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Skeletal muscle in MuRF1 null mice is not spared in low-gravity conditions, indicating atrophy proceeds by unique mechanisms in space
No full textMicrogravity exposure is associated with loss of muscle mass and strength. The E3 ubiquitin ligase MuRF1 plays an integral role in degrading the contractile apparatus of skeletal muscle; MuRF1 null (KO) mice have shown protection in ground-based models of muscle atrophy. In contrast, MuRF1 KO mice subjected to 21 days of microgravity on the International Space Station (ISS) were not protected from muscle atrophy. In a time course experiment microgravity-induced muscle loss on the ISS showed MuRF1 gene expression was not upregulated. A comparison of the soleus transcriptome profiles between spaceflight and a publicly available data set for hindlimb suspension, a claimed surrogate model of microgravity, showed only marginal commonalities between the models. These findings demonstrate spaceflight induced atrophy is unique, and that understanding of effects of space requires study situated beyond the Earth's mesosphere
One-Pot Electrochemical Nickel-Catalyzed Decarboxylative Sp2–Sp3 Cross-Coupling
No full textA one-pot electrochemical nickel-catalyzed decarboxylative sp2–sp3 cross-coupling reaction has been developed using redox-active esters prepared in situ from alkyl carboxylates and N-hydroxyphthalimide tetramethyluronium hexafluorophosphate (PITU). This undivided cell one-pot method enables C–C bond formation using inexpensive, benchtop-stable reagents with isolated yields up to 95% with good functional group tolerance, which includes nitrile, ketone, ester, alkene and selectivity over other aromatic halogens
5,5- and 5,5-Membered Spirocyclic Indoline-pyrrolidinone Hit Finding Libraries
No full textThe production of two libraries based on spirocyclic indolinepyrrolidinones is described. These libraries were selected from numerous spirocyclic indolinepyrrolidinone scaffolds by following the library evaluation procedure we introduced in 2005, based on virtual values as well as on measured properties of prototype compounds. The library production yielded in 176 and 428 compounds respectively, which could be isolated in sufficient amounts and purities
Stereo-controlled lithiation-methylation and subsequent aminolysis of a chiral epoxide in continuous flow
No full textIn this master thesis the lithiation and methylation of epoxide 1 was initially developed in batch and then transferred into a flow process. The lithiated epoxide 2 is an unstable species, and so is an ideal case for processing by flow chemistry. Various electrophiles and organometallic bases were screened in batch reactions before the transfer into flow was done. The stability of the oxiranyl anion 2 was studied with anisaldehyde as substitute electrophile, allowing us to overcome a probable clustering-effect of the lithiated epoxide 2. The stereo-retention of the methylation was shown. The flow process was then optimized to obtain acceptable conversion at accessible temperatures. The optimization of the deprotonation in flow was done with anisaldehyde as electrophile before the methylation was optimized. A large screening of parameters was conducted: concentration of starting solutions, equivalents of reagents, residence times for deprotonation and methylation as well as the temperature. It was possible to handle the low boiling points of these compounds by careful sampling which minimized losses to headspaces. The aminolytic ring opening of the methylated epoxide 3 was optimized in the batch microwave unit. A temperature and equivalent screening with NH4OH was done. The possibility of a one sequence approach from epoxide 1 to the amino alcohol 4 was shown. The optimized conditions for the ring opening were successfully used on samples from the flow lithiation methylation
Real-time imaging and quantification of peptide uptake in vitro and in vivo
No full textPeptides constitute an important class of molecules for drug discovery, but many of the leads fail to advance clinically because of poor membrane and tissue permeability. Therefore, assessment of a peptide’s ability to cross cellular membrane is critical when developing novel peptide-based therapeutics. However, current methods suffer from limitations such as the necessity to introduce rather large modifications that require complex chemistry, the inability to provide kinetic information of internalization or distinguish between internalized vs membrane bound compounds, as well as requiring multiple sample manipulation steps. Herein, we report a novel “Split Luciferin Peptide” (SLP) uptake assay that provides non-invasive imaging and quantification of peptide uptake in real-time both in vitro and in vivo using a very sensitive bioluminescent readout. The method is based on a straightforward chemical modification of the peptide of interest with a D-cysteine tag retains the overall peptidic character of the original molecule. This method can in principle be adapted for screening of peptide libraries becoming an important tool for preclinical drug development both in vitro and in vivo
