Synthesis and biological evaluation of new series of quinazoline derivatives as EGFR/HER2 dual-target inhibitors.

It is generally believed that EGFR/HER2 dual-target inhibitors may overcome the resistance of EGFR TKIs caused by HER2 overexpression. The structure-based synthesis and biological evaluation of quinazoline derivatives as EGFR/HER2 dual-target inhibitors has been studied in this paper. II-1, II-2, III-3, III-4 displayed comparable inhibitory potency against EGFR and HER2 and II-1 showed remarkable antiproliferative activities against NCI-H358/PC-9/Calu-3/NCI-H1781 (EGFR IC50 = 0.30 nM, HER2 IC50 = 6.07 nM, NCI-H358 GI50 = 23.30 nM, PC-9 GI50 = 1.95 nM, Calu-3 GI50 = 23.13 nM NCI-H1781 GI50 = 41.61 nM).

Chicoric Acid Prevents Neuroinflammation and Neurodegeneration in a Mouse Parkinson's Disease Model: Immune Response and Transcriptome Profile of the Spleen and Colon.

Chicoric acid (CA), a polyphenolic acid compound extracted from chicory and echinacea, possesses antiviral, antioxidative and anti-inflammatory activities. Growing evidence supports the pivotal roles of brain-spleen and brain-gut axes in neurodegenerative diseases, including Parkinson's disease (PD), and the immune response of the spleen and colon is always the active participant in the pathogenesis and development of PD. In this study, we observe that CA prevented dopaminergic neuronal lesions, motor deficits and glial activation in PD mice, along with the increment in striatal brain-derived neurotrophic factor (BDNF), dopamine (DA) and 5-hydroxyindoleacetic acid (5-HT). Furthermore, CA reversed the level of interleukin-17(IL-17), interferon-gamma (IFN-γ) and transforming growth factor-beta (TGF-ß) of PD mice, implicating its regulatory effect on the immunological response of spleen and colon. Transcriptome analysis revealed that 22 genes in the spleen (21 upregulated and 1 downregulated) and 306 genes (190 upregulated and 116 downregulated) in the colon were significantly differentially expressed in CA-pretreated mice. These genes were functionally annotated with GSEA, GO and KEGG pathway enrichment, providing the potential target genes and molecular biological mechanisms for the modulation of CA on the spleen and gut in PD. Remarkably, CA restored some gene expressions to normal level. Our results highlighted that the neuroprotection of CA might be associated with the manipulation of CA on brain-spleen and brain-gut axes in PD.

A New γ-Glutamyltranspeptidase-Based Intracellular Self-Assembly of Fluorine-18 Labeled Probe for Enhancing PET Imaging in Tumors.

γ-Glutamyltranspeptidase (GGT) is a cell -membrane-associated enzyme which has been recognized as a promising biomarker for the diagnosis of many malignant tumors. Herein, we rationally designed a fluorine-18 labeled small-molecule probe, [18F]γ-Glu-Cys(StBu)-PPG(CBT)-AmBF3 (18F-1G), by applying a biocompatible CBT-Cys condensation reaction and ingeniously decorating it with a GGT-recognizable substrate, γ-glutamate (γ-Glu), for enhancing PET imaging to detect GGT level of tumors in living nude mice. The probe had exceptional stability at physiological conditions, but could be efficiently cleaved by GGT, followed by a reduction-triggered self-assembly and formation of nanoparticles (NPs) progressively that could be directly observed by transmission electron microscopy (TEM). In in vitro cell experiments, 18F-1G showed GGT-targeted uptake contrast of 2.7-fold to that of 18F-1 for the detection of intracellular GGT level. Moreover, the higher uptake in GGT overexpressed HCT116 tumor cells (∼4-fold) compared to GGT-deficient L929 normal cells demonstrated that 18F-1G was also capable of distinguishing some tumor cells from normal cells. In vivo PET imaging revealed enhanced and durable radioactive signal in tumor regions after 18F-1G coinjecting with 1G, thus allowing real-time detection of endogenous GGT level with high sensitivity and noninvasive effect. We anticipated that our probe could serve as a new tool to investigate GGT-related diseases in the near future.

Isoliquiritigenin-induced vasodilation by activating large-conductance Ca2+ -activated K+ channels in mouse mesenteric arteries.

