29 research outputs found

    Beyond 'Criminology vs. Zemiology': Reconciling crime with social harm

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    Since its emergence at the start of the twenty-first century, zemiology and the field of harm studies more generally, has borne an ambiguous and, at times, seemingly antipathetic relationship with the better-established field of criminology. Whilst the tension between the perspectives is, at times, overstated, attempts to reconcile the perspectives have also proved problematic, such that, at present, it appears that they risk either becoming polarized into mutually antagonistic projects, or harmonized to the point that zemiology is simply co-opted within criminology. Whilst tempting to view this as nothing more than an academic squabble, it is the central argument put forward in this chapter that the current trend towards either polariziaton or harmonization of the criminological and zemiological projects, risks impoverishing both perspectives, both intellectually and, more fundamentally, in terms of their capacity to effect meaningful social change. To this end, this chapter offers a critical reflection of recent attempts to reconcile the social harm perspective with criminology, focussing in particular on Majid Yar’s attempts to do so using the concept of ‘recognition’ derived from critical theory. It is suggested that such attempts, whilst important in the contribution they make to developing a theory of harm, are necessarily flawed by their reliance on an implicit assumption of a shared conception of harm underpinning both the concept of ‘crime’ and ‘social harm’. By contrast, it is the central argument put forward in this chapter that zemiology and criminology are best understood as divergent normative projects which, whilst sharing many of the same goals with regards to the improvement of the criminal justice system and the tackling of social problems, differ primarily in the means by which they seek to achieve these. Therefore, rather than denying this debate through the collapsing of one perspective into the other, or polarizing them into hostiles camps, it is only by recognising the nature of this debate and fostering dialogue between the perspectives that we can achieve our shared goals and effect meaningful change

    Design and synthesis of soluble and cell-permeable PI3Kδ inhibitors for long-acting inhaled administration

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    PI3Kδ is a lipid kinase that is believed to be important in the migration and activation of cells of the immune system. Inhibition is hypothesised to provide a powerful yet selective immunomodulatory effect that may be beneficial for the treatment of conditions such as asthma or rheumatoid arthritis. In this work we describe the identification of inhibitors based on a thiazolopyridone core structure and their subsequent optimisation for inhalation. The initially identified compound (13) had good potency and isoform selectivity but was not suitable for inhalation. Addition of basic substituents to a region of the molecule pointing to solvent was tolerated (enzyme inhibition pIC50 >9) and by careful manipulation of the pKa and lipophilicity we were able to discover compounds (20b, 20f) with good lung retention and cell potency that could be taken forward to in-vivo studies where significant target engagement could be demonstrated

    Synthesis and functionalization of ring-fused 2-pyridones : Targeting pili formation in E. coli

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    Bicyclic dihydrothiazolo fused 2-pyridones have been studied as a new class of antibacterial agents, termed pilicides, that target the formation of adhesive bacterial surface organelles (pili) in pathogenic bacteria. Synthetic methods to further functionalize the bicyclic 2-pyridone scaffold have been developed in order to increase water-solubility and thereby facilitate biological evalua-tions. This was accomplished by introducing aminomethylenes at the open position C-6. Tertiary amines were introduced via a microwave–assisted Mannich reaction and a synthetic route based on a formyl intermediate gave access to primary, secondary and tertiary amines, but also to other interesting functionalities. Biological evaluation confirmed that several of the function-alized compounds inhibited pili formation in uropathogenic E. coli., as dem-onstrated by assays of hemagglutination, biofilm formation and adherence to bladder cells. Co-crystallizing one of the pilicides with the target protein gave information about the binding site and based on this a mechanism of action was proposed, which was supported experimentally by surface plas-mon resonance and single point mutations in the protein. Furthermore, the previously developed acylketene imine reaction used to prepare bicyclic thiazolo fused 2-pyridone pilicides has been developed to allow preparation of other ring-fused 2-pyridone systems. Benzo[a]quinolizine-4-ones and indolo[2,3-a]quinolizine-4-ones could be prepared in a fast and simple manner starting from dihydroisoquinolines and a β-carboline. Finally, this method could also be applied for the preparation of heteroatom analogs of the previously studied sulfur containing pilicides. Biological evaluations established that the sulfur atom can be replaced by oxygen and still maintain the ability to prevent pili assembly

    Using Macrocyclic G-Quadruplex Ligands to Decipher the Interactions Between Small Molecules and G-Quadruplex DNA

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    This study aims to deepen the knowledge of the current state of rational G4-ligand design through the design and synthesis of a novel set of compounds based on indoles, quinolines, and benzofurans and their comparisons with well-known G4-ligands. This resulted in novel synthetic methods and G4-ligands that bind and stabilize G4 DNA with high selectivity. Furthermore, the study corroborates previous studies on the design of G4-ligands and adds deeper explanations to why a) macrocycles offer advantages in terms of G4-binding and -selectivity, b) molecular pre-organization is of key importance in the development of strong novel binders, c) an electron-deficient aromatic core is essential to engage in strong arene-arene interactions with the G4-surface, and d) aliphatic amines can strengthen interactions indirectly through changing the arene electrostatic nature of the compound. Finally, fundamental physicochemical properties of selected G4-binders are evaluated, underscoring the complexity of aligning the properties required for efficient G4 binding and stabilization with feasible pharmacokinetic properties.This article also appears in: Society Volumes: Sweden.</p

