RESUMO
The use of controlled precursors for reaction optimisation is not always practical. One approach to limiting the use of controlled substances is to instead use 'model compounds'. Herein, two model compounds resembling norephedrine and ephedrine were selected based on their (i) structural similarity (i.e., presence of key functional groups) and (ii) availability from multiple suppliers without restriction. Model compounds 2-amino-1-phenylethanol and 2-(methylamino)-1-phenylethanol (halostachine), were compared to norephedrine and pseudoephedrine by firstly subjecting them to transformations known in the synthesis of amphetamines, and secondly, comparing the compounds using colourimetric spot tests, FTIR and NMR.
Assuntos
Anfetaminas , Estimulantes do Sistema Nervoso Central , Espectroscopia de Ressonância Magnética , Espectroscopia de Infravermelho com Transformada de Fourier , Anfetaminas/química , Estimulantes do Sistema Nervoso Central/química , Humanos , Efedrina/química , Colorimetria , Fenilpropanolamina/química , Pseudoefedrina/química , Modelos QuímicosRESUMO
Herein the synthesis of 1,8-naphthalimides functionalised as the 3,4-dihydroxy-1,8-naphthalimide (catechol, Nap-Cat) and the corresponding 15-crown-5 (Nap-Crown) is reported. These compounds represent the first examples where these two recognition groups are directly incorporated into the 1,8-naphthalimide ring system. Both Nap-Cat and Nap-Crown were evaluated for their capacity to respond to analytes such as H2O2 (a mimic for cellular oxidation) and metal ions (as elements of environmental and physiological interest). While slow oxidation was observed for Nap-Cat upon prolonged exposure to H2O2, no significant changes in photophysical properties were observed upon treatment of Nap-Crown with metal ions.
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Antibiotic proliferation in the environment and their persistent nature is an issue of global concern as they induce antibiotic resistance threatening both human health and the ecosystem. Antibiotics have therefore been categorized as emerging pollutants. Fluoroquinolone (FQs) antibiotics are an emerging class of contaminants that are used extensively in human and veterinary medicine. The recalcitrant nature of fluoroquinolones has led to their presence in wastewater, effluents and water bodies. Even at a low concentration, FQs can stimulate antibacterial resistance. The main sources of FQ contamination include waste from pharmaceutical manufacturing industries, hospitals and households that ultimately reaches the wastewater treatment plants (WWTPs). The conventional WWTPs are unable to completely remove FQs due to their chemical stability. Therefore, the development and implementation of more efficient, economical, convenient treatment and removal technologies are needed to adequately address the issue. This review provides an overview of the technologies available for the removal of fluoroquinolone antibiotics from wastewater including adsorptive removal, advanced oxidation processes, removal using non-carbon based nanomaterials, microbial degradation and enzymatic degradation. Each treatment technology is discussed on its merits and limitations and a comparative view is presented on the choice of an advanced treatment process for future studies and implementation. A discussion on the commercialization potential and eco-friendliness of each technology is also included in the review. The importance of metabolite identification and their residual toxicity determination has been emphasized. The last section of the review provides an overview of the policy interventions and regulatory frameworks that aid in retrofitting antibiotics as a central key focus contaminant and thereby defining the discharge limits for antibiotics and establishing safe manufacturing practices.
Assuntos
Ecossistema , Poluentes Químicos da Água , Antibacterianos , Fluoroquinolonas/análise , Humanos , Tecnologia , Eliminação de Resíduos Líquidos , Águas Residuárias/análise , Poluentes Químicos da Água/análiseRESUMO
Methodology to access fluorescent 3-amido-1,8-naphthalimides using direct Buchwald-Hartwig amidation is described. The protocol was successfully used to couple a number of substrates (including an alkylamide, an arylamide, a lactam and a carbamate) to 3-bromo-1,8-naphthalimide in good yield. To further exemplify the approach, a set of scriptaid analogues with amide substituents at the 3-position were prepared. The new compounds were more potent than scriptaid at a number of histone deacetylase (HDAC) isoforms including HDAC6. Activity was further confirmed in a whole cell tubulin deacetylation assay where the inhibitors were more active than the established HDAC6 selective inhibitor Tubastatin. The optical properties of these new, highly active, compounds make them amenable to cellular imaging studies and theranostic applications.
