Design, Synthesis, and Biological Evaluation of 2-Arylaminopyrimidine Derivatives as Dual Cathepsin L and JAK Inhibitors for the Treatment of Acute Lung Injury.

Acute lung injury (ALI) is a disease characterized by pulmonary inflammation, blood barrier functional disorder, and hypoxemia. Herein, a series of 2-aminopyrimidine derivatives were synthesized. Most of them exhibited inhibitory effects on inflammatory cytokines IL-6 and IL-8 in human bronchial epithelial (HBE) cells at a concentration of 5 μM without significant cytotoxicity.

The Synthesis of Benzazepines via Sequential [3 + 2]-Annulation and [3,3]-Sigmatropic Rearrangement.

A novel annulation reaction of prop-2-ynylsulfonium salts with sulfur ylides and nitrosobenzenes has been developed, affording various benzazepines in moderate to good yields. Prop-2-ynylsulfonium salts act as C synthons in the reactions, providing a promising benzazepine skeleton in a one-pot operation with readily accessible starting materials.

Inhibition of cathepsin L ameliorates inflammation through the A20/NF-κB pathway in endotoxin-induced acute lung injury.

Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a severe inflammatory condition that remains refractory; however, its molecular mechanisms are largely unknown. Previous studies have shown numerous compounds containing 4-indolyl-2-aminopyrimidine that display strong anti-inflammatory properties. In our research, we identified that a 4-Indole-2-Arylaminopyrimidine derivative named "IAAP" suppressed lipopolysaccharide (LPS)-induced inflammation.

Ru-Catalyzed C-H Alkylation of 4-Aryl-pyrrolo[2,3-]pyrimidines with Diazo Compounds: An Access to Fluorescent Fused Heteroarenes.

A Ru(II)-catalyzed migratory insertion of carbene into C-H bonds of 4-aryl-pyrrolo[2,3-]pyrimidines has been developed. This transformation endows the facile fabrication of C-C bonds with high atom economy, good regioselectivity, and wide functional group tolerance, exploiting the directing properties of pyrimidinic nitrogen. In addition, the planar polycyclic pyrrolo-pyrimido-isoindole framework has been accomplished from a cascade reaction of bromination, cyclization, and decarboxylation of synthesized products.

PhI(OAc)-Promoted Site-Selective C-H Chlorination of (Hetero)arenes with -Toluenesulfonyl Chloride.

An efficient and practical system for metal-free catalytic chlorination of (hetero)arenes by using readily available and inexpensive TsCl and PhI(OAc) is described. This newly developed protocol has been achieved by the nonsymmetric iodane generated by a combination of PhI(OAc) and TsCl. The broad substrate scope, good functional group tolerance, excellent regioselectivity, and short reaction times make this method attractive for the late-stage chlorination of complex drug-like scaffolds.

Deletion of histamine H2 receptor in VTA dopaminergic neurons of mice induces behavior reminiscent of mania.

Hyperfunction of the dopamine system has been implicated in manic episodes in bipolar disorders. How dopaminergic neuronal function is regulated in the pathogenesis of mania remains unclear. Histaminergic neurons project dense efferents into the midbrain dopaminergic nuclei.

Ligand-Enabled C6-Selective C-H Arylation of Pyrrolo[2,3-] Pyrimidine Derivatives with Pd Catalysts: An Approach to the Synthesis of EGFR Inhibitor AEE-788.

Herein, we report the Pd(II)-catalyzed direct C-H arylation of pyrrolo[2,3-]pyrimidine derivatives with aryl iodides, which is enabled by bidentate pyridine-pyridine ligands. A range of aryl iodides proved to be suitable coupling partners affording the desired products in good yields with high levels of C6 selectivity. This protocol features good tolerance of reactive functional groups, mild reaction conditions, and a simple reaction system, which provides an expeditious route to an essential class of 6-arylpyrrolo[2,3-]pyrimidines frequently found in bioactive compounds, and provides a step-economical access to the second-generation EGFR inhibitor AEE-788.

Iron-catalyzed benzylic C-H thiolation photoinduced ligand-to-metal charge-transfer.

Here, we describe an iron-catalyzed benzylic C-H thiolation of alkylarenes photoinduced ligand-to-metal charge-transfer. The protocol features operational simplicity, mild reaction conditions, and the use of FeCl as catalyst and thiols/disulfides as sulfur sources, which enables the transformation of diverse benzylic C-H bonds into C-S bonds with a high efficiency.

Visible-Light-Induced Highly Site-Selective Direct C-H Phosphorylation of Pyrrolo[2,3-]pyrimidine Derivatives with H-Phosphine Oxides.