Isoliquiritigenin (ISL) is a flavonoid substance with a chalcone structure, which exerts anti-tumour, anti-oxidation and anti-inflammatory activity. The large-conductance calcium-activated potassium channel (BKCa ) is an important potassium channel with negative feedback regulation on the vascular smooth muscle cells (VSMCs) membrane. The activation of BKCa channel causes the hyperpolarization of VSMCs. It plays an important role in relaxation of blood vessels. Previous studies have shown that ISL causes the relaxation of the aorta and the basilar artery of the rat. However, there have not been studies on regulation of ISL in mesenteric arteries. To examine whether ISL causes the relaxation of the mesenteric artery of mice, we recorded vasodilation of mouse mesenteric arterial rings with a myograph. After contraction of arterial rings with phenylephrine, we added ISL to the arterial rings and measured its relaxation effect. To further examine which channel was involved in this relaxation effect, we tested the effects of ISL on endothelium-dependent and endothelium-independent vasodilation. Then we used BKCa channel blockers tetraethylammonium and iberiotoxin, to detect whether the BKCa channel is involved in ISL-induced vasodilation. Mesenteric arterial smooth muscle cells were isolated by enzyme digestion. Bis-(1, 3-dibutylbarbituric acid) trimethine oxonol staining was used to measure membrane potential of mesenteric arterial smooth muscle cells. We identified a vasodilation effect caused by ISL on mouse mesenteric arterial rings pre-contracted by phenylephrine in a concentration-dependent manner, with an EC50 of 13.71 ± 1.1 µmol/L. The vasodilation effect of ISL is endothelium-independent. K+ channel inhibitors tetraethylammonium and iberiotoxin reduced the vasodilation induced by ISL which suggested the involvement of BKCa channel.

Discovery and biological evaluation of novel G protein-coupled receptor 119 agonists for type 2 diabetes.

G protein-coupled receptor 119 (GPR119) is a member of the GPCR family promising to be the target for type 2 diabetes mellitus (T2DM) treatment. In this work, 30 novel compounds were designed, synthesized, and evaluated by in vitro cAMP activation assay, where compounds II-14 and II-18 showed the best potency with EC50 values of 69 and 99 nM, respectively. In the oral glucose tolerance test, compound II-18 showed even more efficacious activity in lowering blood excursions than MBX-2982 at a fixed dose of 30 mg/kg. Here, we report that compound II-18 with its excellent agonistic activity and its orally effective activity in decreasing blood glucose deviations may serve as a potent GPR119 agonist for the treatment of T2DM.

Synthesis and biological evaluation of novel 5,6-dihydropyrimido[4,5-f]quinazoline derivatives as potent CDK2 inhibitors.

As serine/threonine kinase, the cyclin dependent kinase 2 (CDK2) is a promising target for various diseases such as cerebral hypoxia, cancer, and neurodegenerative diseases. Here we reported the structure-based synthesis and biological evaluation of novel 5,6-dihydropyrimido[4,5-f]quinazoline derivatives as CDK2 inhibitors, which exhibited potent CDK2 inhibitory activities, as well as anticancer activities in low concentration against two human cancer cell lines (MCF-7 and HCT116). In particular, compounds 11a and 11f (IC50 values of 0.11 and 0.09 µM for CDK2, respectively) have demonstrated significantly inhibitory potency against CDK2 and have showed great inhibitory activities against MCF-7 and HCT116 cell lines.

Transition-Metal-Free Trifluoromethylation of Aldehyde Derivatives with Sodium Trifluoromethanesulfinate.

A metal-free and cost-effective synthetic protocol for the trifluoromethylation of N,N-disubstituted hydrazones with Langlois's reagent (CF3SO2Na) to afford the corresponding functionalized trifluoromethyl ketone hydrazones has been established. It is proposed that a radical/SET mechanism proceeding via a trifluoroalkyl radical may be involved in the reaction. Applications of the methodology in industry will be found and the development of new methods for trifluoromethylation with Langlois's reagent will be continued in our laboratory.

Interleukin 10 protects primary melanocyte by activation of Stat-3 and PI3K/Akt/NF-κB signaling pathways.

Vitiligo is a common melanocytopenic disorder of the skin, with acquired focal depigmentation. Normal human skin relies on melanocytes to provide photoprotection and thermoregulation by producing melanin. Interleukin 10 (IL-10) is a pleiotropic immunoregulatory cytokine drawing more and more researchers' attention. The present study was conducted to investigate the effects of IL-10 on melanocytes and elucidate the underlying mechanisms. We proved that IL-10 play no role in regulating melanogenesis of normal human foreskin-derived epidermal melanocytes (NHEM). IL-10 stimulation activated the JAK/Stat-3 and PI3K/Akt signaling pathways. Moreover, IL-10 treatment increased translocation of p65 NF-κB into the nuclear compartment, and up-regulated expression of the pro-survival proteins Bcl-2 and Bcl-xL. IL-10 restored anti-apoptotic proteins expression and suppressed cytochrome c release in H2O2-induced apoptosis. In conclusion, IL-10 may provide pro-survival cues to melanocytes and be applied in the treatment of vitiligo and other depigmenting disorders.

