Fluorogenic Chemical Probe Strategy for Precise Tracking of Mitochondrial Polarity.

Mitochondrial polarity is a critical indicator of numerous pathological and biological processes; thus, the development of fluorescent probes capable of targeting mitochondria and visually monitoring its polarity is of great significance. In this study, fluorescent probes were designed with a N, N-dialkylamino rhodol scaffold as the fluorophore sensitive to polarity environments, in which the alkyl chain length was adjusted rationally to obtain distinct polarity recognition modes. By integrating mitochondria targeting groups, three fluorogenic chemical probes , , and have been obtained, featuring the capability to target mitochondria and monitor its polarity precisely, dynamically and visually.

Integration of serum pharmacochemistry with network pharmacology to reveal the potential mechanism of Yangqing Chenfei formula for the treatment of silicosis.

Objective: To explore the mechanisms of Yangqing Chenfei formula (, YCF) in the treatment of silicosis through a comprehensive strategy consisting of serum pharmacochemistry, network pharmacology analysis, and validation.

Methods: An ultrahigh-performance liquid chroma-tography-tandem mass spectrometry method was used to confirm the active components in YCF-medicated serum. Then, we obtained targets for active components and genes for silicosis from multiple databases.

Yangqing Chenfei formula alleviates crystalline silica induced pulmonary inflammation and fibrosis by suppressing macrophage polarization.

Objective: To explore the underlying mechanisms of the effects of Yangqing Chenfei formula (, YCF) on inflammation and fibrosis in silicosis inhibition of macrophage polarization.

Methods: A silicotic rat model was established a single intratracheal instillation of silica particles on the first day of week 0. Subsequently, YCF was administered intragastrically to silicotic rats during weeks 0-2 and 5-8 twice daily.

Yangqing Chenfei formula alleviates silica-induced pulmonary inflammation in rats by inhibiting macrophage M1 polarization.

Background: Yangqing Chenfei formula (YCF) is a traditional Chinese medicine formula for early-stage silicosis. However, the therapeutic mechanism is unclear. The purpose of this study was to determine the mechanism for the effects of YCF on early-stage experimental silicosis.

Design and synthesis of aminopyridine containing biaryls reducing c-MYC protein levels in cells.

The c-MYC oncogene transcription factor has been implicated in cell cycle regulation controlling cell growth and proliferation. It is tightly regulated in normal cells, but has been shown to be deregulated in cancer cells, and is thus an attractive target for oncogenic therapies. Building upon previous SAR, a series of analogues containing benzimidazole core replacements were prepared and evaluated, leading to the identification of imidazopyridazine compounds that were shown to possess equivalent or improved c-MYC HTRF pEC values, lipophilicity, solubility, and rat pharmacokinetics.

[Digoxin alleviates pulmonary fibrosis by regulating phosphatidylinositol-3-kinase/Akt signaling through inhibiting the activation of fibroblast: an in vivo and in vitro experiment].

Objective: To investigate the effect of digoxin on bleomycin-induced pulmonary fibrosis in mice, and investigate its possible mechanism through in vitro and in vivo experiments.

Methods: (1) In vivo experiment: 60 C57/BL6J mice were randomly divided into control group, pulmonary fibrosis model group (model group), pirfenidone (300 mg/kg) group, digoxin 1.0 mg/kg and 0.

Discovery of Proline-Based p300/CBP Inhibitors Using DNA-Encoded Library Technology in Combination with High-Throughput Screening.

E1A binding protein (p300) and CREB binding protein (CBP) are two highly homologous and multidomain histone acetyltransferases. These two proteins are involved in many cellular processes by acting as coactivators of a large number of transcription factors. Dysregulation of p300/CBP has been found in a variety of cancers and other diseases, and inhibition has been shown to decrease Myc expression.

Electronically Engineering Water Resistance in Methane Combustion with an Atomically Dispersed Tungsten on PdO Catalyst.

