Access to 8-Azabicyclo[3,2,1]octanes via the [3 + 2] Cycloaddition of Oxidopyridinium Ions to Maleimides.

Herein, we reported a unique and operationally simple method to assemble 8-azabicyclo[3,2,1]octanes by using oxidopyridinium ions and maleimides as synthons. The features of good to high yields and good functional group tolerance are achieved regularly under mild conditions. Of note, oxidopyridinium ions undergo a [3 + 2] cycloaddition on their C2 and C6 positions.

Structure-activity relationship of pyrazol-4-yl-pyridine derivatives and identification of a radiofluorinated probe for imaging the muscarinic acetylcholine receptor M4.

There is an accumulating body of evidence implicating the muscarinic acetylcholine receptor 4 (M4) in schizophrenia and dementia with Lewy bodies, however, a clinically validated M4 positron emission tomography (PET) radioligand is currently lacking. As such, the aim of this study was to develop a suitable M4 PET ligand that allows the non-invasive visualization of M4 in the brain. Structure-activity relationship studies of pyrazol-4-yl-pyridine derivates led to the discovery of target compound 12 - a subtype-selective positive allosteric modulator (PAM). The radiofluorinated analogue, [18F]12, was synthesized in 28 ± 10% radiochemical yield, >37 GBq/µmol and an excellent radiochemical purity >99%. Initial in vitro autoradiograms on rodent brain sections were performed in the absence of carbachol and showed moderate specificity as well as a low selectivity of [18F]12 for the M4-rich striatum. However, in the presence of carbachol, a significant increase in tracer binding was observed in the rat striatum, which was reduced by >60% under blocking conditions, thus indicating that orthosteric ligand interaction is required for efficient binding of [18F]12 to the allosteric site. Remarkably, however, the presence of carbachol was not required for high specific binding in the non-human primate (NHP) and human striatum, and did not further improve the specificity and selectivity of [18F]12 in higher species. These results pointed towards significant species-differences and paved the way for a preliminary PET study in NHP, where peak brain uptake of [18F]12 was found in the putamen and temporal cortex. In conclusion, we report on the identification and preclinical development of the first radiofluorinated M4 PET radioligand with promising attributes. The availability of a clinically validated M4 PET radioligand harbors potential to facilitate drug development and provide a useful diagnostic tool for non-invasive imaging.

A novel monoacylglycerol lipase-targeted 18F-labeled probe for positron emission tomography imaging of brown adipose tissue in the energy network.

Monoacylglycerol lipase (MAGL) constitutes a serine hydrolase that orchestrates endocannabinoid homeostasis and exerts its function by catalyzing the degradation of 2-arachidonoylglycerol (2-AG) to arachidonic acid (AA). As such, selective inhibition of MAGL represents a potential therapeutic and diagnostic approach to various pathologies including neurodegenerative disorders, metabolic diseases and cancers. Based on a unique 4-piperidinyl azetidine diamide scaffold, we developed a reversible and peripheral-specific radiofluorinated MAGL PET ligand [18F]FEPAD. Pharmacokinetics and binding studies on [18F]FEPAD revealed its outstanding specificity and selectivity towards MAGL in brown adipose tissue (BAT) - a tissue that is known to be metabolically active. We employed [18F]FEPAD in PET studies to assess the abundancy of MAGL in BAT deposits of mice and found a remarkable degree of specific tracer binding in the BAT, which was confirmed by post-mortem tissue analysis. Given the negative regulation of endocannabinoids on the metabolic BAT activity, our study supports the concept that dysregulation of MAGL is likely linked to metabolic disorders. Further, we now provide a suitable imaging tool that allows non-invasive assessment of MAGL in BAT deposits, thereby paving the way for detailed mechanistic studies on the role of BAT in endocannabinoid system (ECS)-related pathologies.

Current status of carbazole hybrids as anticancer agents.

The drug resistance and low specificity of current available chemotherapeutics to cancer cells are the main reasons responsible for the failure of cancer chemotherapy and remain dramatic challenges for cancer therapy, creating an urgent need to develop novel anticancer agents. Carbazole nucleus, widely distributed in nature, is a predominant feature of a vast array of biologically active compounds. Carbazole derivatives exhibited potential antiproliferative activity against different cancer cell lines by diverse mechanisms, inclusive of arrest cell cycle and induce apoptosis, and several anticancer agents are carbazole-based compounds. Thus, carbazole derivatives represent a fertile source for discovery of novel anticancer therapeutic agents. Over the past several years, a variety of carbazole hybrids have been developed as potential anticancer agents. The present review focuses on the recent progress, from 2016 until now, in knowledge on anticancer properties, structure-activity relationships and mechanisms of action of carbazole hybrids to provide a basis for development of relevant therapeutic agents.

