Silent Night : Antagonism of the orexin (or hypocretin) system has recently been identified as a novel mechanism for the treatment of insomnia. Herein, we describe discovery of a dual (OX1R/OX2R) orexin receptor antagonist featuring a 1,4‐diazepane central constraint that blocks orexin signaling in vivo. In telemetry‐implanted rats, oral administration of this antagonist produced a decrease in wakefulness, while increasing REM and non‐REM sleep.
Illuminating an ER enzyme : We report on the design and synthesis of a fluorogenic chemical sensor ( 1 ) to measure sphingosine‐1‐phosphate lyase activity in high‐throughput screening formats, as well as its validation using lyase knockout (Sgpl1?/?) cells.
Conformational restriction of naftopidil led to the discovery of a new class of ligands with a 1,3‐dioxolane (1,3‐oxathiolane, 1,3‐dithiolane) structure that bind to α1 adrenoceptor subtypes and 5‐HT1A receptors. Adequate structural modifications address the selectivity toward one or the other receptor system.
Sensing the signal : A gas chromatography–mass spectrometry (GC–MS) method for the analysis of the quorum‐sensing autoinducer‐2 is described. It allows, for the first time, the direct analysis and accurate determination of this highly water soluble signaling compound, which exists in complex equilibria. The application on the caries‐causing bacterium Streptococcus mutans is described.
Choosing the right compounds to synthesise from large virtual combinatorial libraries is a current challenge for the pharmaceutical industry. Herein we describe a highly optimised method that aligns lead‐like properties with compound diversity. The methods are illustrated by considering a two‐dimensional library based on the interesting spirocyclic bis‐azetidine template.
A series of bicyclic N ‐arylmethyl‐substituted iminoribitols were synthesised and evaluated in vitro against T. vivax nucleoside hydrolase. The importance of the N–Asp40 interaction was confirmed and depends on an optimal pKa value, which can be influenced by substituents. The compounds were active inhibitors of nucleoside hydrolase (IAG‐NH) and are inactive against human purine nucleoside phosphorylase.
Treating African trypanosomiasis : The synthesis and biological evaluation of novel 1‐alkyloxy and 1‐benzyloxyadamantano 2‐guanylhydrazones, their 1‐dioxa congeners and two 1‐benzyladamantano 2‐guanylhydrazones is reported. Preliminary structure–activity relationship data were elucidated and lead compounds suitable for further optimization were discovered.
Choosing chloro : By reshaping the catalytic pocket of a catechol 1,2‐dioxygenase through a structural route alternative to evolution, novel engineered chlorocatechol dioxygenase‐like enzymes were obtained. Variants show an inversion of specificity with a preference for 4‐chlorocatechol and activity on the rarely recognised substrate 4,5‐dichlorocatechol.
Selective MMP inhibitors : Eleven α‐sulfonylphosphonates were synthesized and tested as MMP inhibitors. The IC50 values for most of them are in the nanomolar range against MMP‐2, ‐8, ‐13, and ‐14, with an interesting selectivity profile versus MMP‐9.
Disarmed forces : Inhibition of the central virulence regulator ClpP by structurally refined β‐lactones resulted in dramatically reduced production of devastating virulence factors, including pyrogenic toxin superantigens derived from pathogenic multiresistant Staphylococcus aureus strains. Targeting of this virulence regulator could present an attractive strategy for neutralizing the harmful effects of bacterial pathogens, and help the host immune response to eliminate the disarmed bacteria.
Telmisartan was originally designed as an AT1 antagonist but was later also characterized as a selective PPARγ modulator. This study focused on the identification of the essential structural motifs of telmisartan for PPARγ activation activity, elucidating the individual SAR of each different component (shown).
More than meets the I : The biosynthetic gene cluster for indanomycin was identified from Streptomyces antibioticus NRRL 8167. The framework of the indanomycins includes a tetrahydropyran and a central indane ring system. The final module of the indanomycin polyketide synthase possesses an unusual terminal module lacking an integrated thioesterase.
Zinc‐dependent metalloproteinases such as matrix metalloproteinases (MMPs) and A disintegrin and metalloproteinases (ADAMs) are potential therapeutic targets in many diseases. To better understand their complex role in health and disease, new methodology for activity determination is under development. This concept gives an overview of the available methods for activity‐based proteomic research on these enzymes.
Turn Bak : We present rationally designed scaffolds that mimic the spatial projection of the i, i+4, i+7, and i+11 residues of an α‐helix. A library of biphenyl derivatives was shown by competition fluorescence polarization and ITC to mimic Bak and disrupt the Bak/Bcl‐xL protein–protein interaction. 15N HSQC experiments confirmed that the surface of Bcl‐xL normally occupied by Bak was the target area of our new synthetic inhibitors.
The synthesis of 2′,2′‐difluoro KRN7000 is described. In vivo evaluation demonstrates that this fluorinated glycolipid induces CD1d‐dependent TCR activation of NKT cells, with a bias towards Th2 cytokine production.
Sensible DNA : An electrochemical DNA assay based on specific Salmonella spp. capture probes and enzyme labeling with alkaline phosphatase was optimized by using a 48‐electrode microarray and scanning electrochemical microscopy (SECM). SECM was further used to evaluate potential amplification strategies due to redox cycling.
Transforming the neuroactive toxins of cone snails into small‐size compounds poses a challenge due to the presence of multiple disulfide bridges. Herein we describe our successful efforts in minimizing the size of μ‐conotoxin while retaining its biological activity.
Cyclase‐free at last : A methylene‐interrupted meso‐bis‐epoxide was stereoselectively converted into dihydroxy‐tetrahydrofuran derivatives with excellent de and ee values through an enzyme‐triggered nucleophilic hydrolysis/cyclisation cascade. Molecular modelling showed that the point of enzyme attack was determined by the stereospecificity of the epoxide hydrolase, whereas the stereochemical course of the cyclisation step was solely governed by Baldwin's rules and did not invoke the involvement of a “cyclase”.
2,3‐Benzodiazepine derivatives : 1‐(4‐Aminophenyl)‐3,5‐dihydro‐3‐N‐ethylcarbamoyl‐5‐methyl‐7,8‐methylenedioxy‐4H‐2,3‐benzodiazepin‐4‐one was synthesized, and its enantiomers were separated by chiral HPLC. Pharmacological evaluation of each enantiomer showed that (S)‐(?)‐ 5 appears to be more potent than its optical antipode (R)‐(+)‐ 5 in an AMPA receptor binding assay.
Artificial synapses for femtomolar detection : Amperometry at platinized carbon fibre electrodes has been used to unravel the complexity of β‐lapachone's effects on cellular oxidative stress. α‐Lapachone, the pharmacologically inactive para‐quinone isomer, did not display such characteristics, but over longer incubation periods both quinones induced apoptosis. The observed effects were interpreted in terms of two mechanisms involving opposite reactivities of quinones in living cells.
