This review paper covers the major synthetic approaches attempted towards the synthesis of α-azido ketones, as well as the synthetic applications/consecutive reactions of α-azido ketones.
A series of glycolipid crown ether analogs was prepared by bis-propargylation of lauryl glycoside followed by subsequent click-coupling with ethylene glycol-based diazides. The triazole-linked macrocycles were obtained in remarkable high yields. While the surfactant assembly was affected by presence of sodium ions, suggesting the formation of complexes, no ion-selectivity was observed for the macrocylic ligands. Computational studies suggest a low but significant cation-binding activity of the macrocycle, involving coordination at both oxygen and nitrogen atoms.
Aiming for new glycolipids with enhanced chemical stability and close structural similarity to natural cell membrane lipids for the development of a drug delivery system, we have synthesized double amide analogs of glyco-glycerolipids. The synthesis applied a Staudinger reaction based coupling of a 1,3-diazide with fatty acid chlorides. While the concept furnished the desired glucosides in reasonable yields, the corresponding lactosides formed a tetrahydropyrimidine based 1:1 coupling product instead. This unexpected coupling result likely originates from steric hindrance at the iminophosphorane intermediate and provides an interesting core structure for potentially bioactive surfactants. The assembly behavior of both glycolipid types was investigated by optical polarizing microscopy, DSC and surface tension studies.
The copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction has proven to be a pivotal advance in chemical ligation strategies with applications ranging from polymer fabrication to bioconjugation. However, application in vivo has been limited by the inherent toxicity of the copper catalyst. Herein, we report the application of heterogeneous copper catalysts in azide-alkyne cycloaddition processes in biological systems ranging from cells to zebrafish, with reactions spanning from fluorophore activation to the first reported in situ generation of a triazole-containing anticancer agent from two benign components, opening up many new avenues of exploration for CuAAC chemistry.
Aiming for glycolipid-based vesicles for targeted drug delivery, cationic Guerbet glycosides with spacered click functionality were designed and synthesized. The cationic charge promoted the distribution of the glycolipids during the formulation, thereby leading to homogeneously small vesicles. The positive surface charge of the vesicles stabilizes them against unwanted fusion and promotes interactions of the drug carriers with typical negative charge-dominated target cells. High bioconjugation potential of the functionalized glycolipids based on the copper-catalyzed azide alkyne cycloaddition makes them highly valuable components for targeted drug delivery systems.
Poly(N-isopropylacrylamide) (PNIPA) brushes on silicon substrate was constructed and molecular weight and polydispersity index was controlled precisely. Molecular behavior of the PNIPA grafted surface was observed by using captive bubble contact angle method. A very interesting phenomenon of high density PNIPA grafted membrane with a chloride terminal molecule was observed. The contact angle of high density PNIPA-Cl increased sharply while the temperature rises above 32oC. But in the case of PNIPA gel surface the contact angle result decreases sharply while the temperature reaches above lower critical solution temperature (LCST). In order to identify the reason behind this abnormal behavior of PNIPA-Cl grafted membrane, the terminal chloride molecule of PNIPA chain was modified to less electronegative azide (-N3) as well as carboxylic acid (-COOH). Finally it was found that terminal molecule of high density PNIPA grafted membrane has a great influences on the wettability change of PNIPA membrane in water by changing the temperature.
Corn-cob cellulose supported poly(hydroxamic acid) Cu(II) complex was prepared by the surface modification of waste corn-cob cellulose through graft copolymerization and subsequent hydroximation. The complex was characterized by IR, UV, FESEM, TEM, XPS, EDX and ICP-AES analyses. The complex has been found to be an efficient catalyst for 1,3-dipolar Huisgen cycloaddition (CuAAC) of aryl/alkyl azides with a variety of alkynes as well as one-pot three-components reaction in the presence of sodium ascorbate to give the corresponding cycloaddition products in up to 96% yield and high turn over number (TON 18,600) and turn over frequency (TOF 930h-1) were achieved. The complex was easy to recover from the reaction mixture and reused six times without significant loss of its catalytic activity.