Coumarins as Potential Anti-drug Resistant Cancer Agents: A Mini Review.

Cancer is the main cause of death, and the emergence of resistance by cancer cells towards existing anticancer agents is one of the major problems for effective chemotherapy, creating a great demand for the development of novel anticancer drugs. Coumarins, abundantly found in nature, constitute an important class of pharmacological agents possessing physiological activities. The mechanism investigations elucidated that coumarins could lead to self-programmed cancer cell death (apoptosis) via different mechanisms; thereby coumarin-based derivatives possess potential activity against various forms of cancers, including drug-resistant, even multidrug-resistant cancers. This review article describes the recent progress in the discovery, structural modification, structure-activity relationship, and mechanism of action studies of coumarin-based derivatives with potential activity against drug-resistant cancers, covering articles published between 2010 and 2020.

Organocatalytic atroposelective heterocycloaddition to access axially chiral 2-arylquinolines.

Axially chiral heterobiaryls play a vital role in asymmetric synthesis and drug discovery. However, there are few reports on the synthesis of atropisomeric heterobiaryls compared with axially chiral biaryls. Thus, the rapid enantioselective construction of optically active heterobiaryls and their analogues remains an attractive challenge. Here, we report a concise chiral amine-catalyzed atroposelective heterocycloaddition reaction of alkynes with ortho-aminoarylaldehydes, and obtain a new class of axially chiral 2-arylquinoline skeletons with high yields and excellent enantioselectivities. In addition, the axially chiral 2-arylquinoline framework with different substituents is expected to be widely used in enantioselective synthesis.

Enantioselective NHC-Catalyzed [3+3] Annulation of α-Bromoenals with 2-Aminobenzimidazoles.

A chiral carbene-catalyzed [3+3] annulation of α-bromoenals with 2-aminobenzimidazoles providing pyrimido[1,2-a]benzimidazoles has been described. This protocol features a broad scope and good functional group tolerance. Biological studies indicated that the formed pyrimido[1,2-a]benzimidazole exhibited moderate cytotoxic activity against tumor cells.

Synthesis and evaluation of 6-(11C-methyl(4-(pyridin-2-yl)thiazol-2-yl)amino)benzo[d]thiazol-2(3H)-one for imaging γ-8 dependent transmembrane AMPA receptor regulatory protein by PET.

Transmembrane AMPA receptor regulatory proteins (TARPs) are a recently discovered family of proteins that modulate AMPA receptors activity. Based on a potent and selective TARP subtype γ-8 antagonist, 6-(methyl(4-(pyridin-2-yl)thiazol-2-yl)amino)benzo[d]thiazol-2(3H)-one (compound 9), we perform the radiosynthesis of its 11C-isotopologue 1 and conduct preliminary PET evaluation to test the feasibility of imaging TARP γ-8 dependent receptors in vivo.

Transition-metal-free amination phosphoryl azide for the synthesis of phosphoramidates.

A facile and efficient approach to phosphoramidates was developed via amination of phosphoryl azides. A variety of phosphoramidates were obtained in one step with good to excellent yields under a mild reaction system. The process uses easily available amines as a N source and offers a new opportunity for P-N bond formation.

Synthesis and Preliminary Evaluation of 11 C-Labeled VU0467485/AZ13713945 and Its Analogues for Imaging Muscarinic Acetylcholine Receptor Subtype†4.

Muscarinic acetylcholine receptors (mAChRs) have five distinct subunits (M1 -M5 ) and are involved in the action of the neurotransmitter acetylcholine in the central and peripheral nervous system. Attributed to the promising clinical efficacy of xanomeline, an M1 /M4 -preferring agonist, in patients of schizophrenia and Alzheimer's disease, M1 - or M4 -selective mAChR modulators have been developed that target the topographically distinct allosteric sites. Herein we report the synthesis and preliminary evaluation of 11 C-labeled positron emission tomography (PET) ligands based on a validated M4 R positive allosteric modulator VU0467485 (AZ13713945) to facilitate drug discovery. [11 C]VU0467485 and two other ligands were prepared in high radiochemical yields (>30 %, decay-corrected) with high radiochemical purity (>99 %) and high molar activity (>74 GBq µmol-1 ). In vitro autoradiography studies indicated that these three ligands possess moderate-to-high in vitro specific binding to M4 R. Nevertheless, further physiochemical property optimization is necessary to overcome the challenges associated with limited brain permeability.

Sodium carbonate promoted [3 + 2] annulation of α-halohydroxamates and isocyanates.

A new [3 + 2] annulation of readily available α-halohydroxamates and isocyanates has been developed. This protocol allows a rapid assembly of various hydantoins in good to high yields as well as a broad substrate scope and good functional group tolerance.

