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A dearomative oxidation of pyrroles to Δ3-pyrrol-2-ones is described, which employs a sulfoxide as oxidant, in conjunction with a carboxylic acid anhydride and a Brønsted acid additive. 3-substituted pyrroles undergo regioselective oxidation to give the product isomer in which oxygen has been introduced at the more hindered position. Regioselectivity is rationalized by a proposed mechanism that proceeds by initial thianthrenium introduction at the less-hindered pyrrole α-position, followed by distal attack of an oxygen nucleophile and subsequent elimination of thianthrene. The same reaction conditions are also able to effect a chemoselective oxidation of indoles to indolin-3-ones and additionally of indolin-3-ones to 2-hydroxyindolin-3-ones. Here again, the regio- and chemoselectivities are rationalized through the intermediacy of a thianthrenium salt.
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Small molecule donors (SMDs) play subtle roles in the signaling mechanism and disease treatments. While many excellent SMDs have been developed, dosage control, targeted delivery, spatiotemporal feedback, as well as the efficiency evaluation of small molecules are still key challenges. Accordingly, fluorescent small molecule donors (FSMDs) have emerged to meet these challenges. FSMDs enable controllable release and non-invasive real-time monitoring, providing significant advantages for drug development and clinical diagnosis. Integration of FSMDs with chemotherapeutic, photodynamic or photothermal properties can take full advantage of each mode to enhance therapeutic efficacy. Given the remarkable properties and the thriving development of FSMDs, we believe a review is needed to summarize the design, triggering strategies and tracking mechanisms of FSMDs. With this review, we compiled FSMDs for most small molecules (nitric oxide, carbon monoxide, hydrogen sulfide, sulfur dioxide, reactive oxygen species and formaldehyde), and discuss recent progress concerning their molecular design, structural classification, mechanisms of generation, triggered release, structure-activity relationships, and the fluorescence response mechanism. Firstly, from the large number of fluorescent small molecular donors available, we have organized the common structures for producing different types of small molecules, providing a general strategy for the development of FSMDs. Secondly, we have classified FSMDs in terms of the respective donor types and fluorophore structures. Thirdly, we discuss the mechanisms and factors associated with the controlled release of small molecules and the regulation of the fluorescence responses, from which universal guidelines for optical properties and structure rearrangement were established, mainly involving light-controlled, enzyme-activated, reactive oxygen species-triggered, biothiol-triggered, single-electron reduction, click chemistry, and other triggering mechanisms. Fourthly, representative applications of FSMDs for trackable release, and evaluation monitoring, as well as for visible in vivo treatment are outlined, to illustrate the potential of FSMDs in drug screening and precision medicine. Finally, we discuss the opportunities and remaining challenges for the development of FSMDs for practical and clinical applications, which we anticipate will stimulate the attention of researchers in the diverse fields of chemistry, pharmacology, chemical biology and clinical chemistry. With this review, we hope to impart new understanding thereby enabling the rapid development of the next generation of FSMDs.
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Colorantes Fluorescentes , Bibliotecas de Moléculas Pequeñas , Humanos , Colorantes Fluorescentes/química , Bibliotecas de Moléculas Pequeñas/química , Especies Reactivas de Oxígeno/metabolismo , Animales , Monóxido de Carbono/química , Monóxido de Carbono/metabolismoRESUMEN
The identification and detection of disease-related biomarkers is essential for early clinical diagnosis, evaluating disease progression, and for the development of therapeutics. Possessing the advantages of high sensitivity and selectivity, fluorescent probes have become effective tools for monitoring disease-related active molecules at the cellular level and in vivo. In this review, we describe current fluorescent probes designed for the detection and quantification of key bioactive molecules associated with common diseases, such as organ damage, inflammation, cancers, cardiovascular diseases, and brain disorders. We emphasize the strategies behind the design of fluorescent probes capable of disease biomarker detection and diagnosis and cover some aspects of combined diagnostic/therapeutic strategies based on regulating disease-related molecules. This review concludes with a discussion of the challenges and outlook for fluorescent probes, highlighting future avenues of research that should enable these probes to achieve accurate detection and identification of disease-related biomarkers for biomedical research and clinical applications.
