Facile Construction of Benzo[d][1,3]oxazocine: Reductive Radical Dearomatization of N-Alkyl Quinoline Quaternary Ammonium Salts.

Reductive radical dearomatization N-alkyl quinoline quaternary ammonium salts to synthesize structurally complex and challenging polysubstituted benzo[d][1,3]oxazocines was first reported. The mechanism showed various allyl alcohols can be converted into alkyl radicals under reduction conditions of iron/silane. These radicals then nucleophilically attack the C4 site of N-alkyl quinoline quaternary ammonium salts, and intramolecular cyclization of the resulting intermediate generates the target product. This method not only produced a series of novel polysubstituted benzo[d][1,3]oxazocines but also prepared polycyclic benzo[d][1,3]oxazocines. Finally, this strategy made up for the lack of reductive radical reports on N-alkylquinolinium salts and also had the advantages of mild reaction conditions, wide substrate range, and novel product structure.

Access to 5-Methyl-5H-naphtho[2,3-c]carbazole-8,13-dione Derivatives via Copper-Catalyzed Intramolecular Isomerization.

Carbazole-fused quinones are important compounds for their potential pharmacological activities and photophysical properties. Here, a novel copper-catalyzed intramolecular isomerization process to access a new class of naphtho[2,3-c]carbazole-8,13-dione derivatives via a furan isomerization/γ-H elimination and ß-C elimination/6π-electrocyclization/aromatization cascade is reported. Furthermore, the preliminary photophysical properties of the functional 5-methyl-5H-naphtho[2,3-c]carbazole-8,13-dione derivatives have been studied.

Copper(I)-Mediated Divergent Synthesis of Pyrroquinone Derivatives and 2-Halo-3-amino-1,4-quinones.

A divergent transformation of 2-amino-1,4-quinones for the synthesis of pyrroquinone derivatives and 2-halo-3-amino-1,4-quinones was disclosed. The mechanistic study showed that both the tandem cyclization and halogenation involved a Cu(I)-catalyzed oxidative radical process. This protocol not only constructed a series of novel pyrroquinone derivatives with high atom economy but also provided a new method of halogenation via directed C(sp2)-H functionalization with CuX (X = I, Br, Cl) serving as the X (X = I, Br, Cl) source.

Long-term sciatic nerve block led by a supramolecular arrangement of self-delivery local anesthetic nano systems.

Classical local anesthetics are unsuitable to treat regional pain lasting several days due to their limited duration and systemic toxicity. Self-delivery nano systems without excipients were designed for long-term sensory blocks. 1a self-assembled into different vehicles with different fractions of intermolecular π-π stacking, transported itself into nerve cells, and released single molecules slowly to achieve long-term duration for rats' sciatic nerve block for 11.6 h in water, 12.1 h in water with CO2 and 3.4 h in NS (normal saline). After the counter ions were changed to SO42-, 1e can self-assemble into vesicles and prolong the duration to 43.2 h, which was much longer than the 3.8 h led by (s)-bupivacaine hydrocloride (0.75%). This was mainly caused by the enhancement of self-release and counter ion exchange inside nerve cells, which were affected by the gemini surfactant structure, pKa of the counter ions and π-π stacking interactions.

B(C6F5)3-Catalyzed [4 + 2] Cyclization Strategy: Synthesis and Photophysical Properties of 5H-Naphtho[2,3-c]carbazole-8,13-dione Derivatives.

In this paper, a series of novel carbazolequinones were efficiently obtained by a B(C6F5)3-catalyzed [4 + 2] cyclization reaction. This protocol not only had a simple operation, broad substrate range, and high atomic economy, but also had a low catalyst loading and avoided using metal catalysts. In addition, we constructed diverse new carbazole-fused compounds under different reduction conditions. The results of photophysical characterization showed that the structure of carbazole-fused derivatives had a significant impact on the fluorescence properties.

Gut-derived fungemia due to Kodamaea ohmeri combined with invasive pulmonary aspergillosis: a case report.

BACKGROUND: Kodamaea ohmeri is a rare pathogen with high mortality and is found among blood samples in a considerable proportion; however, gastrointestinal infection of K. ohmeri is extremely rare. Invasive pulmonary aspergillosis is also an uncommon fungal; these two fungal infections reported concomitantly are unprecedented. CASE PRESENTATION: We described a case of a 37-year-old male who got infected with K. ohmeri and invasive pulmonary aspergillosis. We used the mass spectrometry and histopathology to identify these two fungal infections separately. For the treatment of K. ohmeri, we chose caspofungin. As for invasive pulmonary aspergillosis, we used voriconazole, amphotericin B, and then surgery. The patient was treated successfully through the collaboration of multiple disciplines. CONCLUSIONS: We speculate that the destruction of the intestinal mucosa barrier can make the intestine one of the ways for certain fungi to infect the human body.