    Synthesis and Functionalization of Cyclic Sulfonimidamides: A Novel Chiral Heterocyclic Carboxylic Acid Bioisostere

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    An efficient synthesis of aryl substituted cyclic sulfonimidamides designed as chiral nonplanar heterocyclic carboxylic acid bioisosteres is described. The cyclic sulfonimidamide ring system could be prepared in two steps from a trifluoroacetyl protected sulfinamide and methyl ester protected amino acids. By varying the amino acid, a range of different C-3 substituted sulfonimidamides could be prepared. The compounds could be further derivatized in the aryl ring using standard cross-coupling reactions to yield highly substituted cyclic sulfonimidamides in excellent yields. The physicochemical properties of the final compounds were examined and compared to those of the corresponding carboxylic acid and tetrazole derivatives. The unique nonplanar shape in combination with the relatively strong acidity (p<i>K</i><sub>a</sub> 5–6) and the ease of modifying the chemical structure to fine-tune the physicochemical properties suggest that this heterocycle can be a valuable addition to the range of available carboxylic acid isosteres

    Exploring the dispersion and electrostatic components in arene-arene interactions between ligands and G4 DNA to develop G4-ligands

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    G-Quadruplex (G4) DNA structures are important regulatory elements in central biological processes. Small molecules that selectively bind and stabilize G4 structures have therapeutic potential, and there are currently &gt;1000 known G4 ligands. Despite this, only two G4 ligands ever made it to clinical trials. In this work, we synthesized several heterocyclic G4 ligands and studied their interactions with G4s (e.g., G4s from the c-MYC, c-KIT, and BCL-2 promoters) using biochemical assays. We further studied the effect of selected compounds on cell viability, the effect on the number of G4s in cells, and their pharmacokinetic properties. This identified potent G4 ligands with suitable properties and further revealed that the dispersion component in arene-arene interactions in combination with electron-deficient electrostatics is central for the ligand to bind with the G4 efficiently. The presented design strategy can be applied in the further development of G4-ligands with suitable properties to explore G4s as therapeutic targets

    Exploring the Dispersion and Electrostatic Components in Arene–Arene Interactions between Ligands and G4 DNA to Develop G4-Ligands

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    G-Quadruplex (G4) DNA structures are important regulatory elements in central biological processes. Small molecules that selectively bind and stabilize G4 structures have therapeutic potential, and there are currently >1000 known G4 ligands. Despite this, only two G4 ligands ever made it to clinical trials. In this work, we synthesized several heterocyclic G4 ligands and studied their interactions with G4s (e.g., G4s from the c-MYC, c-KIT, and BCL-2 promoters) using biochemical assays. We further studied the effect of selected compounds on cell viability, the effect on the number of G4s in cells, and their pharmacokinetic properties. This identified potent G4 ligands with suitable properties and further revealed that the dispersion component in arene–arene interactions in combination with electron-deficient electrostatics is central for the ligand to bind with the G4 efficiently. The presented design strategy can be applied in the further development of G4-ligands with suitable properties to explore G4s as therapeutic targets

    Exploring the Dispersion and Electrostatic Components in Arene–Arene Interactions between Ligands and G4 DNA to Develop G4-Ligands

    No full text
    G-Quadruplex (G4) DNA structures are important regulatory elements in central biological processes. Small molecules that selectively bind and stabilize G4 structures have therapeutic potential, and there are currently >1000 known G4 ligands. Despite this, only two G4 ligands ever made it to clinical trials. In this work, we synthesized several heterocyclic G4 ligands and studied their interactions with G4s (e.g., G4s from the c-MYC, c-KIT, and BCL-2 promoters) using biochemical assays. We further studied the effect of selected compounds on cell viability, the effect on the number of G4s in cells, and their pharmacokinetic properties. This identified potent G4 ligands with suitable properties and further revealed that the dispersion component in arene–arene interactions in combination with electron-deficient electrostatics is central for the ligand to bind with the G4 efficiently. The presented design strategy can be applied in the further development of G4-ligands with suitable properties to explore G4s as therapeutic targets

    Zemiology at the Border

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    Considering the global proliferation of the criminalisation of immigrants, it is unsurprising that criminological contributions to the study of borders have been expanding at a prolific rate. Academics and researchers from around the globe have levelled severe criticism of practices such as deportation, detention and arbitrary imprisonment. Indeed, this has been an interesting development to observe in a discipline which is often highly administrative. Significant though this is, the reality of more banal and grinding aspects of seeking asylum which are not necessarily linked to criminalisation - enforced welfare dependency, inadequate housing, violent relationships – often go unseen or under-focussed. Drawing from empirical research in Britain and reflecting on activist participation with women seeking asylum, this chapter argues for a zemiology at the border to centralise the concerns of people seeking sanctuary, and to document the everyday harms of asylum so that they might be mitigated or ultimately eradicated
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