Iron-catalyzed direct α-arylation of α-amino carbonyl compounds with indoles.

A mild and general α-arylation of α-amino carbonyls with indoles catalyzed by Fe(ClO4)3 has been developed. C-H activation is smoothly fulfilled by using TBHP as the oxidant with good yields. Two hydrogen dissociations make this transformation more environmentally benign because of high atom efficiency.

Gene Expression Profiling of H9c2 Cells Subjected to H2O2-Induced Apoptosis with/without AF-HF001.

Heart failure represents a major health problem. The development of new drugs to treat this condition is essential. We previously discovered that AF-001 attenuates the cardiac defects caused by heart failure in zebrafish. In this paper, we report the identification of AF-HF001, an AF-001 derivative, and its effects on live cardiomyocytes subjected to oxidative damage. The in vitro results demonstrated that AF-HF001 attenuates the production of reactive oxygen species (ROS) and the myocardial cell apoptosis. A DNA microarray was performed to broadly analyze gene expression after H2O2 treatment with or without AF-HF001. Hierarchical clustering analysis revealed that AF-HF001 modifies the expression of certain genes (Ndufs2, Ndufb6, Ndufb8, Ndufa13, Ndufs3, Ndufs5, TPM1, MYH14, RyR1, and TIMP4) related to ROS production, cardiac contractility and extracellular matrix remodeling. AF-HF001 ameliorates oxidative damage, which may be related to the mitogen-activated protein kinase (MAPK) family and the intrinsic mitochondrial pathway. Altogether, this study suggests that AF-HF001 exhibits potential as a clinical drug candidate for the treatment of heart failure.

Synthesis and biological evaluation of novel bis-aromatic amides as novel PTP1B inhibitors.

A series of bis-aromatic amides was designed, synthesized, and evaluated as a new class of inhibitors with IC50 values in the micromolar range against protein tyrosine phosphatase 1B (PTP1B). Among them, compound 15 displayed an IC50 value of 2.34±0.08 µM with 5-fold preference over TCPTP. More importantly, the treatment of CHO/HIR cells with compound 15 resulted in increased phosphorylation of insulin receptor (IR), which suggested extensive cellular activity of compound 15. These results provided novel lead compounds for the design of inhibitors of PTP1B as well as other PTPs.

Imidazo[4,5-b]pyridine inhibitors of B-Raf kinase.

This Letter details the synthesis and evaluation of imidazo[4,5-b]pyridines as inhibitors of B-Raf kinase. These compounds bind in a DFG-in, αC-helix out conformation of B-Raf, which is a binding mode associated with significant kinase selectivity. Structure-activity relationship studies involved optimization of the ATP-cleft binding region of these molecules, and led to compound 23, an inhibitor with excellent enzyme/cell potency, and kinase selectivity.

Synthesis and SAR studies of praziquantel derivatives with activity against Schistosoma japonicum.

The synthesis and structure-activity relationship (SAR) studies of praziquantel derivatives with activity against adult Schistosoma japonicum are described. Several of them showed better worm killing activity than praziquantel and could serve as leads for further optimization.

1H-2,3-dihydroperimidine derivatives: a new class of potent protein tyrosine phosphatase 1B inhibitors.

A series of 1H-2,3-dihydroperimidine derivatives was designed, synthesized, and evaluated as a new class of inhibitors of protein tyrosine phosphatase 1B (PTP1B) with IC50 values in the micromolar range. Compounds 46 and 49 showed submicromolar inhibitory activity against PTP1B, and good selectivity (3.48-fold and 2.10-fold respectively) over T-cell protein tyrosine phosphatases (TCPTP). These results have provided novel lead compounds for the design of inhibitors of PTP1B as well as other PTPs.

Au(III)-catalyzed intermolecular amidation of benzylic C-H bonds.

Au(III)-catalyzed intermolecular amidations of benzylic C-H bonds with sulfonamides and carboxamides are described. The protocol with the Au-bipy complex/N-bromosuccinimide system provides practical applications for synthesis of various amides via C-H activations. The reaction proceeds with high efficiency to give the corresponding amines, which are extremely useful synthetic intermediates.

Synthesis and antiviral activity of conformational analogues of leucamide A.

