Synthesis of novel Iron(III) chelators based on triaza macrocycle backbone and 1-hydroxy-2(H)-pyridin-2-one coordinating groups and their evaluation as antimicrobial agents

AbstractSeveral novel chelators based on 1-hydroxy-2(1H)-pyridinone coordinating groups decorating a triaza macrocyclic backbone scaffold were synthesised as potential powerful Fe3+ chelators capable of competing with bacterial siderophores. In particular, a novel chloromethyl derivative of 1-hydroxy-2(1H)-pyridinone exploiting a novel protective group for this family of coordinating groups was developed. These are the first examples of hexadentate chelators based on 1-hydroxy-2(1H)-pyridinone to be shown to have a biostatic activity against a range of pathogenic bacteria. Their efficacy as biostatic agents was assessed revealing that minor variations in the structure of the chelator can affect efficacy profoundly. The minimal inhibitory concentrations of our best tested novel chelators approach or are comparable to those for 1,4,7-tris(3-hydroxy-6-methyl-2-pyridylmethyl)-1,4,7-triazacyclononane, the best Fe3+ chelator known to date. The retarding effect these chelators have on microbial growth suggests that they could have a potential application as a co-active alongside antibiotics in the fight against infections

Novel 1-hydroxypyridin-2-one metal chelators prevent and res-cue ubiquitin proteasomal-related neuronal injury in an in vitro model of Parkinson’s disease

Ubiquitin proteasome system (UPS) impairment, excessive cellular oxidative stress and iron dyshomeostasis are key to substantia nigra dopaminergic neuronal de-generation in Parkinson's disease (PD); however, a link between these features remains unconfirmed. By using the proteasome inhibitor lactacystin we confirm that nigral injury via UPS impairment disrupts iron homeostasis, in turn increasing oxi-dative stress and promoting protein aggregation. We demonstrate the neuroprotec-tive potential of two novel 1-hydroxy-2(1H)-pyridinone (1,2-HOPO) iron chelators, compounds C6 and C9, against lactacystin-induced cell death. We demonstrate that this cellular preservation relates to the compounds’ iron chelating capabilities and subsequent reduced capacity of iron to form reactive oxygen species (ROS), where we also show that the ligands act as antioxidant agents. Our results also de-monstrate the ability of C6 and C9 to reduce intracellular lactacystin-induced α-synuclein burden. Stability constant measurements confirmed a high affinity of C6 and C9 for Fe3+ and display a 3:1 HOPO:Fe3+ complex formation at physiological pH. Reducing iron reactivity could prevent the demise of nigral dopaminergic neurons. We provide evidence that the lactacystin model presents with several neuropatho-logical hallmarks of PD related to iron dyshomeostasis and that the novel chelating compounds C6 and C9 can protect against lactacystin-related neurotoxicity

Gender and release from imprisonment: Convict licensing systems in mid to late 19th century England

This paper draws on the research undertaken into the lives and prison experiences of around 650 male and female convicts who were released on licence (an early form of parole) from sentences of long term imprisonment (three years to life) in England in the mid- to late-nineteenth century. Our project confirmed the patterns of offending seen in other studies of female and male offending, namely, that women were committed to periods of long-term imprisonment overwhelmingly for crimes of larceny and sometimes low-level violence (or their criminal backgrounds indicated this type of low-level disorderly behaviour) and only in the minority for crimes of serious interpersonal violence. Similarly, the majority of men were also committed to the convict system for larceny. Yet how male and female offenders were treated by the prison licensing system did differ significantly. The vast majority of all prisoners, male and female, were released early on licence from their prison terms, even those who had committed very serious offences. All licences had several conditions in them and licence-holders were free so long as they met these conditions. Any breach of the above conditions meant that the individual would be returned to prison to serve out the remainder of their sentence.However, a proportion of female offenders were released slightly earlier than their male counterparts, though not directly into the community but on a conditional licence to Female Refuges. Out of the 288 women researched in our project, 200 of them were released in this manner; under further confinement in a refuge. Women stayed in such refuges for on average between six and nine months, before their final release was then approved by the Directors of the Convict Prisons

"Monstrous and indefensible"? Newspaper accounts of sexual assaults on children in nineteenth-century England and Wales

This material has been published in Women's Criminality in Europe, 1600–1914 edited by Edited by Manon van der Heijden, Marion Pluskota, Sanne Muurling, https://doi.org/10.1017/9781108774543. This version is free to view and download for private research and study only. Not for re-distribution or re-use. © 2020 Cambridge University Press.Popular crime reportage of sexual violence has a long history in England. Despite the fact that from the 1830s onwards newspapers and periodicals – and sometimes even law reports – were increasingly liable to skim over the reporting of sexual offences as ‘unfit for publication’, this does not mean that such reportage vanished entirely. Instead, certain linguistic codes and euphemisms were invoked to maintain a respectable discourse. Given the serious problems with gaps in the surviving archival record for modern criminal justice, newspapers remain an essential tool for understanding the history of sexual violence in nineteenth century England and Wales. Using keyword searches in digitized newspaper databases such as the British Newspaper Archive and Welsh Newspapers Database, this chapter examines the continuities and changes in the reporting of sexual violence against children between 1800 and 1900, and explores what these euphemisms and elisions reveal about attitudes to gender and crime in nineteenth-century England and Wales.Peer reviewe