A micellar-friendly, HandaPhos palladacycle pre-catalyst for ppm level Suzuki-Miyaura cross couplings in water under mild conditions
No full textA newly engineered palladacycle that contains substituents on the biphenyl rings and contains the ligand HandaPhos is especially well-matched to an aqueous micellar medium, enabling valued Suzuki-Miyaura couplings to be run not only in water under mild conditions, but at 300 ppm of Pd catalyst. This general methodology has been applied to several targets in both the medicinal and agrochemical areas. Multiple recycling of the aqueous reaction mixture involving both the same as well as different coupling partners has been demonstrated. Low temperature microscopy (cryo-TEM) indicates the nature and size of the particles acting as nanoreactors. Importantly, given the low loadings of Pd invested per reaction, ICP-MS analyses of residual palladium in the products showed levels well within the FDA allowable limits
Magnetization Transfer Ratio (MTR) as a Non-Invasive Biomarker in Small Rodent Peripheral Nerve Injury Models
No full textThe study of myelin density in peripheral nerve injuries and pathologies is largely limited to post-mortem analysis due to the difficulty in obtaining biopsies without affecting nerve function, as well as because of the small size of the tissue and its location. In this study, we used magnetization transfer ratio (MTR) MRI to longitudinally and non-invasively analyze two models of peripheral nerve injury in small rodents, obtained by sciatic nerve crush or lysolecithin injection. Multiple techniques (electrophysiology, gene expression and histology) have been used to validate the extensive MRI analysis and young and old animals have been included for comparison. This study underlines the power of MTR for the study of myelin density in small tissues such as the sciatic nerve of rodents and describes how age significantly affects recovery after injury
[18F]PRIMATX, a New Positron Emission Tomography Tracer for Imaging of Autotaxin in Lung Tissue and Tumor‐Bearing Mice
No full textAutotaxin (ATX) is a secreted enzyme with tissue levels associated with tissue injury, which increase during wound healing and chronic fibrotic diseases. We selected [18F]-(R,E)-3-(4-chloro-2-((5-methyl-2H-tetrazol-2-yl)methyl) phenyl)-1-(4-((5-(2-fluoroethoxy)pyridin-2-yl)methyl)-2-methylpiperazin-1-yl)prop-2-en-1-one ([18F]PRIMATX, [18F]2), a tracer for positron emission tomography, to image ATX expression in vivo. It successfully differentiates expression levels in lung tissue samples from idiopathic pulmonary fibrosis patients, and allows the detection of ATX-expressing tumours in living mice, confirming its potential for development as a clinical imaging agent
Tropifexor-Mediated Abrogation of Steatohepatitis and Fibrosis Is Associated With Antioxidative Gene Expression Profile in Rodents
No full textFarnesoid X receptor (FXR) agonism is emerging as an important potential therapeutic mechanism of action for multiple chronic liver diseases. The bile acid–derived FXR agonist obeticholic acid (OCA; 6-ethyl chenodeoxycholic acid) has shown promise in a phase 2 study in patients with nonalcoholic steatohepatitis (NASH). Here, we report efficacy of a novel, non–bile acid FXR agonist tropifexor (LJN452) in two distinct preclinical models of NASH. The efficacy of tropifexor at <1 mg/kg doses was superior to that of OCA at 25 mg/kg in the liver in both NASH models. In a chemical and dietary model of NASH (STAM model), tropifexor reversed established fibrosis and reduced nonalcoholic fatty liver disease activity score and hepatic triglycerides. In an insulin-resistant, obese NASH model (AMLN), tropifexor markedly reduced steatohepatitis, fibrosis, and profibrogenic gene expression. Transcriptome analysis of livers from AMLN mice revealed 461 differentially expressed genes following tropifexor treatment, which included a combination of signatures associated with reduction of oxidative stress, fibrogenesis, and inflammation. Conclusion: Based on the preclinical validation in animal models, tropifexor is a promising investigational therapy that is currently under phase 2 development for NASH
Interface-rich Aqueous Systems for Sustainable Chemical Synthesis
No full textMimicking enzyme's exquisite activity and selectivity is a long-standing goal for sustainable chemical method development in aqueous media. The use of interface-rich aqueous systems, such as single-chain polymers, micelles and vesicle membranes recently emerged as strategy to emulate the compartmentalisation of natural systems. In aqueous solution, aggregates such as micelles or microemulsion droplets are formed, providing reaction environments different from bulk solutions that frequently improve selectivity and accelerate reaction rates for a wide array of chemical transformations. We present here selected examples of interface-rich aqueous systems and discuss the advantages they offer for chemical synthesis. Particularly metal-catalysed cross-coupling reactions are highlighted and future challenges to perform reactions in interface-rich aqueous media are discussed