1,721,037 research outputs found
Synthesis of D-myo-inositol 1,4,5-triphosphate analogues
No full textThe cytosolic second messenger D-myo-inositol 1,4,5-trisphosphate (InsP₃), has the ability to mobilise Ca²⁺ from intracellular stores. Ca²⁺ controls a wide range of cellular processes, such as cell division and proliferation, apoptosis, fertilisation, gene transcription and muscle contraction. A number of potent InsP₃ receptor agonists are currently known; however, no selective InsP₃Rs antagonists have been reported to date. Using the X-ray crystal structure of the mouse type 1 InsP₃R, a range of analogues (below) has been designed with the intention of these compounds acting as competitive InsP₃Rs antagonists. The successful syntheses of these compounds are reported herein
Development of small molecule CREBBP bromodomain ligands using medicinal chemistry-based approaches
Get PDFThis work explores medicinal chemistry-based approaches to develop CREBBP bromodomain ligands, using protein-ligand X-ray crystallography to enable structure-guided drug design. Here, we report the improvement of affinity and selectivity for a previously reported CREBBP bromodomain inhibitor through; (i) bioisosteric modifications to remove unfavourable enthalpic contributions to binding; and (ii) macrocyclic drug design to favour the CREBBP bromodomain binding mode. These improved ligands were also incorporated into (iii) PROTACs to develop full-length CREBBP degraders as a proof-of-concept for this target. In collaboration with Prof. Dario Neri’s group (ETH Zurich), we use (iv) DNA-encoded chemical library technology to identify novel CREBBP bromodomain fragments and scaffolds. This work has provided valuable insight in the development of selective inhibitors for the CREBBP bromodomain and sets the foundations for applying new technologies to identify novel inhibitors and degraders for this target protein
Developing small molecule ligands for the study of bromodomain-histone interactions
Get PDFDynamic changes in DNA methylation, and post-translational modifications on histone proteins which DNA wraps around, form the basis of epigenetic transfer of information. The histone code refers to different combinations of epigenetic marks, each mediating transcription in a specific manner. Bromodomains are acetyl-lysine readers of the histone protein which interact selectively with acetylated lysine residues on histones. This protein-protein interaction alters gene expression levels, causing specific downstream effects. The human bromodomain family consists of 61 unique proteins, which are divided into eight subfamilies based on sequence similarity. Most research has been focused on the bromodomain and extra C-terminal (BET) family, which has yielded 14 compounds currently in clinical trials. However, only a few selective ligands and no compounds in clinical trials have been reported for other bromodomain families.
Herein is reported, an extensive structure activity relationship of a potent CREBBP bromodomain ligand. The focus was on the cation-π interaction between R1173 and the tetrahydroquinaxolinone, and a good correlation between the computationally calculated electrostatic surface potential and the CREBBP bromodomain binding affinity was observed. Attempts to increase the selectivity of the ligand over the BET bromodomain were unsuccessful. The stability of the dihydroquinaxolinone headgroup was optimised by ring size expansion, which maintained CREBBP affinity and binding mode â the latter of which was confirmed by X-Ray crystallography. The propyl linker was modified by introducing a gem-difluoro group, and due to the conformational effect of the gauche-gauche interaction, a 3-fold affinity increase was observed.
A second project in this dissertation reports the development of a small, modular photo affinity based probe based on a 3,5-dimethylisoxazole acetyl lysine mimic. This probe could be crosslinked to purified bromodomain proteins with up to 30% efficiency and subsequently modified via CuAAc chemistry to attach a fluorophore or biotin tag. The probe can crosslink to BRD4(1), CREBBP, WDR9(2) and the parasitic bromodomain TcBDF3.</p
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Synthesis and development of light-activated molecular probes
Get PDFJudicious addition of photolabile caging groups (PCGs) to protect biologically im- portant molecules, has enabled the development of many powerful chemical tools for the study of biological processes. These tools have the potential to be activated in a cellular setting by irradiation with light of appropriate wavelengths, restoring functionality, with excellent spatial and temporal control.
This D. Phil. dissertation highlights two biologically relevant examples where PCGs can be applied: (i) 4,5-dimethoxynitrobenzyl (DMNB) caged derivatives of GSH and ESG, were synthesised and uncaging of the DMNB group at 350 nm to reveal the free α-carboxylic acid of the glycine residue was demonstrated. These molecules have the potential to probe the binding mode within the KefC KTN binding domain, a ligand-gated K+ efflux system, critical for bacterial response to electrophilic assault. The molecules are currently with collaborators awaiting further evaluation.
(ii) The wavelength-dependent application of PCGs toward the study of protein post- translational modifications (PTMs) was developed. PTMs modulate protein function and have a ubiquitous role in a diverse range of cellular functions.
A wavelength selective sequential pair of PCGs was developed and demonstrated in a tripeptide, using the diethylamino coumarin (DEACM), which was cleaved at 420 nm, and the DMNB caging group, which was subsequently cleaved at 350 nm.
A chromatically orthogonal pair of PCGs, with possible applications in both organic synthesis and biological systems, incorporating the BODIPY-based and DEACM caging groups, which could be cleaved at 530 nm and 420 nm, respectively, was also developed.
Photolysis was conducted on a tripeptide and hexapeptide and an in vitro application was demonstrated where when caged, the peptide was not susceptible to peptidolysis when incubated with enzymes. Following irradiation at 420 nm, the DEACM group was uncaged and the peptide underwent peptidolysis in the presence of Endoproteinase AspN, whereas following irradiation at 530 nm to uncage the BODIPY group, the peptide underwent peptidolysis in the presence of Endoproteinase LysC. These results not only provide conclusive evidence of the ability of this pair of caging groups to act in a wavelength orthogonal sense but also demonstrates the potential applicability of the pair to biochemical studies.
This pair of PCGs represents the first example of an orthogonal pair of caging groups where both PCGs could be cleaved, at wavelengths longer than 400 nm, in a sequence independent manner.</p
The synthesis of 5-substituted hydantoins
No full textThe Bucherer-Bergs reaction is a classical multi-component reaction that yields hydantoins, which can be hydrolysed to afford α-amino acids. Hydantoins have many uses in modern organic synthesis, and this moiety has been included in a number of therapeutic agents, which have a wide range of biological activities. Herein, we report a mild synthesis of 5- and 5,5-substituted hydantoins from α-aminonitriles using Hünig’s base and carbon dioxide. This reaction can be performed in excellent yields, using a variety of organic solvents and is applicable to a range of substrates. In an extension to the above methodology, a one-pot Lewis acid-catalysed synthesis of hydantoins from ketones has also been developed and optimised in organic media. This reaction can be performed in excellent yields and is suitable for the synthesis of 5- and 5,5-substituted hydantoins
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Get PDFWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
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