Pillar5arenes are 1(5)paracyclophane derivatives consisting of 1,4-disubstituted hydroquinones linked by methylene bridges in the 2,5-positions. The first report of these novel macrocycles was in ...2008, when 1,4-dimethoxypillar5arene was prepared in 22% yield, and subsequent improvements in synthetic methods have allowed the number of derivatives to expand significantly. In addition to D(5) symmetric pillar5arenes, asymmetric pillar5arenes with two different substituents in the 1- and 4-positions and copillar5arenes consisting of two different repeat units in a 4 : 1 ratio have been synthesised. Crystallographic, computational and spectroscopic studies are starting to shed light on the compounds' unusual inclusion phenomena, from gelation and transportation of water through nanotubes to the formation of chromogenic rotaxanes. Applications as molecular sensors are starting to appear with a focus on guest detection by fluorescence quenching. This tutorial review will provide a summary of research into the pillar5arenes since their recent discovery.
Midbrain dopaminergic neurons are essential for appropriate voluntary movement, as epitomized by the cardinal motor impairments arising in Parkinson’s disease. Understanding the basis of such motor ...control requires understanding how the firing of different types of dopaminergic neuron relates to movement and how this activity is deciphered in target structures such as the striatum. By recording and labeling individual neurons in behaving mice, we show that the representation of brief spontaneous movements in the firing of identified midbrain dopaminergic neurons is cell-type selective. Most dopaminergic neurons in the substantia nigra pars compacta (SNc), but not in ventral tegmental area or substantia nigra pars lateralis, consistently represented the onset of spontaneous movements with a pause in their firing. Computational modeling revealed that the movement-related firing of these dopaminergic neurons can manifest as rapid and robust fluctuations in striatal dopamine concentration and receptor activity. The exact nature of the movement-related signaling in the striatum depended on the type of dopaminergic neuron providing inputs, the striatal region innervated, and the type of dopamine receptor expressed by striatal neurons. Importantly, in aged mice harboring a genetic burden relevant for human Parkinson’s disease, the precise movement-related firing of SNc dopaminergic neurons and the resultant striatal dopamine signaling were lost. These data show that distinct dopaminergic cell types differentially encode spontaneous movement and elucidate howdysregulation of their firing in early Parkinsonism can impair their effector circuits.
Supramolecular chemistry is often described as the study of chemistry beyond the simple molecular level yet it is often forgotten how many of the pioneering su-pramolecular chemists looked to ...molecular biology for their ideas. The search for an aldolase enzyme mimic, the discovery of crown ethers that transported potas-sium as efficiently as valinomycin, and the synthesis of an antitubercular com-pound that resembled a transmembrane protein, all point to a biological inspira-tion. Since the field emerged in the last quarter of the 20th Century, advances in the synthesis of multifunctional molecules, coupled to a greater understanding of biological processes at the molecular level, have led supramolecular chemists to design compounds that not only mimic those in Nature but also have diagnostic and therapeutic applications. The book opens with an overview of supramolecular chemistry. In subsequent chapters parallels are drawn with biological phenomena: the formation of proteins and other biomolecules, the evolution of cells, and the design of channel-forming molecules and enzymes. The application of supramolecular principles to sensors and magic bullet therapies is explained and the future of supramolecular therapeutics is considered. The exciting combination of supramolecular chemistry and nanotechnology is discussed together with the likelihood that nanoengineered smart materials could one day circulate in the body to treat patients before they became aware of any symptoms. Supramolecular Chemistry: From Biological Inspiration to Biomedical Applications is aimed at postgraduates working at the chemistry/life science interface and final year undergraduate advanced options in supramolecular chemistry. It is hoped that it will also be of value to academics and professionals interested in the relevance of supramolecular chemistry to biology and vice versa.
Calixarenes and related macrocycles have been shown to have antimicrobial effects since the 1950s. This review highlights the antimicrobial properties of almost 200 calixarenes, resorcinarenes, and ...pillararenes acting as prodrugs, drug delivery agents, and inhibitors of biofilm formation. A particularly important development in recent years has been the use of macrocycles with substituents terminating in sugars as biofilm inhibitors through their interactions with lectins. Although many examples exist where calixarenes encapsulate, or incorporate, antimicrobial drugs, one of the main factors to emerge is the ability of functionalized macrocycles to engage in multivalent interactions with proteins, and thus inhibit cellular aggregation.
