Palladium-Catalyzed O-Glycosylation through π-π Interactions.

A stereodivergent synthesis of ß- and α-O-glycosides using 3-O-quinaldoyl glucals was developed by palladium catalysis at 60 and 110 °C respectively. Various alcohols, monosaccharides, and amino acid were glycosylated to form ß- and α- products in good yields with high stereoselectivity. Mechanistic studies indicated no classic Pd-N (quinoline) coordination, but π-π stacking interactions promoted the anomeric stereodiversity. The practicality was demonstrated by glycosylating natural products/drugs and synthesizing a complex tetrasaccharide.

Facile synthesis of 2-vinylindolines via a phosphine-mediated α-umpolung/Wittig olefination/cyclization cascade process.

A novel phosphine-mediated α-umpolung/Wittig olefination/cyclization cascade process between o-aminobenzaldehydes and Morita-Baylis-Hillman (MBH) carbonates has been ingeniously developed. This protocol serves as a practical tool for the facile synthesis of a broad range of 2-vinylindolines in moderate to good yields under mild reaction conditions. The applicability of this method was demonstrated with gram-scale reaction and various transformations of the corresponding product.

Stereocontrolled Synthesis of Aryl C-Nucleosides under Ambient Conditions.

A stereocontrolled synthesis of an aryl C-nucleoside has been developed using D-ribals and arylboronic acids catalyzed by palladium without additional ligands in common solvents under an open-air atmosphere at room temperature. This protocol features very mild conditions, simplicity in operation, exclusive ß-stereoselectivity, broad substrate scopes, and good compatibility with reactive amino and hydroxyl groups. The functionalization of unsaturated C-nucleosides and the late-stage glycosylation of natural products/drugs demonstrated the high practicality of this strategy.

Stereoselective Synthesis of ß-S-Glycosides via Palladium Catalysis.

S-Glycosides are more resistant to enzymatic and chemical hydrolysis and exhibit higher metabolic stability than common O-glycosides, demonstrating their widespread application in biological research and drug development. In particular, ß-S-glycosides are used as antirheumatic, anticancer, and antidiabetic drugs in clinical practice. However, the stereoselective synthesis of ß-S-glycosides is still highly challenging. Herein, we report an effective ß-S-glycosylation using 3-O-trichloroacetimidoyl glycal and thiols under mild conditions. The C3-imidate is designed to guide Pd to form a complex with glucal from the upper face, followed by Pd-S (thiols) coordination to realize ß-stereoselectivity. This method demonstrates excellent compatibility with a broad scope of various thiol acceptors and glycal donors with yields up to 87% and a ß/α ratio of up to 20:1. The present ß-S-glycosylation strategy is used for late-stage functionalization of drugs/natural products such as estrone, zingerone, and thymol. Overall, this novel and simple operation approach provides a general and practical strategy for the construction of ß-thioglycosides, which holds high potential in drug discovery and development.

C-Doped LiVO3 Honeycombs Derived from the Biomass Template Strategy for Superior Lithium Storage.

LiVO3 as a prospective anode for lithium-ion batteries has drawn considerable focus based on its superior ion transfer capability and relatively elevated specific capacity. Nevertheless, the inherent low electrical conductivity and sluggish reaction kinetics hindered its commercial application. Herein, C-doped LiVO3 honeycombs (C-doped LiVO3 HCs) are designed via introducing low-cost and scalable biomass carbon as a template, and the influence of the structure on the lithium storage property is systematically studied. The prepared C-doped LiVO3 HC electrode delivers a high reversible capacity of 743.7 mA h g-1 at 0.5 A g-1 after 400 cycles and superior high-rate performance with an average discharge capacity of 420.8 mA h g-1 even at 5.0 A g-1. The remarkable comprehensive electrochemical performance is attributed to the high electrical conductivity caused by carbon doping and rapid ion transport triggered by the honeycomb structure. This work may offer a rational design on both the hierarchical structure and doping engineering of future battery electrodes.

Highly Regio- and Diastereoselective Phosphine-Catalyzed [2 + 4] Annulation of Benzofuran-Derived Azadienes with Allyl Carbonates: Access to Spiro[benzofuran-cyclohexanes].