Grafting Polytetrafluoroethylene Micropowder via in Situ Electron Beam Irradiation-Induced Polymerization.

Decreasing the surface energy of polyacrylate-based materials is important especially in embossed holography, but current solutions typically involve high-cost synthesis or encounter compatibility problems. Herein, we utilize the grafting of polytetrafluoroethylene (PTFE) micropowder with poly (methyl methacrylate) (PMMA). The grafting reaction is implemented via in situ electron beam irradiation-induced polymerization in the presence of fluorinated surfactants, generating PMMA grafted PTFE micropowder (PMMA⁻g⁻PTFE). The optimal degree of grafting (DG) is 17.8%. With the incorporation of PMMA⁻g⁻PTFE, the interfacial interaction between polyacrylate and PTFE is greatly improved, giving rise to uniform polyacrylate/PMMA⁻g⁻PTFE composites with a low surface energy. For instance, the loading content of PMMA⁻g⁻PTFE in polyacrylate is up to 16 wt %, leading to an increase of more than 20 degrees in the water contact angle compared to the pristine sample. This research paves a way to generate new polyacrylate-based films for embossed holography.

Fe-catalyzed esterification of amides via C-N bond activation.

An efficient Fe-catalyzed esterification of primary, secondary, and tertiary amides with various alcohols for the preparation of esters was performed. The esterification process was accomplished with FeCl3·6H2O, which is a stable, inexpensive, environmentally friendly catalyst with high functional group tolerance.

Synthesis of tricyclic quinazolinones via intramolecular cyclization of 3-(2-aminoalkyl)-2-(phenylamino)quinazolin-4(3H)-ones.

Bioactive tricyclic quinazolines class of 3,4-dihydro-1H-pyrimido[2,1-b]quinazolin-6(2H)-ones I and 2,3-dihydroimidazo[2,1-b]quinazolin-5(1H)-ones II were synthesized by the formic acid-catalyzed intramolecular cyclization of 3-(2-aminoalkyl)-2-(phenylamino)quinazolin-4(3H)-ones 1 in high yields. A plausible mechanism of the cyclization step is proposed.

Mechanical properties and permeability of porous chitosan-poly(p-dioxanone)/silk fibroin conduits used for peripheral nerve repair.

Some poly(p-dioxanone) (PDO) homopolymers were first synthesized and the selected PDO was conjugated onto chitosan using a group-protecting method to produce chitosan-poly(p-dioxanone) (CH-PDO) copolymers with various PDO percentages changing from around 30 to 60 wt%. The CH-PDO with the PDO content of around 42 wt% was used to blend with prescribed amounts of silk fibroin (SF) to build porous single-lumen conduits that are intended to be used for long-gap peripheral nerve repair. Some genipin-crosslinked CH-PDO/SF conduits were endowed with an average porosity of around 60% in their porous wall, and with changed pore-sizes varying from around 10 to ca. 70 µm using optimized processing conditions. After being degraded in a PBS medium containing a certain amount of lysozyme for various periods up to 8 weeks, some optimal CH-PDO/SF conduits were able to retain their compressive load and deformation recovery at around 59 N/m and 73% in wet state, respectively. In addition, the achieved CH-PDO/SF conduits allowed the permeation of nutritional molecules with various molecular weights while showing a certain ability to prevent cells from infiltrating through the conduit wall. Cell culture confirmed that the optimized CH-PDO/SF conduits were able well supported the growth of rat glioma C6 cells. These results suggest that presently developed CH-PDO/SF conduits have promising potential for long-gap peripheral nerve repair.

[Investigation of exogenous stimulus effect on the interaction of CdSe/ZnS quantum dots/TiO2 nanocomposites with human serum albumin by resonance light scattering].

The interaction between CdSe/ZnS(quantum dots)/TiO2 nanocomposites and human serum albumin(HSA) was investigated by resonance light scattering (RLS) spectroscopic methods under approximate physiological conditions. Much important information of the interaction between CdSe/ZnS(Quantum Dots)/TiO2 nanocomposites and HSA was obtained by studying comprehensively the Exogenous influence factors of nanocomposites concentration, pH, NaCl concentration, reaction temperature, detection time, coexisting ions, surfactants, sequence of adding to the sample etc. It was showed that the new formation of complex system is likely to enhance the protein hydrophobic cavity and tend to focus the hydrophobic interface in aqueous solution, resulting in strengthening the intensity of resonance light scattering; Also it is very sensitive to the changes in the pH value in the system; The sensitivity of I(RLS) in system can be increased by the appropriate NaCl concentration; The value of IRLS in system would be changed with the change in the concentration of coexisting ions; The value of I(RLS) in system is basically stable when the reaction time reaches 5 min; The value of I(RLS) in system is not exactly the same with a surfactant, and strong electrostatic interaction has occurred between oppositely charged surfactant and nano composites; It is obvious that the value of I(RLS) in complex system is affected by the sequence of adding to sample; It has the incomplete monotonically increasing trend with the changes in temperature. The information is useful for providing theoretical supporting for the mechanism of interaction between nanomaterials and bio-macromolecule, and for understanding the biocompatibility and safety of nano-materials.

