QPH-FR: A Novel Quinoa Peptide Enhances Chemosensitivity by Targeting Leucine-Rich Repeat-Containing G Protein-Coupled Receptor 5 in Colorectal Cancer.

Chemoresistance is one of the difficulties in the treatment of colorectal cancer (CRC), and the enhanced stemness of tumor cells is the underlying contributing factor. Leucine-rich repeat-containing G-protein-coupled receptor 5 (LGR5) is a classical marker of CRC stem cells and can be an important potential target for CRC chemotherapy. Quinoa, a protein-rich plant, offers potential as a source of high-quality active peptides.

Enantioselective Synthesis of 2,3,3a,8a-Tetrahydrofuro[2,3-]benzofuran Scaffolds Enabled by Cu(II)/SPDO-Catalyzed [3+2] Cycloaddition of 2,3-Dihydrofuran and Quinone Esters.

An asymmetric [3+2] cycloaddition of quinone esters with 2,3-dihydrofuran has been realized via a newly developed Cu(II)/SPDO complex. It provides straightforward access to 2,3,3a,8a-tetrahydrofuro[2,3-]benzofurans (TFB) with high enantioselectivity (up to 97.5:2.

Tumor-associated macrophages confer colorectal cancer 5-fluorouracil resistance by promoting MRP1 membrane translocation via an intercellular CXCL17/CXCL22-CCR4-ATF6-GRP78 axis.

Chemotherapy represents a major type of clinical treatment against colorectal cancer (CRC). Aberrant drug efflux mediated by transporters acts as a key approach for tumor cells to acquire chemotherapy resistance. Increasing evidence implies that tumor-associated macrophages (TAMs) play a pivotal role in both tumorigenesis and drug resistance.

Polyphenols from whole millet grain (Setaria italica) alleviate glucose and lipid homeostasis in diet-induced obese mice by increasing endogenous GLP-1.

Background: Foxtail millet (Setaria italica) is a whole millet grain that has been considered for improving the disorder of glucose and lipid metabolism. The purpose of the work is to explore the extraction and enrichment of polyphenols from foxtail millets which can regulate the disorder of glucose and lipid metabolism by increasing endogenous GLP-1 (glucagon-like peptide-1).

Results: The optimum ultrasound-assisted extraction (UAE) of foxtail millet polyphenols (FMPs) was as follows: 70 °C and 400 W and 70% ethanol concentration, further purification using macroporous resin.

Asymmetric Intramolecular Hydroalkylation of Internal Olefin with Cycloalkanone to Directly Access Polycyclic Systems.

An asymmetric intramolecular hydroalkylation of unactivated internal olefins with tethered cyclic ketones was realized by the cooperative catalysis of a newly designed chiral amine (SPD-NH ) and Pd complex, providing straightforward access to either bridged or fused bicyclic systems containing three stereogenic centers with excellent enantioselectivity (up to 99 % ee) and diastereoselectivity (up to >20 : 1 dr). Notably, the bicyclic products could be conveniently transformed into a diverse range of key structures frequently found in bioactive terpenes, such as Δ -protoilludene, cracroson D, and vulgarisins. The steric hindrance between the Ar group of the SPD-NH catalyst and the branched chain of the substrate, hydrogen-bonding interactions between the N-H of the enamine motif and the C=O of the directing group MQ, and the counterion of the Pd complex were identified as key factors for excellent stereoinduction in this dual catalytic process by density functional theory calculations.

Discovery of 2,5-disubstituted furan derivatives featuring a benzamide motif for overcoming P-glycoprotein mediated multidrug resistance in MCF-7/ADR cell.

P-glycoprotein (P-gp) is one of the drug efflux transporters that triggers multidrug resistance (MDR) in cells. Herein, by utilizing the strategies of active skeleton splicing and structural optimization on the lead compound 5 m, a total of 50 novel 2,5-disubstituted furan derivatives were designed, synthesized, and screened for P-gp inhibitory activity. The structure-activity relationship analysis enabled the identification of an important pharmacophore N-phenylbenzamide, which resulted in the discovery of a promising drug lead compound Ⅲ-8.