An efficient and highly regioselective C6-phosphorylation protocol for pyrrolo[2,3-]pyrimidine (7-DAP) derivatives with various H-phosphine oxides induced by visible light at room temperature is described for the first time. This protocol has been successfully achieved by the combination of Na-eosin Y as a photocatalyst and LPO as an oxidant under transition metal- and additive-free conditions. The broad substrate scope, good functional group tolerance, excellent regioselectivity, and air tolerant conditions make this process favorable for the functional modification of pyrrolo[2,3-]pyrimidine scaffold and enrich the phosphorylated 7-DAP compounds for further biological evaluation.

Ruthenium-catalysed direct C-H amidation of 4-aryl-pyrrolo[2,3-]pyrimidines with acyl/phosphoryl azides.

A ruthenium-catalysed arene C-H amidation of 4-aryl-pyrrolo[2,3-]pyrimidine derivatives with acyl azides or phosphoryl azides as the nitrogen sources toward C-N bond formation was developed. This protocol could offer a novel and direct approach to access a series of amidated and phosphoramidated pyrrolo[2,3-]pyrimidine derivatives in moderate to good yields, thereby evading the general Curtius rearrangement. The protocol features significant functional group tolerance and a single-step process, with the release of only innocuous molecular nitrogen as the byproduct.

LiBF-Promoted Aromatic Fluorodetriazenation under Mild Conditions.

An efficient and mild fluorination method through LiBF-promoted aromatic fluorodetriazenation of 3,3-dimethyl-1-aryltriazenes is developed. The reaction proceeds smoothly and tends to complete within 2 h in the absence of a protic acid or strong Lewis acid. This method tolerates a wide range of functional groups and affords the aryl fluoride products in moderate to excellent yields.

Palladium-Catalyzed Highly Regioselective C6 Arylation of Pyrrolo[2,3-]pyrimidine Derivatives with Arylboronic Acids.

A mild and selective C6 arylation strategy for pyrrolo[2,3-]pyrimidine derivatives with arylboronic acids at room temperature is described. This unified protocol has been achieved by the synergistic combination of Pd(II)/TEMPO catalysis and CFCOH promotion under silver-, base-, and additive-free conditions. The broad substrate scope, good functional group tolerance, excellent regioselectivity, and air and moisture tolerant conditions make this process attractive for the effective synthesis and modification of targeted small molecule drugs.

Palladium-catalysed site-selective arene C-H fluoroalkoxylation of 4-aryl-pyrrolo[2,3-]pyrimidines.

A palladium-catalysed direct arene C-H fluoroalkoxylation of 4-aryl-pyrrolo[2,3-]pyrimidine derivatives with fluorinated alcohols is described. Highly site-selective mono- or bis-fluoroalkoxylation can be achieved by tuning the reaction conditions, affording various fluoroalkoxylated pyrrolo[2,3-]pyrimidine derivatives in moderate to good yields, which offer rational tailoring of their biological activity for their application in the field of pharmaceutical chemistry.

TIGAR alleviates oxidative stress in brain with extended ischemia via a pentose phosphate pathway-independent manner.

TP53-induced glycolysis and apoptosis regulator (TIGAR) alleviates oxidative stress and protects against ischemic neuronal injury by shifting glucose metabolism into the pentose phosphate pathway (PPP). However, the brain alters glucose metabolism from PPP to glycolysis during prolonged ischemia. It is still unknown whether and how TIGAR exerts the antioxidant activity and neuroprotection in prolonged ischemic brains.

Design, synthesis, and biological evaluation of C-8 modified curcumol derivatives against colorectal cancer cell lines.

A series of structurally modified curcumol derivatives at C-8 position were designed and synthesized, whose structures were confirmed by H NMR,C NMR, and HRMS analysis. The tested compounds were evaluated for antitumor activity against colorectal cancer cell lines SW620, HCT116, and CaCo2. Many of the tested candidates exhibited higher inhibition efficiency than curcumol.

BNIP3L/NIX-mediated mitophagy: molecular mechanisms and implications for human disease.

Mitophagy is a highly conserved cellular process that maintains the mitochondrial quantity by eliminating dysfunctional or superfluous mitochondria through autophagy machinery. The mitochondrial outer membrane protein BNIP3L/Nix serves as a mitophagy receptor by recognizing autophagosomes. BNIP3L is initially known to clear the mitochondria during the development of reticulocytes.

Pd-Catalyzed solvent-controlled site-selective arene C-H monoacyloxylation of pyrrolo[2,3-]pyrimidine derivatives.