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Biomarcadores , Colorantes Fluorescentes , Colorantes Fluorescentes/química , Humanos , Biomarcadores/análisis , Biomarcadores/metabolismo , Animales , Neoplasias/diagnóstico , Enfermedades Cardiovasculares/diagnóstico , Enfermedades Cardiovasculares/metabolismo , Inflamación/diagnóstico , Encefalopatías/diagnóstico , Encefalopatías/diagnóstico por imagenRESUMEN
Enzyme-based electrochemical biosensors play an important role in point-of-care diagnostics for personalized medicine. For such devices, lipid cubic phases (LCP) represent an attractive method to immobilize enzymes onto conductive surfaces with no need for chemical linking. However, research has been held back by the lack of effective strategies to stably co-immobilize enzymes with a redox shuttle that enhances the electrical connection between the enzyme redox center and the electrode. In this study, we show that a monoolein (MO) LCP system doped with an amphiphilic redox mediator (ferrocenylmethyl)dodecyldimethylammonium bromide (Fc12) can be used for enzyme immobilization to generate an effective biosensing platform. Small-angle X-ray scattering (SAXS) showed that MO LCP can incorporate Fc12 while maintaining the Pn3m symmetry morphology. Cyclic voltammograms of Fc12/MO showed quasi-reversible behavior, which implied that Fc12 was able to freely diffuse in the lipid membrane of LCP with a diffusion coefficient of 1.9 ± 0.2 × 10-8 cm2 s-1 at room temperature. Glucose oxidase (GOx) was then chosen as a model enzyme and incorporated into 0.2%Fc12/MO to evaluate the activity of the platform. GOx hosted in 0.2%Fc12/MO followed Michaelis-Menten kinetics toward glucose with a KM and Imax of 8.9 ± 0.5 mM and 1.4 ± 0.2 µA, respectively, and a linearity range of 2-17 mM glucose. Our results therefore demonstrate that GOx immobilized onto 0.2% Fc12/MO is a suitable platform for the electrochemical detection of glucose.
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Técnicas Biosensibles , Glucosa , Dispersión del Ángulo Pequeño , Difracción de Rayos X , Oxidación-Reducción , Glucosa Oxidasa/metabolismo , Enzimas Inmovilizadas/metabolismo , Técnicas Biosensibles/métodos , ElectrodosRESUMEN
The condensation of readily available O-substituted carbamates with 2,5-dimethoxytetrahydrofuran gives N-alkoxycarbonyl pyrroles in a single step and in good yield. By this method, several common amine protecting groups can be introduced on the pyrrole nitrogen. With the exception of N-Boc, N-alkoxycarbonyl groups have seen only minimal use for protection of the pyrrole nitrogen to date. Here, we show that N-alkoxycarbonyl protection can endow pyrrole with distinct reactivity in comparison with N-sulfonyl protection, for example, in a pyrrole acylation protocol employing carboxylic acids with a sulfonic acid anhydride activator.
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The non-benzenoid aromatic system azulene is sufficiently nucleophilic at C1 that it can react with a protonated aldehyde to form an α-azulenyl alcohol. This in turn may be protonated and undergo loss of water to give an azulene α-carbocation. We report the isolation of such azulenyl cations as salts with non-coordinating anions. The salts have been characterised by NMR, UV/Vis absorption and (in certain cases) X-ray crystallography. Reduction of representative salts to afford azulenyl(aryl) methylenes has been demonstrated.