Tumor-secreted GRP78 induces M2 polarization of macrophages by promoting lipid catabolism.

Macrophages in hypoxic regions of advanced colorectal tumors often exhibit M2-type features, but prefer oxygen-consuming lipid catabolism, which is contradictory in oxygen demand and supply. In this study, the results from bioinformatics analysis and intestinal lesions immunohistochemistry of 40 colorectal cancer patients illustrated that glucose-regulatory protein 78 (GRP78) was positively correlated with M2 macrophages. Furthermore, tumor-secreted GRP78 could enter macrophages and polarize them to M2-type.

Novel Benzo Five-Membered Heterocycle Derivatives as P-Glycoprotein Inhibitors: Design, Synthesis, Molecular Docking, and Anti-Multidrug Resistance Activity.

A proposed strategy to overcome multidrug resistance (MDR) of anticancer drugs in chemotherapy is to disable the efflux function of P-glycoprotein (P-gp). In this study, based on ring-merging and fragment-growing strategies, 105 novel benzo five-membered heterocycle derivatives were designed, synthesized, and screened. Exploration of the structure-activity relationship (SAR) led to the identification of with low cytotoxicity and promising reversal activity to doxorubicin in MCF-7/ADR cells.

Salvianolic acid A attenuates inflammation-mediated atherosclerosis by suppressing GRP78 secretion of endothelial cells.

Ethnopharmacological Relevance: Salvianolic acid A (SAA) is the main active component of the classic anti-atherosclerotic drug Salvia miltiorrhiza Bunge. Inflammation-induced infiltration of monocyte/macrophages into the vascular wall is the initiating step in atherogenesis, and targeted blocking of this step may provide a promising avenue for the precise treatment of atherosclerosis. However, the effect of salvianolic acid A on macrophages is still unknown.

Design, synthesis and biological evaluation of novel phenylfuran-bisamide derivatives as P-glycoprotein inhibitors against multidrug resistance in MCF-7/ADR cell.

The co-administration of anticancer drugs and P-glycoprotein (P-gp) inhibitors was a treatment strategy to surmount multidrug resistance (MDR) in anticancer chemotherapy. In this study, novel phenylfuran-bisamide derivatives were designed as P-gp inhibitors based on target-based drug design, and 31 novel compounds were synthesized and screened on MCF-7/ADR cells. The result of bioassay revealed that compound y12d exhibited low cytotoxicity and promising MDR reversal activity (IC = 0.

Recent advances in the applications of pyrazolone derivatives in enantioselective synthesis.

Pyrazolones and pyrazoles, featuring nitrogen-nitrogen bonds, are two of the most important classes of heterocycles, owing to their widespread occurrence in medicinal chemistry and functional materials. The last decade has witnessed a rapid increase in the construction of chiral pyrazolone and pyrazole derivatives, with the application of pyrazolone derivatives as powerful synthons. Since our last review in 2018, a large number of new achievements has emerged in this area, requiring a timely update.

Enantioselective Construction of 2-Aryl-2,3-dihydrobenzofuran Scaffolds Using Cu/SPDO-Catalyzed [3 + 2] Cycloaddition.

A new, efficient approach toward the preparation of 2-aryl-2,3-dihydrobenzofuran scaffolds through the Cu/SPDO-catalyzed [3 + 2] cycloaddition between quinone ester and styrene derivatives has been developed. The procedure features excellent enantioselectivities (up to 99% ee), high yields (up to 96%), and broad substrate tolerance. Additionally, asymmetric synthesis of natural corsifurans A and B from commercially available starting materials has also been achieved in two or three steps using this reaction as a key transformation.

Development of a UPLC-MS/MS Method for the Quantification of VS-5584 and Its Application in Pharmacokinetic Studies in Rats.

VS-5584 is a small-molecular compound that showed equivalent activity against mTOR and all class I PI3K isoforms and demonstrated preclinical activity in diverse cancer cell lines and xenograft tumor model, and rational combination of VS-5584 and other target therapies achieved promising outcomes in oncology. In the present study, we established and validated a simple and sensitive UPLC-MS/MS method for the determination of VS-5584 in plasma samples. VS-5584 was separated via an Acquity UPLC BEH C18 column, with a mobile phase composed of acetonitrile and 0.