Assuntos
Inibidores de Histona Desacetilases/química , Hidroxilaminas/química , Naftalenos/química , Quinolinas/química , Acetilação , Amidas/química , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/metabolismo , Ácidos Hidroxâmicos/farmacologia , Indóis/farmacologia , Naftalimidas/químicaRESUMO
An intracellular fluorescence competition assay was developed to assess the capability of inhibitor candidates to engage histone deacetylase (HDAC) inside living cells and thus diminish cell uptake and staining by the HDAC-targeted fluorescent probe APS. Fluorescence cell microscopy and flow cytometry showed that pre-incubation of living cells with candidate inhibitors led to diminished cell uptake of the fluorescent probe. The assay was effective because the fluorescent probe (APS) possessed the required performance properties, including bright fluorescence, ready membrane diffusion, selective intracellular HDAC affinity, and negligible acute cytotoxicity. The concept of an intracellular fluorescence competition assay is generalizable and has broad applicability since it obviates the requirement to use the isolated biomacromolecule target for screening of molecular candidates with target affinity.
Assuntos
Fluorescência , Corantes Fluorescentes/farmacologia , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/metabolismo , Células A549 , Relação Dose-Resposta a Droga , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/química , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/química , Humanos , Microscopia de Fluorescência , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
The real-time observation of chemical bond formation at the single-molecule level is one of the great challenges in the fields of organic and biomolecular chemistry. Valuable information can be gleaned that is not accessible using ensemble-average measurements. Although remarkably sophisticated techniques for monitoring chemical reactions have been developed, the ability to detect the specific formation of a chemical bond in situ at the single-molecule level has remained an elusive goal. Amide bonds are routinely formed from the aminolysis of N-hydroxysuccinimide (NHS) esters by primary amines, and the protocol is widely used for the synthesis, cross-linking, and labeling of peptides and proteins. Herein, a plasmonic nanocavity was applied to study aminolysis reaction for amide bond formation, which was initiated by single nanoparticle collision events between suitably functionalized free-moving gold nanoparticles and a gold nanoelectrode in an aqueous buffer. By means of simultaneous surface enhanced Raman spectroscopy (SERS) and single-entity electrochemistry (EC) measurements, we have probed the dynamic evolution of amide bond formation in the aminolysis reaction with 10 s of millisecond time resolution. Hence, we demonstrate that single-entity EC-SERS is a valuable and sensitive technique by which chemical reactions can be studied at the single-molecule level.
RESUMO
An efficient and functional group tolerant route to access hydroxy 1,8-naphthalimides has been used to synthesise a range of mono- and disubstituted hydroxy-1,8-naphthalimides with fluorescence emissions covering the visible spectrum. The dialkoxy substituted compounds prepared possess high quantum yields (up to 0.95) and long fluorescent lifetimes (up to 14 ns). The method has been used to generate scriptaid analogues that successfully inhibit HDAC6 in vitro with tubulin acetylation assays confirming that these compounds are more effective than tubastatin.
Assuntos
Desacetilase 6 de Histona/antagonistas & inibidores , Inibidores de Histona Desacetilases/farmacologia , Naftalimidas/farmacologia , Tubulina (Proteína)/metabolismo , Células A549 , Acetilação/efeitos dos fármacos , Cor , Fluorescência , Inibidores de Histona Desacetilases/química , Humanos , Naftalimidas/químicaRESUMO
A fluorescent, naphthalimide-based, NADH mimic has been synthesised as a reversible, biocompatible, "on-off" probe for the detection of changes in intracellular redox environment (both oxidation and reduction). Interconversion was confirmed by means of electrochemistry and also 1H NMR, UV-vis and fluorescence spectroscopy. The reversibility was also successfully detected in A549 cells under simulated redox stress.
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Candida albicans is one of the most prevalent fungal pathogens involved in hospital acquired infections. It binds to glycans at the surface of epithelial cells and initiates infection. This process can be blocked by synthetic carbohydrates that mimic the structure of cell surface glycans. Herein we report the evaluation of a series of divalent glycosides featuring aromatic (benzene, squaramide) and bicyclic aliphatic (norbornene) scaffolds, with the latter being the first examples of their kind as small molecule anti-adhesion glycoconjugates. Galactosides 1 and 6, built on an aromatic core, were most efficient inhibitors of adhesion of C. albicans to buccal epithelial cells, displacing up to 36% and 48%, respectively, of yeast already attached to epithelial cells at 138 µM. Remarkably, cis-endo-norbornene 21 performed comparably to benzene-core derivatives. Conformational analysis reveals a preference for compounds 1 and 21 to adopt folded conformations. These results highlight the potential of norbornenes as a new class of aliphatic scaffolds for the synthesis of anti-adhesion compounds.