B(C6F5)3-catalyzed oxidation of α-diazoesters using DMF and molecular oxygen as oxygen sources.

A metal-free catalytic oxidation of α-diazoesters via a green environmental-friendly route was developed. The α-diazoesters were converted to α-ketoesters using DMF and molecular oxygen as oxygen sources and B(C6F5)3 as the catalyst, without any additives. This protocol has a broad adaptability of substrates and good compatibility with a range of functional groups, and it offers new insight into reactions catalyzed by B(C6F5)3.

Copper-catalyzed one-pot amine-alkylation of quinones with amines and alkanes.

A copper-catalyzed one-pot amine-alkylation of quinones with amines and alkanes in the presence of di-tert-butyl peroxide (DTBP) was developed via a radical reaction process. Various alkanes and aromatic or aliphatic amines with diverse structures and electronic properties are suitable substrates, and the chirality of amines can be maintained for the transformation. This method has high step and atom economy for straightforward access to aminated and alkylated quinones from readily available starting materials.

t-BuOK mediated oxidative coupling amination of 1,4-naphthoquinone and related 3-indolylnaphthoquinones with amines.

The transition-metal free amination of 1,4-naphthoquinone and related 3-indolylnaphthoquinones with amines, such as various (hetero)aromatic amine and aliphatic amine via t-BuOK-mediated oxidative coupling at room temperature has been developed. This reaction provides efficient access to the biologically important and synthetically useful 2-amino-1,4-naphthoquinones and 2-amino-3-indolylnaphthoquinones with good yields under mild conditions. The present protocol is simple, practical and shows good functional group tolerance. In addition, the obtained 2-amino-3-indolylnaphthoquinones were further transformed to synthesize polycyclic N-heterocycles.

Boron-catalyzed dehydrative allylation of 1,3-diketones and ß-ketone esters with 1,3-diarylallyl alcohols in water.

A metal-free catalytic allylation with atom economy and green environment friendly was developed. Allylic alcohols could be directly dehydrated in water by B(C6F5)3, without using any base additives. The reaction can afford the corresponding monoallylated product in moderate to high yield and has been performed on a gram-scale, and a quaternary carbon center can be constructed for the active methine compounds of 1,3-diketones or ß-ketone esters in this process. The product can be further converted, such as the synthesis of tetra-substituted pyrazole compounds, or 1,4-dienes and functionalized dihydropyrans.

Corrigendum: Dapagliflozin Attenuates Hyperglycemia Related Osteoporosis in ZDF Rats by Alleviating Hypercalciuria.

[This corrects the article DOI: 10.3389/fendo.2019.00700.].

A Construction of α-Alkenyl Lactones via Reduction Radical Cascade Reaction of Allyl Alcohols and Acetylenic Acids.

An iron-catalyzed cascade reaction of radical reduction of allyl alcohols and acetylenic acids to construct polysubstituted α-alkenyl lactones has been developed. In this paper, various allyl alcohols can form allyl ester intermediates and are further transformed into alkyl radicals, which form products through intramolecular reflex-Michael addition. In addition, this method can be used to prepare spirocycloalkenyl lactones. Interestingly, this protocol can be used to synthesize the skeleton structure of natural products. Moreover, the product can be further transformed into a ß-methylene tetrahydrofuran and tetrahydrofuran diene.

Cobalt-Catalyzed Cycloamination: Synthesis and Photophysical Properties of Polycyclic N-Heterocycles.

The first earth-abundant cobalt-catalyzed cycloamination of indolylquinones and various (hetero)aromatic amine under ligand-free conditions for the synthesis of polycyclic N-heterocycles has been developed. The process allows facile access to polycyclic N-heterocycles with tolerance of chloride, bromide, amino, thio, etc. groups in moderate to high yields (up to 89%). In addition, The photophysical properties of the synthesized products were evaluated. These products exhibit interesting fluorescence properties, which is promising for fluorescent probes.

Chemoselective Hydrosilylation of the α,ß-Site Double Bond in α,ß- and α,ß,γ,δ-Unsaturated Ketones Catalyzed by Macrosteric Borane Promoted by Hexafluoro-2-propanol.

The B(C6F5)3-catalyzed chemoselective hydrosilylation of α,ß- and α,ß,γ,δ-unsaturated ketones into the corresponding non-symmetric ketones in mild reaction conditions is developed. Nearly 55 substrates including those bearing reducible functional groups such as alkynyl, alkenyl, cyano, and aromatic heterocycles are chemoselectively hydrosilylated in good to excellent yields. Isotope-labeling studies revealed that hexafluoro-2-propanol also served as a hydrogen source in the process.