A novel highly regio- and diastereoselective phosphine-catalyzed [2 + 4] annulation of benzofuran-derived azadienes (BDAs) with acidic hydrogen-tethered allyl carbonates has been developed ingeniously. A range of functionalized spiro[benzofuran-cyclohexane] derivatives with two consecutive stereocenters were smoothly obtained in moderate to excellent yields under mild reaction conditions from readily available materials. Moreover, this method is a practical and scalable strategy that creates the core structural motif of the fungistatic drug, griseofulvin.

Stereoselective Synthesis of O-Glycosides with Borate Acceptors.

Borate esters have been applied widely as coupling partners in organic synthesis. However, the direct utilization of borate acceptors in O-glycosylation with glycal donors remains underexplored. Herein, we describe a novel O-glycosylation resulting in the formation of 2,3-unsaturated O-glycosides and 2-deoxy O-glycosides mediated by palladium and copper catalysis, respectively. This O-glycosylation method tolerated a broad scope of trialkyl/triaryl borates and various glycals with exclusive stereoselectivities in high yields. All the desired aliphatic/aromatic O-glycosides and 2-deoxy O-glycosides were generated successfully, without the hemiacetal byproducts and O→C rearrangement because of the nature of borate esters. The utility of this strategy was demonstrated by functionalizing the 2,3-unsaturated glycoside products to form saturated ß-O-glycosides, 2,3-deoxy O-glycosides, and 2,3-epoxy O-glycosides.

Synthesis and inhibitory activity of euparin derivatives as potential dual inhibitors against α-glucosidase and protein tyrosine phosphatase 1B (PTP1B).

Diabetes mellitus is a serious threat to human life and health. The α-glucosidase and protein tyrosine phosphatase 1B (PTP1B) were important targets for the treatment of type 2 diabetes mellitus. In this paper, euparin, a natural product from Eupatorium chinense possessed extensive pharmacological activities, was selected as the lead compound. It was derived into chalcone compounds with high efficiency, and the inhibitory activities of these 30 products on α-glucosidase and PTP1B were tested. The results showed that compounds 12 and 15 had good inhibitory activities against both enzymes. The IC50 value of 12 to inhibit α-glucosidase and PTP1B was 39.77 and 39.31 µM, and the IC50 value of 15 to inhibit α-glucosidase and PTP1B was 9.02 and 3.47 µM, respectively. In addition, molecular docking results showed that compounds 12 and 15 exhibited good binding affinities toward both α -glucosidase and PTP1B with negative binding energies. The results of the present study demonstrate that compounds 12 and 15 might be beneficial in the treatment of type 2 diabetes.

Stereoselective Synthesis of 2-Deoxy Glycosides via Iron Catalysis.

An Fe-catalyzed 2-deoxy glycosylation method was developed from 3,4-O-carbonate glycals directly at room temperature. This novel approach enabled facile access to alkyl and aryl 2-deoxy glycosides in high yields with exclusive α-stereoselectivity, tolerating various alcohols, phenols, and glycals. The synthetic utility and advantage of this strategy have been demonstrated by the modification of six natural products and the construction of a tetrasaccharide.

Coordination effect enabled palladium-catalyzed regioselective O-alkylation of 2-pyridones.

A novel tactic for the regioselective O-alkylation of 2-pyridones has been realized through palladium catalysis in moderate to high yields. The coordination effect between palladium and nitrogen on the pyridine ring plays a versatile role.

Stereoselective O-Glycosylation of Glycals with Arylboronic Acids Using Air as the Oxygen Source.

An open-air palladium-catalyzed O-glycosylation was developed using glycals and arylboronic acids with base additives at ambient conditions. The novel approach enabled facile access to various O-glycosides in high yields, with exclusive 1,4-cis-stereoselectivity tolerating reactive hydroxyl/amino groups. Mechanistic studies indicated that chemo-/stereoselectivity arose from the coordination between palladium and phenols generated in situ by oxidizing arylboronic acids, followed by an intramolecular attack. Isotope-labeling experiments revealed that the oxygen of O-glycosidic bonds came from O2.

Direct N-Glycosylation of Amides/Amines with Glycal Donors.