An efficient and highly regioselective Pd-catalyzed direct arene C(sp)-H acyloxylation of pyrrolo[2,3-]pyrimidine derivatives is reported. The key strategy involves the utilization of the unique reactivity of pyrrolo[2,3-]pyrimidine and the employment of pyrrolo[2,3-]pyrimidine as the directing group. A variety of monoacyloxylated pyrrolo[2,3-]pyrimidine derivatives can be achieved by switching the solvents under mild conditions, and they can be further modified and exhibit various biological activities.

Design, synthesis and structure-activity relationship studies of 4-indole-2-arylaminopyrimidine derivatives as anti-inflammatory agents for acute lung injury.

Acute lung injury/acute respiratory distress syndrome (ALI/ARDS), a clinically high mortality disease, has not been effectively treated till now, and the development of anti-acute lung injury drugs is imminent. Acute lung injury was efficiently treated by inhibiting the cascade of inflammation, and reducing the inflammatory response in the lung. A series of novel compounds with highly efficient inhibiting the expression of inflammatory factors were designed by using 4-indolyl-2-aminopyrimidine as the core skeleton.

Natural compounds modulate the autophagy with potential implication of stroke.

Stroke is considered a leading cause of mortality and neurological disability, which puts a huge burden on individuals and the community. To date, effective therapy for stroke has been limited by its complex pathological mechanisms. Autophagy refers to an intracellular degrading process with the involvement of lysosomes.

Design, synthesis, and anticancer activity evaluation of curcumol derivatives.

A new series of C-14 curcumol derivatives as potent anticancer agents were designed and synthesized by click reaction, whose structures were confirmed by H NMR,C NMR, and HRMS analysis. All the synthesized compounds were evaluated for antitumor activity against colorectal cancer cell lines SW620 and HCT116. Most of them exhibited higher inhibitory activity than curcumol.

Recent developments of small molecules with anti-inflammatory activities for the treatment of acute lung injury.

Acute Lung Injury (ALI) can be caused by various diseases or conditions such as sepsis, pneumonia, trauma, shock, and inhalation of toxic gases. Many efforts have been made to identify new agents capable of treating ALI, and many compounds have shown interesting activities in the treatment of ALI. However, most of these compounds have only been tested for their clinical significance using in vitro and in vivo animal models.

Discovery and biological evaluation of proteolysis targeting chimeras (PROTACs) as an EGFR degraders based on osimertinib and lenalidomide.

Epidermal growth factor receptor (EGFR) is one of the important and valuable drug targets. Overexpression of EGFR is associated with the development of many types of cancer. In this study, three PROTACs small molecules (16a-16c) were designed, synthesized and evaluated for their cytotoxicity against the growth in different NSCLC cell line and the degradation effect.

Identification of constituents in Gui-Zhi-Jia-Ge-Gen-Tang by LC-IT-MS combined with LC-Q-TOF-MS and elucidation of their metabolic networks in rat plasma after oral administration.

Gui-Zhi-Jia-Ge-Gen-Tang (GZJGGT) is a traditional Chinese medicine (TCM) prescription commonly used to treat cervical spondylopathy, scapulohumeral periarthritis, etc. Though it is widely applied in clinical practice, the effective constituents of GZJGGT remain unclear. This was the first report on the identification of the chemical constituents from GZJGGT in vitro and in vivo using LC-IT-MS combined with LC-Q-TOF-MS.

Liposomal doxorubicin loaded PLGA-PEG-PLGA based thermogel for sustained local drug delivery for the treatment of breast cancer.

The aim of this research is to utilize a hybrid system of liposomal doxorubicin (DOX-Lip) loaded thermogel (DOX-Lip-Gel) to realize the steady sustained delivery of doxorubicin (DOX), a small hydrophilic drug, for the treatment of breast cancer locally. Herein, liposomal doxorubicin was prepared via the traditional film dispersion method with the particle size of 75 nm and drug entrapment efficiency of 86%. And, the triblock copolymer of poly (D, L-lactide-co-glycolide)-b-poly (ethylene glycol)-b-poly (D, L-lactide -co-glycolide) (PLGA-PEG-PLGA) was synthesized via ring-opening polymerization to prepare the thermosensitive hydrogel through dissolving the polymers in DOX-Lip solution.

Characterization of the chemical constituents in Hongjingtian injection by liquid chromatography quadrupole time-of-flight mass spectrometry.

Hongjingtian injection is made from Rhodiola wallichiana and used in the treatment of stable angina pectoris associated with coronary heart disease. In this study, the chemical constituents in Hongjingtian injection were comprehensively studied using liquid chromatography quadrupole time-of-flight mass spectrometry. A total of 49 compounds were identified or assumed, including 10 organic acids, nine phenylethanoids, 10 phenylpropanoids, two flavonoid glycosides, seven monoterpene glycosides, seven octylglycosides and four other types of compounds.