RESUMO
Fluorescent scriptaid analogues with excellent HDAC6 selectivity (HDAC1/6â¯>â¯500) and potency (HDAC6 IC50â¯<â¯5â¯nM) have been synthesised and evaluated. The highly fluorescent nature of the compounds (up to ΦFâ¯=â¯0.83 in DMSO and 0.38 in aqueous buffer) makes them ideally suited for cellular imaging and visualisation of their cytoplasmic localisation was readily accomplished. Whole organism imaging in zebrafish confirmed both the vascular localisation of the new inhibitors and the impact of HDAC6 inhibition on in vivo development.
Assuntos
Desacetilase 6 de Histona/antagonistas & inibidores , Hidroxilaminas/química , Quinolinas/química , Animais , Vasos Sanguíneos/diagnóstico por imagem , Vasos Sanguíneos/metabolismo , Citoplasma/metabolismo , Diagnóstico por Imagem/métodos , Fluorescência , Inibidores de Histona Desacetilases/farmacocinética , Inibidores de Histona Desacetilases/uso terapêutico , Hidroxilaminas/síntese química , Hidroxilaminas/farmacocinética , Quinolinas/síntese química , Quinolinas/farmacocinética , Peixe-Zebra/metabolismoRESUMO
The design, synthesis and evaluation of a small series of potent amphiphilic norbornane antibacterial agents has been performed (compound 10 MICâ¯=â¯0.25⯵g/mL against MRSA). Molecular modelling indicates rapid aggregation of this class of antibacterial agent prior to membrane association and insertion. Two fluorescent analogues (compound 29 with 4-amino-naphthalimide and 34 with 4-nitrobenz-2-oxa-1,3-diazole fluorophores) with good activity (MICâ¯=â¯0.5⯵g/mL against MRSA) were also constructed and confocal microscopy studies indicate that the primary site of interaction for this family of compounds is the bacterial membrane.
Assuntos
Antibacterianos/farmacologia , Peptídeos Catiônicos Antimicrobianos/farmacologia , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Norbornanos/farmacologia , Peptidomiméticos/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Peptídeos Catiônicos Antimicrobianos/síntese química , Peptídeos Catiônicos Antimicrobianos/química , Membrana Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Staphylococcus aureus Resistente à Meticilina/citologia , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Norbornanos/química , Peptidomiméticos/síntese química , Peptidomiméticos/química , Relação Estrutura-AtividadeRESUMO
Phenylalanine functionalised norbornene (9:Na) functions as a potent, low molecular-mass (MW = 333 Da) ionic organogelator with a minimum gelating concentration of 0.5 wt% in THF, i-PrOH, 1,4-dioxane and n-BuOH. Fibrous crystals form in the gel and X-ray crystallography identified a cation mediated helical assembly process controlled by the chirality of the phenylalanine. In addition to excellent gelating properties 9:Na readily forms aqueous biphasic and triphasic systems.
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Drugs that recapitulate aspects of the exercise adaptive response have the potential to provide better treatment for diseases associated with physical inactivity. We previously observed reduced skeletal muscle class IIa HDAC (histone deacetylase) transcriptional repressive activity during exercise. Here, we find that exercise-like adaptations are induced by skeletal muscle expression of class IIa HDAC mutants that cannot form a corepressor complex. Adaptations include increased metabolic gene expression, mitochondrial capacity, and lipid oxidation. An existing HDAC inhibitor, Scriptaid, had similar phenotypic effects through disruption of the class IIa HDAC corepressor complex. Acute Scriptaid administration to mice increased the expression of metabolic genes, which required an intact class IIa HDAC corepressor complex. Chronic Scriptaid administration increased exercise capacity, whole-body energy expenditure and lipid oxidation, and reduced fasting blood lipids and glucose. Therefore, compounds that disrupt class IIa HDAC function could be used to enhance metabolic health in chronic diseases driven by physical inactivity.