Improving the low-temperature water-resistance of methane combustion catalysts is of importance for industrial applications and it is challenging. A stepwise strategy is presented for the preparation of atomically dispersed tungsten species at the catalytically active site (Pd nanoparticles). After an activation process, a Pd-O-W -like nanocompound is formed on the PdO surface with an atomic scale interface.

Cell-Based Drug Discovery: Identification and Optimization of Small Molecules that Reduce -MYC Protein Levels in Cells.

Elevated expression of the -MYC oncogene is one of the most common abnormalities in human cancers. Unfortunately, efforts to identify pharmacological inhibitors that directly target MYC have not yet yielded a drug-like molecule due to the lack of any known small molecule binding pocket in the protein, which could be exploited to disrupt MYC function. We have recently described a strategy to target MYC indirectly, where a screening effort designed to identify compounds that can rapidly decrease endogenous -MYC protein levels in a amplified cell line led to the discovery of a compound series that phenocopies -MYC knockdown by siRNA.

A DNA Hypomethylation Signature Predicts Antitumor Activity of LSD1 Inhibitors in SCLC.

Epigenetic dysregulation has emerged as an important mechanism in cancer. Alterations in epigenetic machinery have become a major focus for targeted therapies. The current report describes the discovery and biological activity of a cyclopropylamine containing inhibitor of Lysine Demethylase 1 (LSD1), GSK2879552.

Diels-Alder reactions of 12-hydroxy-9(10®20)-5aH-abeo-abieta-1(10),8(9),12(13)-triene-11,14-dione.

12-Hydroxy-9(10-->20)-5aH-abeo-abieta-1(10),8(9),12(13)-triene-11,14-dione (quinone 2) served as the dienophile in numerous intermolecular Diels-Alder reactions. These cycloadditions were conducted either thermally (including microwave heating) or with Lewis acid activation. While most dienes reacted with quinone 2 in good chemical yield, others were incompatible under the experimental conditions used.

Identification of Potent, Selective, Cell-Active Inhibitors of the Histone Lysine Methyltransferase EZH2.

The histone H3-lysine 27 (H3K27) methyltransferase EZH2 plays a critical role in regulating gene expression, and its aberrant activity is linked to the onset and progression of cancer. As part of a drug discovery program targeting EZH2, we have identified highly potent, selective, SAM-competitive, and cell-active EZH2 inhibitors, including GSK926 (3) and GSK343 (6). These compounds are small molecule chemical tools that would be useful to further explore the biology of EZH2.

EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations.

In eukaryotes, post-translational modification of histones is critical for regulation of chromatin structure and gene expression. EZH2 is the catalytic subunit of the polycomb repressive complex 2 (PRC2) and is involved in repressing gene expression through methylation of histone H3 on lysine 27 (H3K27). EZH2 overexpression is implicated in tumorigenesis and correlates with poor prognosis in several tumour types.

Discovery of orally bioavailable 1,3,4-trisubstituted 2-oxopiperazine-based melanocortin-4 receptor agonists as potential antiobesity agents.

A study that was designed to identify plausible replacements for highly basic guanidine moiety contained in potent MC4R agonists, as exemplified by 1, led to the discovery of initial nonguanidine lead 5. Propyl analog 23 was subsequently found to be equipotent to 5, whereas analogs bearing smaller and branched alkyl groups at the 3 position of the oxopiperazine template demonstrated reduced binding affinity and agonist potency for MC4R. Acylation of the NH2 group of the 4F-D-Phe residue of 3-propyl analog 23 significantly increased the binding affinity and the functional activity for MC4R.

Design, synthesis, and evaluation of proline and pyrrolidine based melanocortin receptor agonists. A conformationally restricted dipeptide mimic approach.

The design, synthesis, and structure-activity relationships (SAR) of a series of novel proline and pyrrolidine based melanocortin receptor (MCR) agonists are described. To validate a conformationally constrained Arg-Nal dipeptide analogue strategy, we first synthesized and evaluated a test set of cis-(2R,4R)-proline analogues (21a-g). All of these compounds showed significant binding and agonist potency at the hMC1R, hMC3R, and hMC4R.