Direct N-glycosylation between glycals and amides/amines was achieved with exclusive stereoselectivity in moderate to high yields. Various amides, amines, and 3,4-O-carbonate-glycals were tolerated, and unique ß-N-glycosides were obtained. The strategy was based on palladium-catalyzed decarboxylative allylation, and the high 1,4-cis-selectivity was proposed because of the hydrogen bonding effect. Notably, all the synthesized products were subjected to preliminary bioactivity studies, revealing that three compounds were cytotoxic to tumor cells and nontoxic to normal human cells.

Open-Air Stereoselective Construction of C-Aryl Glycosides.

A new methodology of stereoselective C-glycosylation has been developed with 3,4-O-carbonate glycals and boronic acids, catalyzed by 1,2-bis(phenylsulfinyl)ethane palladium(II) acetate under open-air conditions at room temperature. This mild method is simple in operation, wide in substrate range, and tolerant in alcoholic/phenolic hydroxyl and amino groups. High to excellent yields were observed for all substrates tested, with the driving force mainly contributed by decarboxylation. Meanwhile, the high 1,4-trans-selectivity was achieved by steric effects as proposed.

Trametenolic acid B protects against cerebral ischemia and reperfusion injury through modulation of microRNA-10a and PI3K/Akt/mTOR signaling pathways.

Trametenolic acid B (TAB) was a lanostane-type triterpenoid isolated from the trametes lactinea (Berk.) Pat. We have previously reported that extract from trametes lactinea (Berk.) Pat and TAB could efficiently improve learning and memory ability of the cerebral ischemia injury rats and suppress mitochondrial-mediated apoptosis in hydrogen peroxide damaged SH-SY5Y cells. However, the potential mechanisms have not been fully understood yet. The current study was to further investigate the protective effect of TAB on oxygen glucose deprivation/reoxygenation (OGD/R)-damaged SH-SY5Y cells and cerebral ischemia/reperfusion (I/R) injury rats, as well as its mechanisms involved. Cell experiments demonstrated that TAB (10, 20 and 40 µg/mL) protected OGD/R-induced SH-SY5Y cell injury by promoting cell proliferation and suppressing LDH leakage; Meanwhile, the results in vivo showed that TAB (20, 40 and 80 mg/kg) might significantly ameliorate the neurological deficit score, cerebral edema, neuronal cell loss and apoptosis, suppress cerebral infarction volume of the cerebral I/R injury rats. Further studies in vitro and in vivo indicated TAB could efficiently reduce OGD/R-damaged SH-SY5Y cell and cerebral I/R rat serum ROS, LDH and MDA levels, elevate SOD, GSH-Px and CAT activities, downregulate miR-10a mRNA and Bax, cytochrome C, cleaved-caspase-3 and cleaved-caspase-9 protein expressions, upregulate p-PIK3CA, p-Akt, p-mTOR, Bcl-2, pro-caspase-9 and pro-caspase-3 protein expressions and p-PIK3CA/PIK3CA, p-Akt/Akt, p-mTOR/mTOR ratios (P < 0.05 or P < 0.01, respectively). Our present study indicated that TAB possessed neuroprotective property against ODG/R and I/R injury by suppressing miR-10a expression, activating PI3K/Akt/mTOR signaling pathway, thereby reducing mitochondrial-mediated apoptosis, which provided a new insight for interpreting the underlying mechanisms of TAB' neuroprotective effect and a candidate agent to treat cerebral I/R injury.

Odorless Isocyanide Chemistry: One-Pot Synthesis of Heterocycles via the Passerini and Postmodification Tandem Reaction Based on the in Situ Capture of Isocyanides.

This paper reports the tandem reaction strategy of the Passerini/Staudinger/aza-Wittig reaction based on the in situ capture of isocyanides. According to this strategy, isocyanides are synthesized in situ and immediately work as the substrate for the Passerini reaction and postmodification tandem reaction in one pot. In addition, two types of new compounds, 5-oxo-3,5-dihydrobenzo[ e][1,4]oxazepines and 6-oxo-5,6-dihydro-2 H-1,4-oxazines, were synthesized using the tandem reaction strategy that includes five-step transformations in one pot.

Diastereoselective Synthesis of C-Vinyl Glycosides via Gold(I)-Catalyzed Tandem 1,3-Acyloxy Migration/Ferrier Rearrangement.