Assuntos
Proteínas Correpressoras/metabolismo , Metabolismo Energético , Histona Desacetilases/metabolismo , Metabolismo dos Lipídeos , Animais , Domínio Catalítico , Linhagem Celular , Metabolismo Energético/efeitos dos fármacos , Metabolismo Energético/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Hidroxilaminas/administração & dosagem , Hidroxilaminas/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Metabolismo dos Lipídeos/genética , Fatores de Transcrição MEF2/genética , Fatores de Transcrição MEF2/metabolismo , Camundongos , Mutação/genética , Oxirredução , Condicionamento Físico Animal , Ligação Proteica/efeitos dos fármacos , Quinolinas/administração & dosagem , Quinolinas/farmacologia , Transcrição Gênica/efeitos dos fármacosRESUMO
Research using 1,8-naphthalimide derivatives has expanded rapidly in recent years owing to their cell-permeable nature, ability to target certain cellular locations and fluorescent properties. Here we describe the synthesis of three new esters of 4-hydroxy-N-propyl-1,8-naphthalimide (NAP) and the development of a simple and sensitive assay protocol to measure the activity of carboxylester hydrolases. The NAP fluorophore was esterified with short (butyrate), medium (octanoate) and long (palmitate) chain fatty acids. The esters were spectroscopically characterised and their properties investigated for their suitability as assay substrates. The esters were found to be relatively stable under the conditions of the assay and levels of spontaneous hydrolysis were negligible. Non-specific hydrolysis by proteins such as bovine serum albumin was also minimal. A simple and rapid assay methodology was developed and used to analyse a range of commercially available enzymes that included enzymes defined as lipases, esterases and phospholipases. Clear differences were observed between the enzyme classes with respect to the hydrolysis of the various chain length esters, with lipases preferentially hydrolysing the medium chain ester, whereas esterases reacted more favourably with the short ester. The assay was found to be highly sensitive with the fluorophore detectable to the low nM range. These esters provide alternate substrates from established coumarin-based fluorophores, possessing distinctly different excitation (447 nm) and emission (555 nm) optima. Absorbing at 440-450 nm also offers the flexibility of analysis by UV-visible spectrophotometry. This represents the first instance of a naphthalimide-derived compound being used to analyse these enzymes.
Assuntos
Esterases/metabolismo , Ésteres/química , Fluorescência , Lipase/metabolismo , Naftalimidas/química , Ascomicetos/enzimologia , Proteínas de Bactérias/metabolismo , Candida/enzimologia , Hidrolases de Éster Carboxílico/química , Hidrolases de Éster Carboxílico/metabolismo , Esterases/química , Ácidos Graxos/química , Ácidos Graxos/metabolismo , Corantes Fluorescentes/química , Proteínas Fúngicas/metabolismo , Cinética , Lipase/química , Pseudomonas fluorescens/enzimologia , EspectrofotometriaRESUMO
The synthesis of a centrally functionalized, ribbon-shaped [6]polynorbornane ligand L that self-assembles with Pd(II) cations into a {Pd2 L4 } coordination cage is reported. The shape-persistent {Pd2 L4 } cage contains two axial cationic centers and an array of four equatorial H-bond donors pointing directly towards the center of the cavity. This precisely defined supramolecular environment is complementary to the geometry of classic octahedral complexes [M(XY)6 ] with six diatomic ligands. Very strong binding of [Pt(CN)6 ](2-) to the cage was observed, with the structure of the host-guest complex {[Pt(CN)6 ]@Pd2 L4 } supported by NMR spectroscopy, MS, and X-ray data. The self-assembled shell imprints its geometry on the encapsulated guest, and desymmetrization of the octahedral platinum species by the influence of the D4h -symmetric second coordination sphere was evidenced by IR spectroscopy. [Fe(CN)6 ](3-) and square-planar [Pt(CN)4 ](2-) were strongly bound. Smaller octahedral anions such as [SiF6 ](2-) , neutral carbonyl complexes ([M(CO)6 ]; M=Cr, Mo, W) and the linear [Ag(CN)2 ](-) anion were only weakly bound, showing that both size and charge match are key factors for high-affinity binding.
Assuntos
Exoesqueleto Energizado , Cristalografia por Raios X , Modelos MolecularesRESUMO
Selectivity is demonstrated in a supramolecular host:guest system using a receptor with a non-linear binding site. For the "open" receptor 1 strong binding for both flexible and rigid guests was observed. Receptor 2, with a "blocked" binding site, also bound flexible guests effectively but its affinity for rigid guests was 50 fold lower.