Enantioselective Synthesis of 3,3'-Disubstituted 2-Amino-2'-hydroxy-1,1'-binaphthyls by Copper-Catalyzed Aerobic Oxidative Cross-Coupling.

A challenging direct asymmetric catalytic aerobic oxidative cross-coupling of 2-naphthylamine and 2-naphthol, using a novel Cu /SPDO system, has been successfully developed for the first time. Enantioenriched 3,3'-disubstituted NOBINs were achieved and could be readily derived to divergent chiral ligands and catalysts. This reaction features high enantioselectivities (up to 96 % ee) and good yields (up to 80 %).

Development of a ultra-performance LC-MS/MS method for quantification of GW788388 and its applications in pharmacokinetic study in rats.

GW788388 is a selective and orally active TGF-β1 receptor inhibitor that shows potent activity in renal fibrosis. We aimed to establish and validate a simple and sensitive ultra-performance LC-MS/MS method for the determination of GW788388 in plasma samples. GW788388 in rat plasma was processed with protein precipitation method and then separated on a C column.

Atroposelective Synthesis of Axially Chiral 3-Arylindoles by Copper-Catalyzed Asymmetric Cross-Coupling of Indoles with Quinones and Naphthoquinones.

A copper-catalyzed direct asymmetric coupling of C2 sterically-hindering-group-substituted indoles with quinone and naphthoquinone esters was developed by using the spirocyclic pyrrolidine oxazoline (SPDO) ligand, which was accomplished by metal catalysis for the first time. Diverse structures of axially chiral 3-arylindoles were obtained with good to high enantioselectivities in good to high yields. This protocol can be expanded to implement β-coupling with naphthoquinone esters, providing an alternative way to prepare β-substituted derivatives of both naphthols and naphthoquinones.

Quantitation of capmatinib, a mesenchymal-epithelial transition factor inhibitor by UPLC-MS/MS in rat plasma and its application to a pharmacokinetic study.

Capmatinib is an orally bioavailable mesenchymal-epithelial transition factor inhibitor with anticancer activity, which has proved preclinical activity in multiple cancer trials. The present study aimed to develop a fast and reliable assay approach to quantify capmatinib in rat plasma. After protein precipitation with acetonitrile, the chromatographic separation was achieved with an Acquity UPLC BEH C column, and subsequently detected with positive electrospray ionization via a triple quadrupole tandem mass spectrometer.

Nongenetic engineering strategies for regulating receptor oligomerization in living cells.

Cell surface receptors are important proteins that mediate communication between the cells and their outside environment, and also play essential roles in the control of a wide variety of biological processes, such as cell cycle, proliferation, communication, migration and apoptosis. Receptor oligomerization is an essential signal transduction mechanism that cell surface receptors use to transmit extracellular signals into the internal cytosol cellular machinery. Therefore, regulating receptor oligomerization provides an opportunity to customize cellular signaling and to direct cellular behavior in a user-defined manner.

Catalytic Asymmetric Total Syntheses of (-)-Galanthamine and (-)-Lycoramine.

The catalytic asymmetric total syntheses of the biologically important and therapeutically valuable alkaloids (-)-galanthamine and (-)-lycoramine have been divergently achieved from commercially available 3-butyn-1-ol. A newly developed spirocyclic pyrrolidine (SPD)-catalyzed enantioselective Robinson annulation rapidly constructs the key -hydrodibenzofuran core, which bears an all-carbon quaternary stereocenter of the target molecules with an excellent stereoselective control. Additionally, the current asymmetric synthetic strategy provides an alternative approach toward the syntheses of (-)-galanthamine and its analogues.

Development of bifunctional organocatalysts and application to asymmetric total synthesis of naucleofficine I and II.

