Rigid and concave, 2,4-cis-substituted azetidine derivatives: A platform for asymmetric catalysis

A series of single enantiomer, 2,4-<i>cis</i>-disubstituted amino azetidines were synthesised and used as ligands for copper-catalysed Henry reactions of aldehydes with nitromethane. Optimisation of ligand substituents and the reaction conditions was conducted. The enantiomeric excess of the formed products was highest when alkyl aldehydes were employed in the reaction (>99% e.e.). The absolute stereochemistry of one representative azetidine derivative salt was determined by analysis of the Flack parameter of an XRD single crystal structure. The origin of selectivity in catalysis was investigated computationally, revealing the importance of the amino-substituent in determining the stereochemical outcome. A racemic platinum complex of a <i>cis</i>-disubstituted azetidine is examined by XRD single crystal structure analysis with reference to its steric parameters, and analogies to the computationally determined copper complex catalyst are drawn.<br

Palladium and platinum 2,4-cis-amino azetidine and related complexes

Crystal structures and structural interpretation of complexes of azetidine (and related) ligands coordinated to palladium(II) and platinum(II)

Data_Sheet_2_Palladium and Platinum 2,4-cis-amino Azetidine and Related Complexes.ZIP

<p>Seven N,N'-palladium(II) chloride complexes, one N,N'-palladium(II) acetate complex of 2,4-cis-azetidines where prepared and analyzed by single crystal XRD. Two platinum(II) chloride N,N'-complexes of 2,4-cis-azetidines where prepared and analyzed by single crystal XRD. Computational analysis and determination of the %Vbur was examined conducted. A CNN' metallocyclic complex was prepared by oxidative addition of palladium(0) to an ortho bromo 2,4-cis-disubstituted azetidine and its crystal structure displays a slightly pyramidalized metal-ligand orientation.</p

Data_Sheet_3_Palladium and Platinum 2,4-cis-amino Azetidine and Related Complexes.ZIP

<p>Seven N,N'-palladium(II) chloride complexes, one N,N'-palladium(II) acetate complex of 2,4-cis-azetidines where prepared and analyzed by single crystal XRD. Two platinum(II) chloride N,N'-complexes of 2,4-cis-azetidines where prepared and analyzed by single crystal XRD. Computational analysis and determination of the %Vbur was examined conducted. A CNN' metallocyclic complex was prepared by oxidative addition of palladium(0) to an ortho bromo 2,4-cis-disubstituted azetidine and its crystal structure displays a slightly pyramidalized metal-ligand orientation.</p

Experimental Testing of Quantum Mechanical Predictions of Mutagenicity: Aminopyrazoles

A computational method for predicting the likelihood of aromatic amines being active in the Ames test for mutagenicity was trialed on a set of aminopyrazoles. A virtual array of compounds was generated from the available sets of hydrazines and α-cyanoaldehydes (or ketones) and quantum mechanical calculations used to compute a probability of being active in the Ames test. The compounds selected for synthesis and testing were not based on the predictions and so spanned the range of predicted probabilities. The subsequently generated results of the Ames test were in good correspondence with the predictions and confirm this approach as a useful means of predicting likely mutagenic risk

Data_Sheet_1_Palladium and Platinum 2,4-cis-amino Azetidine and Related Complexes.PDF

<p>Seven N,N'-palladium(II) chloride complexes, one N,N'-palladium(II) acetate complex of 2,4-cis-azetidines where prepared and analyzed by single crystal XRD. Two platinum(II) chloride N,N'-complexes of 2,4-cis-azetidines where prepared and analyzed by single crystal XRD. Computational analysis and determination of the %Vbur was examined conducted. A CNN' metallocyclic complex was prepared by oxidative addition of palladium(0) to an ortho bromo 2,4-cis-disubstituted azetidine and its crystal structure displays a slightly pyramidalized metal-ligand orientation.</p