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The local inflammatory environment of the cell promotes the growth of epithelial cancers. Therefore, controlling inflammation locally using a material in a sustained, non-steroidal fashion can effectively kill malignant cells without significant damage to surrounding healthy cells. A promising class of materials for such applications is the nanostructured scaffolds formed by epitope presenting minimalist self-assembled peptides; these are bioactive on a cellular length scale, while presenting as an easily handled hydrogel. Here, we show that the assembly process can distribute an anti-inflammatory polysaccharide, fucoidan, localized to the nanofibers within the scaffold to create a biomaterial for cancer therapy. We show that it supports healthy cells, while inducing apoptosis in cancerous epithelial cells, as demonstrated by the significant down-regulation of gene and protein expression pathways associated with epithelial cancer progression. Our findings highlight an innovative material approach with potential applications in local epithelial cancer immunotherapy and drug delivery.
Assuntos
Apoptose , Citocinas , Alicerces Teciduais , Materiais Biocompatíveis , Sistemas de Liberação de Medicamentos , Regulação da Expressão Gênica , Humanos , Hidrogéis , Nanofibras , Neoplasias Epiteliais e GlandularesRESUMO
Incorporating phenylpyridine- and triazolylpyridine-based ligands decorated with methylsulfonate or tetraethylene glycol (TEG) groups, a series of iridium(III) complexes has been created for green and blue electrogenerated chemiluminescence under analytically useful aqueous conditions, with tri-n-propylamine as a coreactant. The relative electrochemiluminescence (ECL) intensities of the complexes were dependent on the sensitivity of the photodetector over the wavelength range and the pulse time of the applied electrochemical potential. In terms of the integrated area of corrected ECL spectra, with a pulse time of 0.5 s, the intensities of the Ir(III) complexes were between 18 and 102 % that of [Ru(bpy)3 ](2+) (bpy=2,2'-bipyridine). However, when the intensities were measured with a typical bialkali photomultiplier tube, the signal of the most effective blue emitter, [Ir(df-ppy)2 (pt-TEG)](+) (df-ppy=2-(2,4-difluorophenyl)pyridine anion, pt-TEG=1-(2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)ethyl)-4-(2-pyridyl)-1,2,3-triazole), was over 1200 % that of the orange-red emitter [Ru(bpy)3 ](2+) . A combined experimental and theoretical investigation of the electrochemical and spectroscopic properties of the Ir(III) complexes indicated that the greater intensity from [Ir(df-ppy)2 (pt-TEG)](+) relative to those of the other Ir(III) complexes resulted from a combination of many factors, rather than being significantly favored in one area.
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A small series of norbornane bisether diguanidines have been synthesized and evaluated as antibacterial agents. The key transformation-bisalkylation of norbornane diol 6-was not successful using Williamson methodology but has been accomplished using Ag2O mediated alkylation. Further functionalization to incorporate two guanidinium groups gave rise to a series of structurally rigid cationic amphiphiles; several of which (16d, 16g and 16h) exhibited antibiotic activity. For example, compound 16d was active against a broad range of bacteria including Pseudomonas aeruginosa (MIC = 8 µg/mL), Escherichia coli (MIC = 8 µg/mL) and methicillin-resistant Staphylococcus aureus (MIC = 8 µg/mL).
RESUMO
A range of solid-state NMR techniques is used to characterise a molecular host:guest complex consisting of a [5]polynorbornane bisurea host binding a terephthalate dianion guest. Detailed information is obtained on the molecular dynamics and associations from the point of view of both the host and guest molecules. The formation of the complex in the solid state is confirmed using (1)H 2D exchange NMR, and the 180° flipping of the (2)H-labelled terephthalate guest and its eventual expulsion from the complex at elevated temperatures are quantified using variable-temperature (2)H spin-echo experiments. Two-dimensional (1)H-(13)C HETCOR spectra obtained under fast magic angle spinning conditions (60 kHz) show a high resolution despite the poor crystallinity of the solid complex, and clearly reveal changes in the rigidity of the host molecule when complexed. Short-range intra- and intermolecular (1)H-(1)H proximities are also detected using 2D SQ-DQ correlation methods, providing insight into the molecular packing in the solid phase.