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With synthetic cannabinoid receptor agonist (SCRA) use still prevalent across Europe and structurally advanced generations emerging, it is imperative that drug detection methods advance in parallel. SCRAs are a chemically diverse and evolving group, which makes rapid detection challenging. We have previously shown that fluorescence spectral fingerprinting (FSF) has the potential to provide rapid assessment of SCRA presence directly from street material with minimal processing and in saliva. Enhancing the sensitivity and discriminatory ability of this approach has high potential to accelerate the delivery of a point-of-care technology that can be used confidently by a range of stakeholders, from medical to prison staff. We demonstrate that a range of structurally distinct SCRAs are photochemically active and give rise to distinct FSFs after irradiation. To explore this in detail, we have synthesized a model series of compounds which mimic specific structural features of AM-694. Our data show that FSFs are sensitive to chemically conservative changes, with evidence that this relates to shifts in the electronic structure and cross-conjugation. Crucially, we find that the photochemical degradation rate is sensitive to individual structures and gives rise to a specific major product, the mechanism and identification of which we elucidate through density-functional theory (DFT) and time-dependent DFT. We test the potential of our hybrid "photochemical fingerprinting" approach to discriminate SCRAs by demonstrating SCRA detection from a simulated smoking apparatus in saliva. Our study shows the potential of tracking photochemical reactivity via FSFs for enhanced discrimination of SCRAs, with successful integration into a portable device.
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Agonistas de Receptores de Cannabinoides , Drogas Ilícitas , Humanos , Agonistas de Receptores de Cannabinoides/química , Sistemas de Atención de Punto , Detección de Abuso de Sustancias/métodosRESUMEN
Mixtures of sulfobetaine based lipids with phosphocholine phospholipids are of interest in order to study the interactions between zwitterionic surfactants and the phospholipids present in cell membranes. In this study we have investigated the structure of mixed monolayers of sulfobetaines and phosphocholine phospholipids. The sulfobetaine used has a single 18-carbon tail, and is referred to as SB3-18, and the phospholipid used is DMPC. Surface pressure-area isotherms of the samples were used to determine whether any phase transitions were present during the compression of the monolayers. Neutron and X-ray reflectometry were then used to investigate the structure of these monolayers perpendicular to the interface. We found that the average headgroup and tail layer thickness was reasonably consistent across all mixtures, with a variation of less than 3 Å reported in the total thickness of the monolayers at each surface pressure. However, by selective deuteration of the two components of the monolayers, it was found that the two components have different tail layer thicknesses. For the mixture with equal compositions of DMPC and SB3-18 or with a higher composition of DMPC the tail tilts were found to be constant, resulting in a greater tail layer thickness for SB3-18 due to its longer tail. For the mixture higher in SB3-18 this was not the case, the tail tilt angle for the two components was found to be different and DMPC was found to have a greater tail layer thickness than SB3-18 as a result.
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Fosfolípidos , Agua , Betaína/análogos & derivados , Carbono , Dimiristoilfosfatidilcolina/química , Fosfolípidos/química , Fosforilcolina , Propiedades de Superficie , Tensoactivos , Agua/químicaRESUMEN
AzuFluor® 435-DPA-Zn, an azulene fluorophore bearing two zinc(II)-dipicolylamine receptor motifs, exhibits fluorescence enhancement in the presence of adenosine diphosphate. Selectivity for ADP over ATP, AMP and PPi results from appropriate positioning of the receptor motifs, since an isomeric sensor cannot discriminate between ADP and ATP.
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Adenosina Difosfato/análisis , Azulenos/química , Colorantes Fluorescentes/química , Humanos , Estructura Molecular , Espectrometría de FluorescenciaRESUMEN
Small-molecule based fluorescent probes are increasingly important for the detection and imaging of biological signaling molecules due to their simplicity, high selectivity and sensitivity, whilst being non-invasive, and suitable for real-time analysis of living systems. With this perspective we highlight sensing mechanisms including Förster resonance energy transfer (FRET), intramolecular charge transfer (ICT), photoinduced electron transfer (PeT), excited state intramolecular proton transfer (ESIPT), aggregation induced emission (AIE) and multiple modality fluorescence approaches including dual/triple sensing mechanisms (DSM or TSM). Throughout the perspective we highlight the remaining challenges and suggest potential directions for development towards improved small-molecule fluorescent probes suitable for biosensing.
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A palladium-catalyzed domino arylation-cyclization of biocatalytically derived cyclic 1,3-dienes is demonstrated. The reaction introduces a high degree of structural complexity in a single step, giving access to tricyclic tetrahydrofluorenones with full regio- and stereoselectivity. The transformation proceeds through a novel acylation-terminated Heck-type sequence, and quantum chemical calculations indicate that C-H activation is involved in the terminating acylation step.