A novel gold-catalyzed C-glycosylation has been developed to gain access to α,(Z)-selective C-vinyl glycosides, starting from readily available glycals and propargylic carboxylate. This reaction involves a tandem intermolecular gold-catalyzed 1,3-acyloxy migration/Ferrier rearrangement with the involvement of allenic ester as the glycosyl acceptor. A wide range of substrate scope with good to excellent yields was achieved with complete diastereoselectivity.

Design, synthesis and biological evaluation of bisabolangelone oxime derivatives as potassium-competitive acid blockers (P-CABs).

With the aim of searching novel P-CABs, seven bisabolangelone oxime derivatives were designed, synthesized, characterized and evaluated the H(+),K(+)-ATPase inhibitory activities guided by computer aided drug design methods. The binding free energy calculations were in good agreement with the experiment results with the correlation coefficient R of -0.9104 between ΔGbind and pIC50 of ligands. Compound 5 exhibited the best inhibitory activity (pIC50=6.36) and most favorable binding free energy (ΔGbind=-47.67 kcal/mol) than other derivatives. The binding sites of these compounds were found to be the hydrophobic substituted groups with the Cys813 residue by the decomposed binding free energy analysis.

Cytotoxic 1,3-Thiazole and 1,2,4-Thiadiazole Alkaloids from Penicillium oxalicum: Structural Elucidation and Total Synthesis.

Two new thiazole and thiadiazole alkaloids, penicilliumthiamine A and B (2 and 3), were isolated from the culture broth of Penicillium oxalicum, a fungus found in Acrida cinerea. Their structures were elucidated mainly by spectroscopic analysis, total synthesis and X-ray crystallographic analysis. Biological evaluations indicated that compound 1, 3a and 3 exhibit potent cytotoxicity against different cancer cell lines through inhibiting the phosphorylation of AKT/PKB (Ser 473), one of important cancer drugs target.

Computational insights into the interaction mechanism of triazolyl substituted tetrahydrobenzofuran derivatives with H(+),K(+)-ATPase at different pH.

The interaction mechanism of triazolyl substituted tetrahydrobenzofuran derivatives (compound 1 (N, N-Dipropyl-1-(2-phenyl-4,5,6,7-tetrahydrobenzofuran-4-yl)-1H-1,2,3-triazole-4-methanamine) and 2 (1-(2-Phenyl-4,5,6,7-tetrahydrobenzofuran-4-yl)-4-(morpholin-4-ylmethyl)-1H-1,2,3-triazole)) with H(+),K(+)-ATPase at different pH were studied by induced-fit docking, QM/MM optimization and MM/GBSA binding free energy calculations of two forms (neutral and protonated form) of compounds. The inhibition activity of compound 1 is measured and almost unchanged at different pH, while the activity of compound 2 increases significantly with pH value decreased. This phenomenon could be explained by their protonated form percentages and the calculated binding free energies of protonated and neutral mixture of compounds at different pH. The binding free energy of protonated form is higher than that of neutral form of compound, and the protonated form could be a powerful inhibitor of H(+),K(+)-ATPase. By the decomposed energy comparisons of residues in binding sites, Asp137 should be the key binding site to protonated form of compound because of the hydrogen bond and electrostatic interactions. These calculation results could help for further rational design of novel H(+),K(+)-ATPase inhibitors.

Synthesis and cytotoxic activities of 2-substituted (25R)-spirostan-1,4,6-triene-3-ones via ring-opening/elimination and 'click' strategy.

To develop more effective antitumor steroidal drugs, we synthesized a library including twenty-two novel cytotoxic 2-alkyloxyl substituted (25R)-spirostan-1,4,6-triene-3-ones and corresponding 1,2,3-triazoles through an abnormal monoepoxide ring-opening/elimination and 'click' reactions. After the cytotoxic evaluations against HepG2, Caski and HeLa cell lines, three steroidal triazoles 5b, 5f and 5m in this library were found to possess potent anti-proliferative effects against Caski cells with the half-inhibitory concentrations (IC50) of 9.4-11.8 µM. The high-efficient and straightforward process was attractive feature for facile preparation of anti-tumor steroidal triazoles.