Dehydration in water: frustrated Lewis pairs directly catalyzed allylization of electron-rich arenes and allyl alcohols.

A frustrated Lewis pair (FLP)-catalyzed allylation of allyl alcohols with electron-rich arenes has been developed. Interestingly, in this reaction, the electron-rich arenes and allyl alcohols are dehydrated in water. What's more, water was the sole byproduct of the reaction. In this protocol, various allyl alcohols can be converted into allyl cations and attacked by the electron-rich arenes to form aryl cation intermediates. Finally, the aryl cation intermediates are deprotonated to give the 1,3-diarylpropenes. In this protocol, indole allyl alcohols can undergo a bimolecular ring closure reaction, and structurally diverse tetrahydroindolo[3,2-b]carbazoles could be smoothly obtained. The reaction is not sensitive to oxygen and has been performed on a gram-scale.

B(C6F5)3-Catalyzed C-C Coupling of 1,4-Naphthoquinones with the C-3 Position of Indole Derivatives in Water.

An atom-economical and environmentally benign approach for the synthesis of indole-substituted 1,4-naphthoquinones from indoles and 1,4-naphthoquinones using readily available Lewis acidic B(C6F5)3 in water and with the recycling of water and part of the catalyst is reported. The reaction proceeded through the B(C6F5)3-catalyzed C(sp2)-H and C(sp2)-H bond coupling of 1,4-naphthoquinones with the C-3 position of indole derivatives in water. This methodology provides a facile protocol for the synthesis of some new indole-substituted 1,4-naphthoquinones in satisfactory yields and with a broad substrate scope. When compared to known methods for the synthesis of indole-substituted 1,4-naphthoquinones, this protocol is practical and efficient and does not require a transition-metal catalyst or toxic organic solvents. In addition, we utilized a simple filtration process for complete recycling of the solvent and the part of the catalyst in each reaction cycle.

Dapagliflozin Attenuates Hyperglycemia Related Osteoporosis in ZDF Rats by Alleviating Hypercalciuria.

Recent studies showed that in patients with type 2 diabetes mellitus (T2DM), Sodium-dependent glucose transporters 2 inhibitor (SGLT2I) may cause potential adverse effects on the skeleton such as increasing the risk of fracture. This risk is possibly mediated by effects induced by all SGLT2I class drugs, but whether Dapagliflozin aggravates osteoporosis in patients with T2DM remains controversial. Therefore, we designed this study to explore how Dapagliflozin affects the metabolism and the quality of bone in T2DM animal models. The effect of Dapagliflozin on the skeleton was evaluated on male ZDF (Zucker Diabetic Fatty) rats-a rat model of diet induced spontaneous T2DM. Dapagliflozin was administrated via gavage at the dosage of 10 mg/kg/day. Bone tissue mineral density and the microarchitecture of tibiae were measured with micro-CT and biomechanics characteristic of the femora were tested using a three-point bending test. Serum bone biomarkers and other metabolic parameters were also tested via ELISA or other assays. Our results found that diabetic rats demonstrated symptoms of osteoporosis and Dapagliflozin could help to alleviate these defections caused by diabetes. Compared to the negative controls, the serum CT (calcitonin) level in ZDF rats as well as the uric calcium and phosphate levels were elevated, and these symptoms were alleviated by Dapagliflozin. Tibiae of Dapagliflozin treated rats demonstrated decreased cortical tissue mineral density while trabecular tissue mineral density and mean bone mineral density received a rise when compared to the matched controls. ZDF rats also showed defections in femora stiffness which could be relieved by Dapagliflozin administration. The mechanism of Dapagliflozin affecting bone quality is possibly connected to the suppression of serum calcitonin and excretion of calcium via urine rose by hyperglycemia. In conclusion, Dapagliflozin can prevent osteoporosis in ZDF rats by alleviating hypercalciuria.

[Electroacupuncture at "Zusanli"(ST36) promotes gastrointestinal motility possibly by suppres-sing excessive autophagy via AMPK/ULK1 signaling in rats with functional dyspepsia].