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Guaiazulene is an alkyl-substituted azulene available from natural sources and is a much lower cost starting material for the synthesis of azulene derivatives than azulene itself. Here we report an approach for the selective functionalisation of guaiazulene which takes advantage of the acidity of the protons on the guaiazulene C4 methyl group. The aldehyde produced by this approach constitutes a building block for the construction of azulenes substituted on the seven-membered ring. Derivatives of this aldehyde synthesised by alkenylation, reduction and condensation are reported, and the halochromic properties of a subset of these derivatives have been studied.
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Azulene is a hydrocarbon isomer of naphthalene known for its unusual colour and fluorescence properties. Through the harnessing of these properties, the literature has been enriched with a series of chemical sensors and dosimeters with distinct colorimetric and fluorescence responses. This review focuses specifically on the latter of these phenomena. The review is subdivided into two sections. Section one discusses turn-on fluorescent sensors employing azulene, for which the literature is dominated by examples of the unusual phenomenon of azulene protonation-dependent fluorescence. Section two focuses on fluorescent azulenes that have been used in the context of biological sensing and imaging. To aid the reader, the azulene skeleton is highlighted in blue in each compound.
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Azulenos/química , Técnicas Biosensibles , Imagenología Tridimensional , Fluorescencia , Modelos Moleculares , Polímeros/síntesis química , Polímeros/químicaRESUMEN
The functionalization of azulenes via reaction with cationic η5-iron carbonyl diene complexes under mild reaction conditions is demonstrated. A range of azulenes, including derivatives of naturally occurring guaiazulene, were investigated in reactions with three electrophilic iron complexes of varying electronic properties, affording the desired coupling products in 43-98% yield. The products were examined with UV-vis/fluorescence spectroscopy and showed interesting halochromic properties. Decomplexation and further derivatization of the products provide access to several different classes of 1-substituted azulenes, including a conjugated ketone and a fused tetracycle.
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Azulene is a bicyclic aromatic chromophore that absorbs in the visible region. Its absorption maximum undergoes a hypsochromic shift if a conjugated electron-withdrawing group is introduced at the C1 position. This fact can be exploited in the design of a colorimetric chemodosimeter that functions by the transformation of a dithioacetal to the corresponding aldehyde upon exposure to Hg2+ ions. This chemodosimeter exhibits good chemoselectivity over other metal cations, and responds with an unambiguous colour change clearly visible to the naked eye. Its synthesis is concise and its ease of use makes it appropriate in resource-constrained environments, for example in determing mercury content of drinking water sources in the developing world.
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This study provides an insight into the prevalence of (fluoro)quinolones (FQs) and their specific quinolone qnrS resistance gene in the Avon river catchment area receiving treated wastewater from 5 wastewater treatment plants (WWTPs), serving 1.5 million people and accounting for 75% of inhabitants living in the catchment area in the South West of England.. Ofloxacin, ciprofloxacin, nalidixic acid and norfloxacin were found to be ubiquitous with daily loads reaching a few hundred g/day in wastewater influent and tens of g/day in receiving waters. This was in contrast to other FQs analysed: flumequine, nadifloxacin, lomefloxacin, ulifloxacin, prulifloxacin, besifloxacin and moxifloxacin, which were hardly quantified. Enantiomeric profiling revealed that ofloxacin was enriched with the S-(-)-enantiomer, likely deriving from its prescription as the more potent enantiomerically pure levofloxacin, alongside racemic ofloxacin. While ofloxacin's enantiomeric fraction (EF) remained constant, high stereoselectivity was observed in the case of its metabolite ofloxacin-N-oxide. The removal efficiency of quinolones during wastewater treatment at 5 WWTPs utilising either trickling filters (TF) or activated sludge (AS), was compound and wastewater treatment process dependent, with AS providing better efficiency than TF. The qnrS resistance gene was ubiquitous in wastewater. Its removal was WWTP treatment process dependent with TF performing best and resulting in significant removal of the gene (from 28 to 75%). AS underperformed with only 9% removal in the case of activated sludge and actual increase in the gene copy number within sequencing batch reactors (SBRs). Interestingly, the data suggests that higher removal of antibiotics could be linked with high prevalence of the gene (SBR and WWTP E) and vice versa, low removal of antibiotic is correlated with lower prevalence of the gene in wastewater effluent (TF, WWTP B and D). This is especially prominent in the case of ofloxacin and could indicate that AS might be facilitating antimicrobial resistance (AMR) prevalence to higher extent than TF. Wastewater-based epidemiology (WBE) was also applied to monitor any potential misuse (e.g. direct disposal) of FQs in the catchment. In most cases higher use of antibiotics with respect to official statistics (i.e. ciprofloxacin, ofloxacin) was observed, which suggests that FQs management practice require further attention.