Herbicide Metabolism: Crop Selectivity, Bioactivation, Weed Resistance, and Regulation

Several grass and broadleaf weed species around the world have evolved multiple-herbicide resistance at alarmingly increasing rates. Research on the biochemical and molecular resistance mechanisms of multiple-resistant weed populations indicate a prevalence of herbicide metabolism catalyzed by enzyme systems such as cytochrome P450 monooxygenases and glutathione S-transferases and, to a lesser extent, by glucosyl transferases. A symposium was conducted to gain an understanding of the current state of research on metabolic resistance mechanisms in weed species that pose major management problems around the world. These topics, as well as future directions of investigations that were identified in the symposium, are summarized herein. In addition, the latest information on selected topics such as the role of safeners in inducing crop tolerance to herbicides, selectivity to clomazone, glyphosate metabolism in crops and weeds, and bioactivation of natural molecules is reviewed

Design and evaluation of bi-functional iron chelators for protection of dopaminergic neurons from toxicants

International audienceWhile the etiology of non-familial Parkinson's disease (PD) remains unclear, there is evidence that increased levels of tissue iron may be a contributing factor. Moreover, exposure to some environmental toxicants is considered an additional risk factor. Therefore, brain-targeted iron chelators are of interest as antidotes for poisoning with dopaminergic toxicants, and as potential treatment of PD. We, therefore, designed a series of small molecules with high affinity for ferric iron and containing structural elements to allow their transport to the brain via the neutral amino acid transporter, LAT1 (SLC7A5). Five candidate molecules were synthesized and initially characterized for protection from ferroptosis in human neurons. The promising hydroxypyridinone SK4 was characterized further. Selective iron chelation within the physiological range of pH values and uptake by LAT1 were confirmed. Concentrations of 10-20 mu M blocked neurite loss and cell demise triggered by the parkinsonian neurotoxicants, methyl-phenyl-pyridinium (MPP+) and 6-hydroxydopamine (6-OHDA) in human dopaminergic neuronal cultures (LUHMES cells). Rescue was also observed when chelators were given after the toxicant. SK4 derivatives that either lacked LAT1 affinity or had reduced iron chelation potency showed altered activity in our assay panel, as expected. Thus, an iron chelator was developed that revealed neuroprotective properties, as assessed in several models. The data strongly support the role of iron in dopaminergic neurotoxicity and suggests further exploration of the proposed design strategy for improving brain iron chelation

Autour de l’enfant : la ronde des professionnels

Un des trait marquants de l’enfance irrégulière et de son traitement depuis le XIXe siècle est la progressive agrégation de nombreux acteurs qui surveillent, jugent, soignent, pansent, observent, rapportent, instruisent, éduquent… Ce numéro de la Revue d’histoire de l’enfance « irrégulière » confronte des études sur quelques-uns d’entre eux. Il est l’occasion de faire un état des connaissances, de lancer des pistes de recherche, de questionner des professions moins ou pas étudiées jusque-là, mais aussi de comparer des dynamiques professionnelles ainsi que des modes de professionnalisation qui varient d’un pays l’autre

Protection from neurodegeneration in the 6-hydroxydopamine (6-OHDA) model of Parkinson's with novel 1-hydroxypyridin-2-one metal chelators

Brain iron accumulation has been associated with inciting the generation of oxidative stress in a host of chronic neurological diseases, including Parkinson's disease. Using the catecholaminergic neurotoxin 6-hydroxydopamine to lesion cellular dopaminergic pathways as a model of Parkinson's disease in culture, a selection of 1-hydroxypyridin-2-one (1,2-HOPO) metal chelators were synthesized and their neuroprotective properties were compared to the 3-hydroxypyridin-4-one; deferiprone (3,4-HOPO; DFP). Protection against 6-OHDA and iron insult by the novel compounds 6 and 9 was comparable to DFP. Iron associated changes by 6-OHDA imply that the neuroprotective capacity of these compounds are due to chelation of the neuronal labile iron pool and the requirement of the iron binding moiety of compound 6 for efficacy supported this hypothesis. In conclusion, two novel 1,2-HOPO's and DFP have comparable neuroprotection against Parkinsonian-associated neurotoxins and supports the continued development of hydroxypyridinone compounds as a non-toxic therapeutic agent in the treatment of neurodegenerative disease