New thiosemicarbazide derivatives 2-6 were synthesised by reacting 2-(ethylsulfanyl)benzohydrazide with various aryl isothiocyanates. The cyclisation of compounds 2-6 under reflux conditions in a basic medium (aqueous NaOH, 4 N) yielded compounds 7-11 that contain a 1,2,4-triazole ring. All of the synthesised compounds were screened for their antioxidant activities. Compounds 2, 3, and 7 showed better radical scavenging in a 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay, with IC50 values of 1.08, 0.22, and 0.74 µg/mL, respectively, compared to gallic acid (IC50, 1.2 µg/mL). Compound 3 also showed superior results in a ferric reducing antioxidant power (FRAP) assay (3054 µM/100 g) compared to those of ascorbic acid (1207 µM/100 g).
The effects of azide on electron transport of exoelectrogens were investigated using air-cathode MFCs. These MFCs enriched with azide at the concentration higher than 0.5mM generated lower current and coulomb efficiency (CE) than the control reactors, but at the concentration lower than 0.2mM MFCs generated higher current and CE. Power density curves showed overshoot at higher azide concentrations, with power and current density decreasing simultaneously. Electrochemical impedance spectroscopy (EIS) showed that azide at high concentration increased the charge transfer resistance. These analyses might reflect that a part of electrons were consumed by the anode microbial population rather than transferred to the anode. Bacterial population analyses showed azide-enriched anodes were dominated by Deltaproteobacteria compared with the controls. Based on these results it is hypothesized that azide can eliminate the growth of aerobic respiratory bacteria, and at the same time is used as an electron acceptor/sink.
This study aimed to detect the presence of enterococci in the root canals of untreated and treated teeth with periapical disease and to compare this to their presence in the saliva and in the immediate surgical environment during root canal treatment. Using an aseptic technique, 33 samples were obtained from 27 untreated and 6 previously treated teeth associated with apical periodontitis. Reduced Transport Fluid (RTF) was used as transport medium. Saliva samples and areas in the surgical environment were also sampled. These were performed prior to chemo-mechanical debrjdement and obturation for every case. The saliva was diluted to 10- J and was plated on Bile Aesculin Azide (BEA) agar whereas the rest of the samples were plated on Bile Aesculin (BE) agar. These plates were then incubated aerobically at 37°C for 48 hours. All the colony types that blackened the agar were sub-cultured to obtain pure isolates and tested on 6.5% sodium chloride (NaCI). Growth on this medium was Gram stained for further confirmation of cell morphology. Gram positive cocci isolated from previous positive test were identified as enterococci. Enterococci were recovered from untreated cases only; from 2 teeth (in 2 patients) prior to chemo-mechanical debridement, from 3 teeth (in 3 patients) prior to obturation and I from saliva sample. A 'total of 5 samples from 5 different patients were positive for enteroco•cci. Sampling in the immediate surgical environment revealed a low occurence in the range of3.0% (1/33) to 15_2% (5/33). In conclusion, the occurence of enterococci in patients and the immediate surgical environment was low number.
Decellularized native extracellular matrix (ECM) biomaterials are widely used in tissue engineering and have reached clinical application as biomesh implants. To enhance their regenerative properties and postimplantation performance, ECM biomaterials could be functionalized via immobilization of bioactive molecules. To facilitate ECM functionalization, we developed a metabolic glycan labeling approach using physiologic pathways to covalently incorporate click-reactive azide ligands into the native ECM of a wide variety of rodent tissues and organs in vivo, and into the ECM of isolated rodent and porcine lungs cultured ex vivo. The incorporated azides within the ECM were preserved after decellularization and served as chemoselective ligands for subsequent bioconjugation via click chemistry. As proof of principle, we generated alkyne-modified heparin, immobilized it onto azide-incorporated acellular lungs, and demonstrated its bioactivity by Antithrombin III immobilization and Factor Xa inhibition. The herein reported metabolic glycan labeling approach represents a novel platform technology for manufacturing click-reactive native ECM biomaterials, thereby enabling efficient and chemoselective functionalization of these materials to facilitate tissue regeneration and repair.