Designed composites for mimicking compressive mechanical properties of articular cartilage matrix.

Collagen, chitosan-polycaprolactone (CH-PCL) copolymer with PCL content of around 40wt% and chondroitin sulfate (CS) were mixed together at various ratios to prepare collagen/CH-PCL/CS composites and the resulting composites were used to build stratified porous scaffolds that are potentially applicable for articular cartilage repair. The ternary composites were designed in such a way that collagen content in the scaffolds decreased from the top layer to the bottom layer while the content of CH-PCL and CS altered in a reversed trend in order to reach partial similarity to cartilage matrix in the composition of main components. Porous structures inside collagen/CH-PCL/CS scaffolds were constructed using a low-temperature deposition processing technique and graded average pore-size and porosity for the scaffolds were established. Such produced scaffolds were further crosslinked using 1-ethyl-3-(3-dimethyl aminopropyl) carbodiimide under optimized conditions, and the obtained scaffolds showed well-defined elastic compressive properties. Compressive modulus (E) and stress at 10% strain (σ10) of full scaffolds in wet state reached about 2.8MPa and 0.3MPa, respectively, and meanwhile, E and σ10 of layers inside hydrated scaffolds changed in a gradient-increased manner from the top layer to the bottom layer with significant differences between contiguous layers, which partially mimics compressive mechanical properties of cartilage matrix. In addition, in vitro culture of cell-scaffold constructs exhibited that scaffolds were able to well support the ingrowth and migration of seeded cells, and cells also showed relatively uniform distribution throughout the scaffolds. These results suggest that the presently developed collagen/CH-PCL/CS scaffolds have promising potential for applications in articular cartilage repair.

An enantioselective cascade reaction between α,ß-unsaturated aldehydes and malonic half-thioesters: a rapid access to chiral δ-lactones.

We disclose a novel efficient enantioselective organocatalytic cascade reaction for the preparation of δ-lactones in good to excellent yields (69-93%) and with high to excellent enantioselectivities (88-96% ee).

Binding investigation on the interaction between Methylene Blue (MB)/TiO2 nanocomposites and bovine serum albumin by resonance light-scattering (RLS) technique and fluorescence spectroscopy.

The interaction between Methylene Blue (MB)/TiO2 nanocomposites and bovine serum albumin (BSA) was investigated by resonance light scattering (RLS), fluorescence, three-dimension spectra and UV-vis absorbance spectroscopy. Several factors which may influence the RLS intensity were also investigated before characterizing MB/TiO2-BSA complex. It was proved that the mechanism of MB/TiO2 nanocomposites binding to BSA was mainly a result of the formation of MB/TiO2-BSA complex. The binding constant of MB/TiO2-BSA is 0.762 × 10(-5) L mol(-1) at 298K. By calculating the binding constant at different temperature, the thermodynamic parameters ΔH, ΔG, and ΔS can be observed and deduced that the hydrophobic interactions played an important role to stabilize the complex. The distance r (3.73 nm) between donor (BSA) and acceptor (MB/TiO2) was obtained according to fluorescence resonance energy transfer (FRET). The binding site for MB/TiO2 on BSA was mainly located in sub-domain IIA. The UV-vis absorbance, circular dichroism and three dimension fluorescence have also been used to investigate the effect of MB/TiO2 on the conformation of BSA.

Toxicity of CdTe QDs with different sizes targeted to HSA investigated by two electrochemical methods.

QDs have large scale application in many important areas with potential of unintentional exposure to the environment or organism during processing of a nanotechnology containing product's life cycle. In this paper, two classical electrochemical methods, cyclic voltammetry and electrochemical impedance spectroscopy were applied to investigate the influence of particle sizes of CdTe QDs on their toxicity targeted to human serum albumin (HSA) under simulative physiological conditions. The results show that the toxicity of yellow emitting QDs (YQDs) on HSA is slightly stronger than that of the green-emitting (GQDs) and red-emitting QDs (RQDs). We also compared these two classical electrochemical methods with the traditional fluorescence spectroscopy through the above results. The electrochemical methods may be more accurate and comprehensive to investigate the toxicity of QDs at the biomacromolecular level under certain conditions, though fluorescence spectroscopy is simpler and more sensitive.