Tunnelman luominen tanssiteoksen ilmeeseen

Opinnäytetyön teemana ovat lapsuuden painajaiset. Kyseessä on taiteellinen produk-tio, joka tarkastelee painajaisten, katoamisen ja näkymisen teemaa liikekielen, kuvan ja typografian keinoin. Usean kuukauden kestänyt projekti edellytti syvää paneutumista aiheeseen. Työ on saanut vaikutteita musiikin, kirjallisuuden ja elokuvateollisuuden kauhugenrestä. Opinnäytetyön tutkielma käsittelee tunnelman luomista tanssiteoksen ilmeessä. Kirjal-linen osio jakautuu kahteen päälukuun: tanssiteoksen visuaaliseen ilmeeseen ja esityk-seen. Graafiseen ilmeeseen lukeutuvat juliste, käsiohjelma, kutsukortti, notaatio ja In-ternet-sivut. Tanssiteoksen suunnitteluun kuuluvat koreografia, lavastus, puvustus ja äänisuunnittelu. Teoksen tekniseen toteutukseen on saatu apua Kymenlaakson ammat-tikorkeakoulun audiovisuaalisen ilmaisun opiskelijoilta. Työn tarkoituksena oli päästä eroon pimeän peloista ja öisin mielikuviin ilmestyvistä mustista hahmoista. Tutkimukseen on kerätty materiaalia lukemalla kirjallisuutta, haastattelemalla ihmisiä, tutustumalla kauhugenreen ja syventymällä omiin painajaiskokemuksiin. Inspiraation lähteinä ovat erityisesti olleet lähiympäristössä tapahtuneet yliluonnolliset ilmiöt ja kauhutarinat. Lopputuloksena tunnelma ei korostunut ainoastaan konkreettisesti vaan myös aineet-tomasti. Prosessin seurauksena tanssiteokseen syntyi sekä fyysinen tila, jossa kauhu nähtiin, että henkinen tila, jossa kauhu aistittiin. Unien pelkotilat ja pimeässä muodos-tuneet hahmot alkoivat vähitellen kadota, kun turtuminen kauhumaailmaan sai otteen.To begin with, the thesis was inspired by fear. In other words, the theme of the thesis was based on childhood nightmares and traumatic memories. All the words, sentences and images have arisen after two months of paranormal research. The thesis was divided into two parts: the visual identity of the contemporary dance show and the dance performance. A poster, a brochure, an invitation card, a notation and an Internet website were included in the visual identity. Theatrical elements, such as choreography, staging, costumes and sound design were included in the dance per-formance. However, the thesis focuses on describing the atmosphere in the visualiza-tion of the dance performance. The main goal of the process was to release the sensi-tive mind and to get rid of the fear of darkness and imaginary creatures. The material for the thesis was collected by reading literature, interviewing people, experiencing dreams and getting absorbed in the horror genre. The performance was inspired by ghost stories and supernatural phenomena in a real life. The atmosphere highlighted not only in a physical but also in a mental way. Eventu-ally, instead of only one stage, two scenes arose as a result of the process. The first one was regarded as a physical scene where horror was seen. The second one was considered a mental scene where the images of nightmare stemmed from. The fear of darkness alleviated due to the examination of the theme and becoming numb for the genre. Little by little, imaginary creatures came to be regarded as insignificant

Protein–Ligand Crystal Structures Can Guide the Design of Selective Inhibitors of the FGFR Tyrosine Kinase

The design of compounds that selectively inhibit a single kinase is a significant challenge, particularly for compounds that bind to the ATP site. We describe here how protein–ligand crystal structure information was able both to rationalize observed selectivity and to guide the design of more selective compounds. Inhibition data from enzyme and cellular screens and the crystal structures of a range of ligands tested during the process of identifying selective inhibitors of FGFR provide a step-by-step illustration of the process. Steric effects were exploited by increasing the size of ligands in specific regions in such a way as to be tolerated in the primary target and not in other related kinases. Kinases are an excellent target class to exploit such approaches because of the conserved fold and small side chain mobility of the active form

Circumventing Seizure Activity in a Series of G Protein Coupled Receptor 119 (GPR119) Agonists

Agonism of GPR119 is viewed as a potential therapeutic approach for the treatment of type II diabetes and other elements of metabolic syndrome. During progression of a previously disclosed candidate <b>1</b> through mice toxicity studies, we observed tonic–clonic convulsions in several mice at high doses. An in vitro hippocampal brain slice assay was used to assess the seizure liability of subsequent compounds, leading to the identification of an aryl sulfone as a replacement for the 3-cyano pyridyl group. Subsequent optimization to improve the overall profile, specifically with regard to hERG activity, led to alkyl sulfone <b>16</b>. This compound did not cause tonic–clonic convulsions in mice, had a good pharmacokinetic profile, and displayed in vivo efficacy in murine models. Importantly, it was shown to be effective in wild-type (WT) but not GPR119 knockout (KO) animals, consistent with the pharmacology observed being due to agonism of GPR119

Use of Small-Molecule Crystal Structures To Address Solubility in a Novel Series of G Protein Coupled Receptor 119 Agonists: Optimization of a Lead and in Vivo Evaluation

G protein coupled receptor 119 (GPR119) is viewed as an attractive target for the treatment of type 2 diabetes and other elements of the metabolic syndrome. During a program toward discovering agonists of GPR119, we herein describe optimization of an initial lead compound, <b>2</b>, into a development candidate, <b>42</b>. A key challenge in this program of work was the insolubility of the lead compound. Small-molecule crystallography was utilized to understand the intermolecular interactions in the solid state and resulted in a switch from an aryl sulphone to a 3-cyanopyridyl motif. The compound was shown to be effective in wild-type but not knockout animals, confirming that the biological effects were due to GPR119 agonism