Recent updates and future perspectives in aziridine synthesis and reactivity.

In this review, selected recent advances in the preparation and reactivity of aziridines using modern synthetic approaches are highlighted, while comparing these new strategies with more classical approaches. This critical analysis is designed to help identify current gaps in the field and is showcasing new and exciting opportunities to move the chemistry of aziridines forward in the future.

Design, Synthesis, and Biological Evaluation of Potent 20S Proteasome Activators for the Potential Treatment of α-Synucleinopathies.

While neurodegenerative diseases affect millions of patients worldwide, there are insufficient available therapeutics to halt or slow down the progression of these diseases. A key pathological feature of several neurodegenerative diseases is the oligomerization and aggregation of specific intrinsically disordered proteins (IDPs) creating neuronal deposits, such as Lewy bodies in Parkinson's disease. Clearance of these pathogenic, aggregation-prone IDPs is mediated by the 20S isoform of the human proteasome. Thus, enhancing the 20S proteasome-mediated proteolysis could be a very useful therapeutic pathway to prevent neurotoxicity. Here, we report the successful development of sub-microM 20S proteasome activators based on a phenothiazine scaffold. This class of compounds prevented the accumulation of pathologically relevant IDPs, such as the pathogenic A53T mutated α-synuclein, in vitro and in mammalian cell lines.

Acylated and alkylated benzo(crown-ethers) form ion-dependent ion channels in biological membranes.

Synthetic ion channels based on benzo(crown-ether) compounds have been previously reported to function as ion-selective channels in planar lipid bilayers, with hydrogen bonding networks implicated in the formation of self-aggregated complexes. Herein, we report the synthesis and characterization of two new families of benzo(crown-ether) compounds, termed monoacylated and monoalkylated benzo(crown-ethers) (MABCE), both of which lack hydrogen bond donors. Depending on the length of alkyl chain substituent and the size of macrocycle, MABCE compounds inhibit bacterial growth and transport ions across biological membranes. Single-channel recordings show that the activity is higher in the presence of K+ as compared with Na+; however, under bionic conditions, open channels do not exhibit any preference between the two ions. These findings reveal that the ionic preference of benzo(crown-ether) compounds is either due to the regulation of assembly of ion-conducting supramolecular complexes or its membrane insertion by cations, as opposed to ion-selective transport through these scaffolds. Furthermore, our data show that the H-bonding network is not needed to form these assemblies in the membrane.

Behavioral and Socioemotional Outcomes of the Legacy for Children™ Randomized Control Trial to Promote Healthy Development of Children Living in Poverty, 4 to 6 Years Postintervention.

OBJECTIVE: The objective of this article was to assess the impact on behavioral and socioemotional development, 4 to 6 years postintervention (depending on the curriculum), of Legacy for Children™, a public health approach to improve child developmental outcomes among families living in poverty. METHODS: Mothers who were recruited prenatally or at the time of childbirth participated in a set of Legacy parallel design randomized control trials between 2001 and 2009 in Miami, Florida, or Los Angeles, California. Of the initial 574 mother-child dyads, 364 completed at least 1 behavioral or socioemotional outcome measure at the third-grade follow-up. Intention-to-treat analyses compared Legacy and comparison groups on behavioral and socioemotional outcomes. RESULTS: Children of Legacy mothers in Los Angeles were at lower risk for externalizing behaviors and poor adaptive skills than children whose mothers did not participate in the intervention. No significant outcome differences by group assignment were found in Miami. CONCLUSION: Group-based positive parenting interventions such as Legacy may have a sustained impact on children's behavioral and socioemotional development several years after intervention completion.

Transport losses in market weight pigs: II. U.S. incidence and economic impact.

