC), were prepared by the radiation grafting (RG) of vinylbenzyl chloride (VBC) onto 25 μm thick poly(ethylene-co-tetrafluoroethylene) (ETFE) films followed by amination with trimethylamine. Reductions in the electron-beam absorbed dose and amount of expensive, potentially hazardous VBC were achieved by using water as a diluent (reduced to 30–40 kGy absorbed dose and 5 vol% VBC) instead of the prior state-of-the-art method that used organic propan-2-ol diluent (required 70 kGy dose and 20 vol% VBC monomer). Furthermore, the water from the aqueous grafting mixture was easily separated from the residual monomer (after cooling) and was reused for a further grafting reaction: the resulting AEM exhibited an ion-exchange capacity of 2.1 mmol g−1 (cf. 2.1 mmol g−1 for the AEM made using a fresh grafting mixture). The lower irradiation doses resulted in mechanically stronger RG-AEMs compared to the reference RG-AEM synthesised using the prior state-of-the-art method. A further positive off-shoot of the optimisation process was the discovery that using water as a diluent resulted in an enhanced (i.e. more uniform) distribution of VBC grafts as proven by Raman microscopy and corroborated using EDX analysis: this led to enhancement in the Cl− anion-conductivities (up to 68 mS cm−1 at 80 °C for the optimised fully hydrated RG-AEMs vs. 48 mS cm−1 for the prior state-of-the-art RG-AEM reference). A down-selected RG-AEM with an ion-exchange capacity = 2.0 mmol g−1, that was synthesised using the new greener protocol with a 30 kGy electron-beam absorbed dose, led to an exceptional beginning-of-life H2/O2 AEMFC peak power density of 1.16 W cm−2 at 60 °C in a benchmark test using industrial standard Pt-based electrocatalysts and unpressurised gas supplies: this was higher than the 0.91 W cm−1obtained with the reference RG-AEM (IEC = 1.8 mmol g−1) synthesised using the prior state-of-the-art protocol