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Quinolonas , Contaminantes Químicos del Agua/análisis , Antibacterianos , Inglaterra , Fluoroquinolonas , Ríos , Aguas del Alcantarillado , Eliminación de Residuos Líquidos , Aguas ResidualesRESUMEN
Microbial arene oxidation of benzoic acid with Ralstonia eutropha B9 provides a chiral highly functionalized cyclohexadiene, suitable for further structural diversification. Subjecting this scaffold to a Pd-catalyzed Heck reaction effects a regio- and stereoselective arylation of the cyclohexadiene ring, with 1,3-chirality transfer of stereogenic information installed in the microbial arene oxidation. Quantum chemical calculations explain the selectivity both by a kinetic preference for the observed arylation position and by reversible carbopalladation in competing positions. Further product transformation allowed the formation of a tricyclic ketone possessing four stereogenic centers. This demonstrates the capability of the method to introduce stereochemical complexity from planar nonchiral benzoic acid in just a few steps.
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Cupriavidus necator/metabolismo , Ciclohexenos/síntesis química , Paladio/química , Benzoatos/química , Catálisis , Cupriavidus necator/química , Yodobencenos/química , Oxidación-Reducción , EstereoisomerismoRESUMEN
Colorimetry is an advantageous method for detecting fluoride in drinking water in a resource-limited context, e. g., in parts of the developing world where excess fluoride intake leads to harmful health effects. Here we report a selective colorimetric chemosensor for fluoride that employs an azulene as the reporter motif and a pinacolborane as the receptor motif. The chemosensor, NAz-6-Bpin, is prepared using the Nozoe azulene synthesis, which allows for its rapid and low-cost synthesis. The chemosensor gives a visually observable response to fluoride both in pure organic solvent and also in water/alcohol binary solvent mixtures.
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The natural product (+)-grandifloracin is a potent "anti-austerity" agent, able to suppress the ability of various pancreatic cancer cell lines to tolerate conditions of nutrient deprivation. Such anti-austerity agents represent a promising approach to cancer chemotherapy. Here we report the synthesis and biological evaluation of racemic analogues of grandifloracin bearing diverse sidechains, of which two show enhanced potency in comparison with the natural product. Additionally, several unexpected by-products containing modifications of the grandifloracin core were isolated, identified and similarly evaluated for biological activity.
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Antineoplásicos Fitogénicos/química , Hidrocarburos Aromáticos con Puentes/química , Antineoplásicos Fitogénicos/síntesis química , Antineoplásicos Fitogénicos/farmacología , Productos Biológicos/síntesis química , Productos Biológicos/química , Productos Biológicos/farmacología , Hidrocarburos Aromáticos con Puentes/síntesis química , Hidrocarburos Aromáticos con Puentes/farmacología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Cristalografía por Rayos X , Humanos , Conformación Molecular , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , EstereoisomerismoRESUMEN
Two-photon fluorescence microscopy has become an indispensable technique for cellular imaging. Whereas most two-photon fluorescent probes rely on well-known fluorophores, here we report a new fluorophore for bioimaging, namely azulene. A chemodosimeter, comprising a boronate ester receptor motif conjugated to an appropriately substituted azulene, is shown to be an effective two-photon fluorescent probe for reactive oxygen species, showing good cell penetration, high selectivity for peroxynitrite, no cytotoxicity, and excellent photostability.