The proline-type organocatalysts has been efficiently employed to catalyze a wide range of asymmetric transformations; however, there are still many synthetically useful and challenging transformations that remain unachievable in an asymmetric fashion. Herein, a chiral bifunctional organocatalyst with a spirocyclic pyrrolidine backbone-derived containing fluoro-alkyl and aryl sulfonamide functionalities, are designed, prepared, and examined in the asymmetric Mannich/acylation/Wittig reaction sequence of 3,4-dihydro-β-carboline with acetaldehyde, acyl halides, and Wittig reagents. As a result, the spirocyclic pyrrolidine trifluoromethanesulfonamide catalyst can facilitate this versatile sequence as demonstrated by 18 examples displaying excellent enantioselectivity (up to 94% ee), as well as moderate to good yields (up to 54% over 3 steps).

Highly atroposelective synthesis of nonbiaryl naphthalene-1,2-diamine N-C atropisomers through direct enantioselective C-H amination.

Nonbiaryl N-C atropisomer is an important structural scaffold, which is present in natural products, medicines and chiral ligands. However the direct enantioselective C-H amination to access optically pure N-C atropisomer is still difficult and rare. Here we report a π-π interaction and dual H-bond concerted control strategy to develop the chiral phosphoric acids (CPAs) catalyzed direct intermolecular enantioselective C-H amination of N-aryl-2-naphthylamines with azodicarboxylates as amino sources for the construction of atroposelective naphthalene-1,2-diamines.

Lewis Base/Brønsted Acid Co-catalyzed Enantioselective Sulfenylation/Semipinacol Rearrangement of Di- and Trisubstituted Allylic Alcohols.

An enantioselective sulfenylation/semipinacol rearrangement of 1,1-disubstituted and trisubstituted allylic alcohols was accomplished with a chiral Lewis base and a chiral Brønsted acid as cocatalysts, generating various β-arylthio ketones bearing an all-carbon quaternary center in moderate to excellent yields and excellent enantioselectivities. These chiral arylthio ketone products are common intermediates with many applications, for example, in the design of new chiral catalysts/ligands and the total synthesis of natural products. Computational studies (DFT calculations) were carried out to explain the enantioselectivity and the role of the chiral Brønsted acid.

Enantioselective synthesis of cis-hydrobenzofurans bearing all-carbon quaternary stereocenters and application to total synthesis of (‒)-morphine.

(‒)-Morphine, which is selected as an essential medicine by World Health Organization, is widely applied in the treatment of the pain-related diseases. Due to its synthetically challenging molecular architecture and important clinical role, extensive synthetic studies of morphine-type alkaloids have been conducted. However, catalytic asymmetric total synthesis of (‒)-morphine remains a long-standing challenge.

Copper-Complex-Catalyzed Asymmetric Aerobic Oxidative Cross-Coupling of 2-Naphthols: Enantioselective Synthesis of 3,3'-Substituted C -Symmetric BINOLs.

A novel chiral 1,5-N,N-bidentate ligand based on a spirocyclic pyrrolidine oxazoline backbone was designed and prepared, and it coordinates CuBr in situ to form an unprecedented catalyst that enables efficient oxidative cross-coupling of 2-naphthols. Air serves as an external oxidant and generates a series of C -symmetric chiral BINOL derivatives with high enantioselectivity (up to 99 % ee) and good yield (up to 87 %). This approach is tolerant of a broader substrates scope, particularly substrates bearing various 3- and 3'-substituents.

Organo-Cation Catalyzed Asymmetric Homo/Heterodialkylation of Bisoxindoles: Construction of Vicinal All-Carbon Quaternary Stereocenters and Total Synthesis of (-)-Chimonanthidine.

A novel chiral spirocyclic amide (SPA)-derived triazolium organocatalyst has been designed and demonstrated to effect asymmetric homo- and heterodialkylations of various bisoxindoles, enabling enantioselective construction of vicinal all-carbon quaternary stereocenters. These reactions feature excellent enantio- and diastereoselectivities (up to 99% ee and >20:1 dr) as well as good to high yields (up to 89% over two steps). As an application of this methodology, the first asymmetric total synthesis of (-)-chimonanthidine has been achieved.