An industry survey representing approximately 310 million (M) market weight pigs was conducted with 20 U.S. slaughter facilities over the calendars years of 2012 to 2015 to determine the incidence, seasonal patterns, and estimated economic impact of dead and non-ambulatory pigs. Each plant entered daily totals in a secure online database for the following variables: 1) pigs slaughtered, 2) dead on arrival (DOA; dead on the truck), 3) euthanized on arrival (EOA; non-ambulatory pig with an injury that required euthanasia), 4) dead in pen (DIP; died after unloading), and 5) non-ambulatory (pig unable to move or keep up with the rest of the group from unloading to stunning). Total dead pigs were calculated as DOA + EOA + DIP, and total losses were calculated as non-ambulatory + total dead. The economic impact was estimated based on the 4-yr weighted averages from USDA annual reports for market swine slaughtered (108,470,550 pigs), live market weight (126.9 kg), and live market price ($1.44/kg). The 4-yr weighted averages for total dead, non-ambulatory, and total losses were 0.26%, 0.63%, and 0.88%, respectively. Total dead consisted of 0.15% DOA, 0.05% EOA, and 0.05% DIP. The months with the highest rates of total dead were July (0.29%), August (0.32%), and September (0.30%), while the lowest incidence rates occurred in February (0.22%), March (0.22%), and April (0.22%). The months with the highest rates of non-ambulatory pigs were observed during the months of October (0.70%), November (0.71%), and December (0.70%), whereas the lowest rates of non-ambulatory pigs were observed during the months of April (0.57%), May (0.53%), and June (0.54%). The following assumptions were used in the economic analysis: 1) dead pigs received no value and 2) non-ambulatory pigs were discounted 30%. Based on these assumptions, the annual cost to the industry for dead and non-ambulatory pigs was estimated to be $52 M ($0.48 per pig marketed) and $37 M ($0.35 per pig marketed), respectively. Therefore, total losses represent approximately $89 M in economic losses or $0.83 per pig marketed. This is the first industry-wide survey on the incidence of transport losses in market weight pigs at U.S. slaughter facilities, and this information is important for establishing an industry baseline and benchmark for transport losses that can be used for measuring industry improvements.

Exploiting in situ NMR to monitor the formation of a metal-organic framework.

The formation processes of metal-organic frameworks are becoming more widely researched using in situ techniques, although there remains a scarcity of NMR studies in this field. In this work, the synthesis of framework MFM-500(Ni) has been investigated using an in situ NMR strategy that provides information on the time-evolution of the reaction and crystallization process. In our in situ NMR study of MFM-500(Ni) formation, liquid-phase 1H NMR data recorded as a function of time at fixed temperatures (between 60 and 100 °C) afford qualitative information on the solution-phase processes and quantitative information on the kinetics of crystallization, allowing the activation energies for nucleation (61.4 ± 9.7 kJ mol-1) and growth (72.9 ± 8.6 kJ mol-1) to be determined. Ex situ small-angle X-ray scattering studies (at 80 °C) provide complementary nanoscale information on the rapid self-assembly prior to MOF crystallization and in situ powder X-ray diffraction confirms that the only crystalline phase present during the reaction (at 90 °C) is phase-pure MFM-500(Ni). This work demonstrates that in situ NMR experiments can shed new light on MOF synthesis, opening up the technique to provide better understanding of how MOFs are formed.

Proteasome Activation to Combat Proteotoxicity.

Loss of proteome fidelity leads to the accumulation of non-native protein aggregates and oxidatively damaged species: hallmarks of an aged cell. These misfolded and aggregated species are often found, and suggested to be the culpable party, in numerous neurodegenerative diseases including Huntington's, Parkinson's, Amyotrophic Lateral Sclerosis (ALS), and Alzheimer's Diseases (AD). Many strategies for therapeutic intervention in proteotoxic pathologies have been put forth; one of the most promising is bolstering the efficacy of the proteasome to restore normal proteostasis. This strategy is ideal as monomeric precursors and oxidatively damaged proteins, so called "intrinsically disordered proteins" (IDPs), are targeted by the proteasome. This review will provide an overview of disorders in proteins, both intrinsic and acquired, with a focus on susceptibility to proteasomal degradation. We will then examine the proteasome with emphasis on newly published structural data and summarize current known small molecule proteasome activators.

Pipecolic esters as minimized templates for proteasome inhibition.

Allosteric regulators of clinically important enzymes are gaining popularity as alternatives to competitive inhibitors. This is also the case for the proteasome, a major intracellular protease and a target of anti-cancer drugs. All clinically used proteasome inhibitors bind to the active sites in catalytic chamber and display a competitive mechanism. Unfortunately, inevitable resistance associated with this type of inhibition drives the search for non-competitive agents. The multisubunit and multicatalytic "proteolytic machine" such as the proteasome is occasionally found to be affected by agents with other primary targets. For example the immunosuppressive agent rapamycin has been shown to allosterically inhibit the proteasome albeit at levels far higher than its mTOR related efficacy. As part of an ongoing program to search for novel proteasome-targeting pharmacophores, we identified the binding domain of rapamycin as required for proteasome inhibition even without the macrocyclic context of the parent compound. By subsequent structure-activity relationship studies, we generated a pipecolic ester derivative compound 3 representing a new class of proteasome inhibitors. Compound 3 affects the core proteasome activities and proliferation of cancer cells with low micromolar/high nanomolar efficacy. Molecular modeling, atomic force microscopy imaging and biochemical data suggest that compound 3 binds into one of intersubunit pockets in the proteasomal α ring and destabilizes the α face and the gate. The α face is used as a docking area for proteasome-regulating protein modules and the gate is critical for controlling access to the catalytic chamber. Thus, the pipecolic ester template elicits a new and attractive mechanism for proteasome inhibition distinct from classical competitive drugs.