Silver diamine fluoride (SDF) is commonly used to arrest caries lesions, especially in early childhood caries. Recently, it was suggested that SDF can be combined with potassium iodide (KI) to minimize the discoloration of demineralized dentine associated with SDF application. However, the antibacterial efficacy of SDF alone or combined with KI on in-situ biofilm is unknown. Hence, we compared the anti-plaque biofilm efficacy of two different commercially available SDF solutions, with or without KI, using an in-situ biofilm, analysed using viability real-time PCR with propidium monoazide (PMA). Appliance-borne in-situ biofilm samples (n = 90) were grown for a period of 6 h in five healthy subjects who repeated the experiment on three separate occasions, using a validated, novel, intraoral device. The relative anti-biofilm efficacy of two SDF formulations; 38.0% Topamine (SDFT) and 31.3%, Riva Star (SDFR), KI alone, and KI in combination with SDFR (SDFR+KI) was compared. The experiments were performed by applying an optimized volume of the agents onto the biofilm for 1min, mimicking the standard clinical procedure. Afterwards the viability of the residual biofilm bacteria was quantified using viability real-time PCR with PMA, then the percentage of viable from total bacteria was calculated. Both SDF formulations (SDFT and SDFR) exhibited potent antibacterial activities against the in-situ biofilm; however, there was non-significant difference in their efficacy. KI alone did not demonstrate any antibacterial effect, and there was non-significant difference in the antibacterial efficacy of SDF alone compared to SDF with KI, (SDFT v SDFR/KI). Thus, we conclude that the antibacterial efficacy of SDF against plaque biofilms is not modulated by KI supplements. Viability real-time PCR with PMA was successfully used to analyze the viability of naturally grown oral biofilm; thus, the same method can be used to test the antimicrobial effect of other agents on oral biofilms in future research.
Novel treatments against migraine are an urgent medical requirement. The α6 subunit-containing GABAA receptors (α6GABAARs) are expressed in trigeminal ganglia (TG), the hub of the trigeminal vascular system (TGVS) that is involved in the pathogenesis of migraine. Here we reveal an unprecedented role of α6GABAARs in ameliorating TGVS activation using several pharmacological approaches in an animal model mimicking pathological changes in migraine. TGVS activation was induced by intra-cisternal (i.c.) instillation of capsaicin in Wistar rats. Centrally, i.c. capsaicin activated the trigeminal cervical complex (TCC) measured by the increased number of c-Fos-immunoreactive (c-Fos-ir) TCC neurons. Peripherally, it elevated calcitonin gene-related peptide immunoreactivity (CGRP-ir) in TG and depleted CGRP-ir in the dura mater. Pharmacological approaches included a recently identified α6GABAAR-selective positive allosteric modulator (PAM), the pyrazoloquinolinone Compound 6, two α6GABAAR-active PAMs (Ro15-4513 and loreclezole), an α6GABAAR-inactive benzodiazepine (diazepam), an α6GABAAR-selective antagonist (furosemide), and a clinically effective antimigraine agent (topiramate). We examined effects of these compounds on both central and peripheral TGVS responses induced by i.c. capsaicin. Compound 6 (3-10 mg/kg, i.p.) significantly attenuated the TCC neuronal activation and TG CGRP-ir elevation, and dural CGRP depletion induced by capsaicin. All these effects of Compound 6 were mimicked by topiramate, Ro15-4513 and loreclezole, but not by diazepam. The brain-impermeable furosemide antagonized the peripheral, but not central, effects of Compound 6. These results suggest that the α6GABAAR in TG is a novel drug target for TGVS activation and that α6GABAAR-selective PAMs have the potential to be developed as a novel pharmacotherapy for migraine.