Design and synthesis of potent and selective 1,3,4-trisubstituted-2-oxopiperazine based melanocortin-4 receptor agonists.

The design and synthesis of a series of potent 1,3,4-trisubstituted-2-oxopiperazine based MC4 agonists are described. The tripeptidomimetic analogs (12a,b and 23) and the dipeptidomimetic 27 displayed single-nanomolar binding affinity and agonist potency for MC4R and excellent selectivity for MC4R relative to MC1R.

Synthesis of Tic-D-Phe Psi[CH2-CH2] isostere and its use in the development of melanocortin receptor agonists.

The first synthesis of Tic-D-Phe Psi[CH(2)-CH(2)] isostere is described, which features diastereoselective alkylation of the tricyclic lactam 14. The use of this novel dipeptide isostere in the development of melanocortin agonists has been demonstrated by the synthesis of peptidomimetic 7 and non-peptidic ligand 27. Both compounds displayed significant binding and agonist potency at the MC4R.

Design, synthesis, and evaluation of proline based melanocortin receptor ligands.

A series of proline based melanocortin ligands has been developed on the basis of initial piperazine leads by using a more conformationally rigid scaffold. A number of these novel ligands showed significant binding affinity for MC3 and MC4 receptors.

Probes for narcotic receptor-mediated phenomena. 33. Construction of a strained trans-5,6-ring system by displacement of a nitro-activated aromatic fluorine. synthesis of the penultimate oxide-bridged phenylmorphans.

The synthesis of the ortho- and para-e isomers in the oxide-bridged 5-phenylmorphan series of rigid tetracyclic compounds was accomplished via rac-5-(2-fluoro-5-nitrophenyl)-2-methyl-2-azabicyclo[3.3.1]nonan-9beta-ol ((+/-)-10), an intermediate containing an aromatic nitro-activated fluorine atom.

Synthesis and pharmacological evaluation of 3-(3,4-dichlorophenyl)-1-indanamine derivatives as nonselective ligands for biogenic amine transporters.

In our efforts toward developing a nonselective ligand that would block the effects of stimulants such as methamphetamine at dopamine (DA), serotonin (5-HT), and norepinephrine (NE) transporters, we synthesized a series of 3-(3,4-dichlorophenyl)-1-indanamine derivatives. Two of the examined higher affinity compounds had a phenolic hydroxyl group enabling preparation of a medium to long chain carboxylic acid ester that might eventually be useful for a long-acting depot formulation. The in vitro data indicated that (-)-(1R,3S)-trans-3-(3,4-dichlorophenyl)-6-hydroxy-N-methyl-1-indanamine ((-)-(1R,3S)-11) displays high-affinity binding and potent inhibition of uptake at all three biogenic amine transporters.

CRHR1 Receptor binding and lipophilicity of pyrrolopyrimidines, potential nonpeptide corticotropin-releasing hormone type 1 receptor antagonists.

A series of compounds related to N-butyl-N-ethyl[2,5,6-trimethyl-7-(2,4,6-trimethylphenyl)pyrrolo[2,3-d]pyrimidin-4-yl]amine (1, antalarmin) have been prepared and evaluated for their CRHR1 binding affinity as the initial step in the development of selective high affinity hydrophilic nonpeptide corticotropin-releasing hormone type 1 receptor (CRHR1) antagonists. Calculated log P (Clog P) values were used to evaluate the rank order of hydrophilicity for these analogues. Introducing oxygenated functionalities (delta-hydroxy or bis-beta-ethereal) into 1 gave more hydrophilic compounds, which had good affinity for the receptor.

Use of Conjugated Dienones in Cyclialkylations: The Total Syntheses of (+/-)-Barbatusol, (+/-)-Pisiferin, (+/-)-Deoxofaveline, (+/-)-Xochitlolone, and (+/-)-Faveline.

Concise syntheses of five tricyclic diterpenoids are reported. The key reaction in each synthesis is a cyclialkylation of a functionalized arene with a Lewis acid-activated conjugated dienone to generate a 6,7,6-fused tricycle.