Small Molecule Modulation of Proteasome Assembly.

The 20S proteasome is the main protease that directly targets intrinsically disordered proteins (IDPs) for proteolytic degradation. Mutations, oxidative stress, or aging can induce the buildup of IDPs resulting in incorrect signaling or aggregation, associated with the pathogenesis of many cancers and neurodegenerative diseases. Drugs that facilitate 20S-mediated proteolysis therefore have many potential therapeutic applications. We report herein the modulation of proteasome assembly by the small molecule TCH-165, resulting in an increase in 20S levels. The increase in the level of free 20S corresponds to enhanced proteolysis of IDPs, including α-synuclein, tau, ornithine decarboxylase, and c-Fos, but not structured proteins. Clearance of ubiquitinated protein was largely maintained by single capped proteasome complexes (19S-20S), but accumulation occurs when all 19S capped proteasome complexes are depleted. This study illustrates the first example of a small molecule capable of targeting disordered proteins for degradation by regulating the dynamic equilibrium between different proteasome complexes.

MOF the beaten track: unusual structures and uncommon applications of metal-organic frameworks.

Over the past few decades, metal-organic frameworks (MOFs) have proved themselves as strong contenders in the world of porous materials, standing alongside established classes of compounds such as zeolites and activated carbons. Following extensive investigation into the porosity of these materials and their gas uptake properties, the MOF community are now branching away from these heavily researched areas, and venturing into unexplored avenues. Ranging from novel synthetic routes to post-synthetic functionalisation of frameworks, host-guest properties to sensing abilities, this review takes a sidestep away from increasingly 'traditional' approaches in the field, and details some of the more curious qualities of this relatively young family of materials.

Small Molecule Enhancement of 20S Proteasome Activity Targets Intrinsically Disordered Proteins.

The 20S proteasome is the main protease for the degradation of oxidatively damaged and intrinsically disordered proteins. When accumulation of disordered or oxidatively damaged proteins exceeds proper clearance in neurons, imbalanced pathway signaling or aggregation occurs, which have been implicated in the pathogenesis of several neurological disorders. Screening of the NIH Clinical Collection and Prestwick libraries identified the neuroleptic agent chlorpromazine as a lead agent capable of enhancing 20S proteasome activity. Chemical manipulation of chlorpromazine abrogated its D2R receptor binding affinity while retaining its ability to enhance 20S mediated proteolysis at low micromolar concentrations. The resulting small molecule enhancers of 20S proteasome activity induced the degradation of intrinsically disordered proteins, α-synuclein, and tau but not structured proteins. These small molecule 20S agonists can serve as leads to explore the therapeutic potential of 20S activation or as new tools to provide insight into the yet unclear mechanics of 20S-gate regulation.

Investigating the geometrical preferences of a flexible benzimidazolone-based linker in the synthesis of coordination polymers.

A series of new group 2 coordination polymers, MgL ={MgL(H2O)(DMF)0.75}∞, CaL = {CaL(DMF)2}∞, SrL = {SrL(H2O)0.5}∞ and BaL = {BaL(H2O)0.5}∞, were synthesized using a flexible benzimidazolone diacetic acid linker (H2L) in which the two carboxylic acid binding sites are connected to a planar core via {-CH2-} spacers that can freely rotate in solution. In a 'curiosity-led' diversion from group 2 metals, the first row transition metal salts Mn2+, Cu2+ and Zn2+ were also reacted with L to yield crystals of MnL = {MnL(DMF)(H2O)3.33}∞, Cu3L2 = {Cu3L2(DMF)2(CHO2)2}∞ and ZnL = {ZnL(DMF)}∞. Crystal structures were obtained for all seven materials. All structures form as two-dimensional sheets and contain six-coordinate centres, with the exception of ZnL, which displays tetrahedrally coordinated metal centres, and Cu3L2 , which contains square planar coordinated metal centres and Cu paddle-wheels. In each structure, the linker adopts one of two distinct conformations, with the carboxylate groups either cis or trans with respect to the planar core. All materials were also characterized by powder X-ray diffraction and thermogravimetric analysis.

Hydroxyamination of olefins using Br-N-(CO2Me)2.

The hydroxyamination reagent Br-N-(CO2Me)2 underwent Markovnikov addition to various olefins in the presence of catalytic BF3·OEt2 and provides efficient access to aminoalcohols. The reaction provided the trans-1-bromo, 2-N-bis-carbamate adduct stereoisomer in all cases. The resulting adduct underwent cyclization to give an oxazolidinone, which could be readily hydrolyzed to an oxazolidin-2-one or an amino alcohol.