ABSTRACT
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.
ABSTRACT
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.
ABSTRACT
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.
ABSTRACT
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.
ABSTRACT
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 OâC 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.
Subject(s)
Borates , Glycosides , Stereoisomerism , Glycosylation , Esters , CatalysisABSTRACT
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.
Subject(s)
Diabetes Mellitus, Type 2 , Glycoside Hydrolase Inhibitors , Humans , Glycoside Hydrolase Inhibitors/pharmacology , Glycoside Hydrolase Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/chemistry , Diabetes Mellitus, Type 2/drug therapy , alpha-Glucosidases/metabolism , Molecular Structure , Protein Tyrosine Phosphatase, Non-Receptor Type 1 , Molecular Docking SimulationABSTRACT
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.
ABSTRACT
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.
ABSTRACT
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.
ABSTRACT
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.
ABSTRACT
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.
Subject(s)
Glycosides/chemical synthesis , Boronic Acids/chemistry , Carbonates/chemistry , Glycosides/chemistry , Glycosylation , Molecular Structure , StereoisomerismABSTRACT
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.
Subject(s)
Brain Ischemia/metabolism , MicroRNAs/biosynthesis , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Reperfusion Injury/metabolism , TOR Serine-Threonine Kinases/metabolism , Triterpenes/therapeutic use , Animals , Brain Ischemia/pathology , Brain Ischemia/prevention & control , Cell Line, Tumor , Dose-Response Relationship, Drug , Humans , Male , MicroRNAs/antagonists & inhibitors , Neuroprotective Agents/pharmacology , Neuroprotective Agents/therapeutic use , Rats , Rats, Sprague-Dawley , Reperfusion Injury/pathology , Reperfusion Injury/prevention & control , Signal Transduction/drug effects , Signal Transduction/physiology , Triterpenes/pharmacologyABSTRACT
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.
ABSTRACT
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.
ABSTRACT
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.
Subject(s)
Enzyme Inhibitors/pharmacology , H(+)-K(+)-Exchanging ATPase/drug effects , Potassium/metabolism , Sesquiterpenes/pharmacology , Drug Design , Drug Evaluation, Preclinical , Oximes/chemistry , Sesquiterpenes/chemistryABSTRACT
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.
Subject(s)
Alkaloids/chemical synthesis , Antineoplastic Agents/chemical synthesis , Cytotoxins/chemical synthesis , Penicillium/chemistry , Thiadiazoles/chemical synthesis , Thiazoles/chemical synthesis , Alkaloids/isolation & purification , Alkaloids/pharmacology , Animals , Antineoplastic Agents/isolation & purification , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Cell Survival/drug effects , Crystallography, X-Ray , Cytotoxins/isolation & purification , Cytotoxins/pharmacology , Gene Expression , Grasshoppers/microbiology , Humans , Molecular Structure , Penicillium/isolation & purification , Proto-Oncogene Proteins c-akt/antagonists & inhibitors , Proto-Oncogene Proteins c-akt/genetics , Proto-Oncogene Proteins c-akt/metabolism , Thiadiazoles/isolation & purification , Thiadiazoles/pharmacology , Thiazoles/isolation & purification , Thiazoles/pharmacologyABSTRACT
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.
Subject(s)
Benzofurans/chemistry , Benzofurans/pharmacology , H(+)-K(+)-Exchanging ATPase/metabolism , Proton Pump Inhibitors/chemistry , Proton Pump Inhibitors/pharmacology , Amino Acid Sequence , Animals , Binding Sites , H(+)-K(+)-Exchanging ATPase/chemistry , Hydrogen-Ion Concentration , Molecular Docking Simulation , Molecular Sequence Data , Sequence Alignment , Swine , ThermodynamicsABSTRACT
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.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Click Chemistry/methods , Spirostans/chemistry , Antineoplastic Agents/chemical synthesis , Chemistry Techniques, Synthetic , Copper/chemistry , Cycloaddition Reaction , Diosgenin/chemistry , Drug Screening Assays, Antitumor , HeLa Cells/drug effects , Hep G2 Cells/drug effects , Humans , Inhibitory Concentration 50 , Magnetic Resonance Spectroscopy , Molecular Structure , Structure-Activity Relationship , Triazoles/chemistryABSTRACT
Seeking a strategy for triggering the cryptic natural product biosynthesis to yield novel compounds in the plant-associated fungus Xylaria sp., the effect of culture conditions on metabolite production was investigated. A shift in the production of five known cytochalasin-type analogues 1-5 to six new α-pyrone derivatives, xylapyrones A-F (compounds 6-11), from a solid to a liquid medium was observed. These compounds were identified by analysis of 1D and 2D NMR and HRMS data. Compounds 1-3 showed moderate cytotoxicity against HepG2 and Caski cancer cell lines with IC50 values ranging from 25 to 63 µM and compounds 4-11 were found to be inactive, with IC50 values>100 µM.
Subject(s)
Biological Products/chemistry , Biological Products/metabolism , Cytochalasins/chemistry , Cytochalasins/metabolism , Xylariales/chemistry , Xylariales/metabolism , Cell Culture Techniques/methods , Cell Line, Tumor , Hep G2 Cells , Humans , Magnetic Resonance Spectroscopy/methodsABSTRACT
In this publication, we design and report the synthesis of calix[4]arene-based ß-diketo derivatives as novel HIV-1 integrase (IN) inhibitors. The target compounds were obtained using Claisen condensation, and their structures were characterized by NMR and ESI-MS. Preliminary bioassays showed that calix[4]arene-based ß-diketo derivatives inhibit strand transfer (ST) with IC50 values between 5.9 and 21.2 µM. Docking studies revealed the predominant binding modes that were distinct from the binding modes of raltegravir, which suggests a novel binding region in the IN active site. Moreover, these compounds are predicted not to interact with some of the key amino acids (GLN148 and ASN155) implicated in viral resistance. Therefore, this series of compounds can further be investigated for a possible chemotype to circumvent resistance to clinical HIV-1 IN inhibitors.