Macrocyclic chemistry has provided chemists with a wealth of molecular ‘hosts’. Ever since resurgence in the field during the 1970s and 1980s these hosts’ similarities to natural structures, such the ...active sites of enzymes, have been noted. Latterly there has been great interest in the recently reported pillarnarenes. As if to underline the importance of these compounds, exciting applications are starting to emerge, from electrochemical sensors to antimicrobial agents. Novel uses appear destined to have an impact on clinical conditions from Alzheimer's disease to cancer treatment. In order to demonstrate the impact of pillarnarenes across the chemistry‐biology interface this review will cover the current state of the art from biomimicry and analyte‐specific detection to emerging clinical applications. Examples include pillarnarene‐based ion channels, enzyme‐responsive compounds, imaging agents, biofilm inhibiting derivatives, drug complexing and drug releasing systems.
The detection and monitoring of lithium in environmental and clinical settings is becoming increasingly important. In this review, sensors incorporating conductive polymers and lithium bronzes are ...discussed, together with electrochemical and spectroscopic approaches. Ionophore-based methods have been employed extensively, with varying degrees of selectivity and sensitivity, and these are discussed in depth.
The pathological end-state of Parkinson disease is well described from postmortem tissue, but there remains a pressing need to define early functional changes to susceptible neurons and circuits. In ...particular, mechanisms underlying the vulnerability of the dopamine neurons of the substantia nigra pars compacta (SNc) and the importance of protein aggregation in driving the disease process remain to be determined. To better understand the sequence of events occurring in familial and sporadic Parkinson disease, we generated bacterial artificial chromosome transgenic mice (SNCA -OVX) that express wild-type α-synuclein from the complete human SNCA locus at disease-relevant levels and display a transgene expression profile that recapitulates that of endogenous α-synuclein. SNCA -OVX mice display age-dependent loss of nigrostriatal dopamine neurons and motor impairments characteristic of Parkinson disease. This phenotype is preceded by early deficits in dopamine release from terminals in the dorsal, but not ventral, striatum. Such neurotransmission deficits are not seen at either noradrenergic or serotoninergic terminals. Dopamine release deficits are associated with an altered distribution of vesicles in dopaminergic axons in the dorsal striatum. Aged SNCA -OVX mice exhibit reduced firing of SNc dopamine neurons in vivo measured by juxtacellular recording of neurochemically identified neurons. These progressive changes in vulnerable SNc neurons were observed independently of overt protein aggregation, suggesting neurophysiological changes precede, and are not driven by, aggregate formation. This longitudinal phenotyping strategy in SNCA -OVX mice thus provides insights into the region-specific neuronal disturbances preceding and accompanying Parkinson disease.
Orthogonal chemistry is a valuable tool in the preparation of complex molecules as heteroglycoclusters. Unfortunately, selective heteroconjugation of multifunctional starting materials remains a ...usually challenging problem to overcome. Herein, we report the first report on harnessing N‐alkylation of N‐acylhydrazone as a key step in the orthogonal synthesis. Sequentially associated with the azido‐alkyne click chemistry, it stands out as a new and straightforward synthetic method of glycoconjugate small molecules, heterodisaccharides, and heteroglycoclusters based on cone p‐tBu‐calix4arene and 1,3‐alt p‐tBu‐thiacalix4arene with potential drug‐like properties.
We report a new orthogonal strategy involving the N‐alkylation of N‐acylhydrazone as a key step. When followed by azido‐alkyne click chemistry, it represents a new and straightforward synthetic method to prepare N‐alkyl‐NAH glycoconjugates of small molecules, heterodisaccharides, and heteroglycoclusters‐based on cone p‐tBu‐calix4arene and 1,3‐alt p‐tBu‐thiacalix4arene with potential drug‐like properties.
Striatal dopamine (DA) is critical for action and learning. Recent data show that DA release is under tonic inhibition by striatal GABA. Ambient striatal GABA tone on striatal projection neurons can ...be determined by plasma membrane GABA uptake transporters (GATs) located on astrocytes and neurons. However, whether striatal GATs and astrocytes determine DA output are unknown. We reveal that DA release in mouse dorsolateral striatum, but not nucleus accumbens core, is governed by GAT-1 and GAT-3. These GATs are partly localized to astrocytes, and are enriched in dorsolateral striatum compared to accumbens core. In a mouse model of early parkinsonism, GATs are downregulated, tonic GABAergic inhibition of DA release augmented, and nigrostriatal GABA co-release attenuated. These data define previously unappreciated and important roles for GATs and astrocytes in supporting DA release in striatum, and reveal a maladaptive plasticity in early parkinsonism that impairs DA output in vulnerable striatal regions.
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![[1]Rotaxanes based on phosp...](http://api.summon.serialssolutions.com/2.0.0/image/issn/XR4PS5YY4K/1369-9261_1144-0546/small "[1]Rotaxanes based on phosphorylated pillar[5]arenes")