OBJECTIVE: To explore the effect of electroacupuncture (EA) at "Zusanli" (ST36) on gastrointestinal motility and expression of autophagy marker LC3 and autophagy signaling pathway molecule AMP-activated protein kinase (AMPK) in rats with functional dyspepsia (FD), so as to explore its mechanisms underlying improvement of FD. METHODS: A total of 40 male SD rats were randomly divided into blank control, model, EA, AMPK inhibitor and EA＋AMPK inhibitor groups, with 8 rats in each group. The FD model was established by tail-clip (30 min/time, twice daily) ＋ single day feeding, and gavage of normal saline (2 mL/time, twice a day) for 2 successive weeks. For rats of EA and EA＋AMPK inhibitor groups, EA (4 Hz, 1.0 mA) was applied to bilateral ST36 for 20 min, once daily for 7 successive days. For rats of the AMPK-inhibitor and EA＋AMPK inhibitor groups, Compound C (20 mg/kg) solution was administered by intraperitoneal injection before every EA administration. The gastric residual rate and small intestinal transit rate were calculated based on the weight of stomach and length of ink propelling and total small intestine, respectively. The expression levels of c-kit, microtubule-associated protein 1 light chain 3, Beclin 1, phosphorylated (p)-AMPK and p-unc-51 like autophagy activating kinase 1(ULK1) in the gastric antrum tissue were detected by using Western blot. RESULTS: Compared with the blank control group, the gastric residual rate and the expression levels of LC3-Ⅱ/LC3Ⅰ， Beclin 1, p-AMPK and p-ULK1 proteins were significantly increased, and the small intestinal transit rate and the expression of c-kit protein obviously decreased in the model group (P<0.01). After EA intervention, modeling-induced increase of gastric residual rate and the expression of LC3-Ⅱ/LC3Ⅰ， Beclin 1, p-AMPK and p-ULK1 proteins, and decrease of small intestinal transit rate and expression of c-kit protein were reversed in the EA, AMPK inhibitor and EA＋AMPK inhibitor groups (P<0.05, P<0.01). The therapeutic effect of EA and EA＋AMPK was significantly superior to that of AMPK inhibitor in down-regulating the expression of LC3Ⅱ/LC3Ⅰ， Beclin 1, p-AMPK and p-ULK1 proteins and in up-regulating the expression of c-kit protein (P<0.05, P<0.01). No significant differences were found among the EA, AMPK inhibitor and EA＋AMPK inhibitor groups in lowering gastric residual rate and elevating the small intestinal transit rate (P>0.05). CONCLUSION: EA at ST36 can promote gastrointestinal motility in FD rats, which is possibly mediated by inhibiting excessive autophagy of interstitial cells of Cajal via down-regulating AMPK/ULK1 signaling.

Metal-free oxidative cross-dehydrogenative coupling of quinones with benzylic C(sp3)-H bonds.

A metal-free cross-dehydrogenative coupling of quinones with toluene derivatives has been established. A series of quinones were subjected to reaction with toluene derivatives in the presence of di-tertbutyl peroxide (DTBP) for direct synthesis of benzylquinones. The method exhibits good functional group tolerance, and desired products were obtained in moderate to good yields. Meanwhile, a radical pathway was proposed to describe the cross-dehydrogenative coupling of quinones with toluene derivatives.

Irbesartan attenuates advanced glycation end products-mediated damage in diabetes-associated osteoporosis through the AGEs/RAGE pathway.

AIMS: Diabetes-associated osteoporosis is mainly caused by the formation and accumulation of advanced glycation end products (AGEs). Angiotensin II type 1 receptor blocker (ARB) has anabolic bone effects on the physicochemical properties of the bone in diabetes. We hypothesized that ARB could inhibit AGEs-induced deleterious effects. MAIN METHODS: In this study, we chose seven-week-old Leprdb/Lepr+ (db/+) and Leprdb/Leprdb (db/db) mice. After 12 week intervention by irbesartan, the microarchitecture and mechanical strength of the bone of seven-week-old db/db mice were investigated systematically. Meanwhile, the molecular mechanisms of the osteoblasts were analyzed, after AGEs or irbesartan were added to the culture. Also, intracellular formation of reactive oxygen species (ROS) was measured with DCF fluorescence. KEY FOUNDINGS: Results showed that 12-week irbesartan treatment could dramatically improve trabecular bone microarchitecture through increasing BV/TV (p = 0.003, +46.7%), Tb.N (p = 0.020, +52.0%), and decreasing that of Tb.Sp (p = 0.005, -21.2%) and SMI (p = 0.007, -26.4%), comparing with the db/db group. Irbesartan could also substantially raise biomechanical parameters including max load (p = 0.013, +20.7%), fracture load (p = 0.014, +70.5%), energy absorption (p = 0.019, +99.4%). Besides, it could inhibit AGEs-induced damage of cell proliferation and osteogenic differentiation of osteoblasts, as well as suppressing the activation of apoptosis caused by AGEs. Moreover, co-incubation with irbesartan could prevent the AGEs-induced increase of intracellular oxidative stress and RAGE expression in osteoblasts. SIGNIFICANCE: In conclusion, this study suggested that irbesartan might play a protective role in diabetes-related bone damages by blocking the deleterious effects of AGEs/RAGE-mediated oxidative stress. This may provide a revolutionary benefits to therapy with irbesartan on diabetic osteoporosis.