In order to study the effect of heterocyclic core conformational state of leucamide A on its anti-influenza virus A activity, five conformational analogues were prepared by replacing the Pro-Leu dipeptide in the molecule with various amino acids. The amino acids used were of 2 to 6 carbons. The results showed that these replacements not only changed the conformational relationship between the 4,2-bisheterocycle tandem pair and the third heterocycle, but also had dramatic effect on its activity against influenza virus A.

Neuroprotection of chicoric acid in a mouse model of Parkinson's disease involves gut microbiota and TLR4 signaling pathway.

Chicoric acid (CA), a polyphenolic acid obtained from chicory and purple coneflower (Echinacea purpurea), has been regarded as a nutraceutical to combat inflammation, viruses and obesity. Parkinson's disease (PD) is a common neurodegenerative disorder, and the microbiota-gut-brain axis might be the potential mechanism in the pathogenesis and development of PD. The results obtained in this study demonstrated that oral pretreatments of CA significantly prevented the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced motor dysfunctions and death of nigrostriatal dopaminergic neurons along with the inhibition of glial hyperactivation and the increment in striatal neurotrophins. 16S rRNA sequence results showed that CA significantly reduced MPTP-induced microbial dysbiosis and partially restored the composition of the gut microbiota to normal, including decreased phylum Bacteroidetes and genera Parabacteroide, as well as increased phylum Firmicutes, genera Lactobacillus and Ruminiclostridium. Besides, CA promoted colonic epithelial integrity and restored normal SCFA production. We also observed that proinflammatory cytokines such as TNF-α and IL-1ß in the serum, striatum and colon were reduced by CA, indicating that CA prevented neuroinflammation and gut inflammation, in which the suppression of the TLR4/MyD88/NF-κB signaling pathway might be the underlying molecular mechanism. These findings demonstrated that CA had neuroprotective effects on MPTP-induced PD mice possibly via modulating the gut microbiota and inhibiting inflammation throughout the brain-gut axis.

Pyrazolopyridine inhibitors of B-RafV600E. Part 2: structure-activity relationships.

Structure-activity relationships around a novel series of B-Raf(V600E) inhibitors are reported. The enzymatic and cellular potencies of inhibitors derived from two related hinge-binding groups were compared and3-methoxypyrazolopyridine proved to be superior. The 3-alkoxy group of lead B-Raf(V600E) inhibitor 1 was extended and minimally affected potency. The propyl sulfonamide tail of compound 1, which occupies the small lipophilic pocket formed by an outward shift of the αC-helix, was expanded to a series of arylsulfonamides. X-ray crystallography revealed that this lipophilic pocket unexpectedly enlarges to accommodate the bulkier aryl group.

Evaluation of the molluscicidal activities of arylpyrrole on Oncomelania hupensis, the intermediate host of Schistosoma japonicum.

The snail Oncomelania hupensis is the only intermediate host of the highly invasive parasite Schistosoma japonicum. Molluscicide is often used to curb transmission of S. japonicum. Niclosamide, the only World Health Organization (WHO) recognized molluscicide, presents major drawbacks, including high cost and toxicity towards aquatic animals. In the present study, a number of aryl pyrrole derivatives (ADs) were synthesized to serve as potential molluscicides and were tested on O. hupensis. To uncover the underlying mechanisms, adenosine triphosphate (ATP) and adenosine diphosphate (ADP) levels were assessed in the soft body of ADs-exposed O. hupensis, using high performance liquid chromatography (HPLC). The effect of C6 on key points of energy metabolism (the activities of complexes I, III, IV and the membrane potential) was determined. We demonstrated that the Compound 6 (C6, 4-bromo-1-(bromomethyl)-2-(4-chlorophenyl)-5-(trifluoromethyl)-1H-pyrrole-3-carbonitrile) exerted the strongest molluscicidal activity against adult O. hupensis at LC50 of 0.27, 0.19, and 0.13 mg/L for 24, 48, and 72 h respectively. Moreover, we found that the bromide on the pyrrole ring of C6 was essential for molluscicidal activity. Furthermore, the ATP content reduced from 194.46 to 139.75 µg/g after exposure to 1/2 LC50, and reduced to 93.06 µg/g after exposure to LC50. ADP, on the other hand, remained the same level before and after C6 exposure. We found that C6, at 1/2 LC50, reduced the membrane potential of O. hupensis, while no significant changes were observed in the activities of complexes I, III, and IV. C6 was identified with excellent activities on O. hupensis. The obtained structure-activity relationship and action mechanism study results should be useful for further compound design and development.

The TDs/aptamer cTnI biosensors based on HCR and Au/Ti3C2-MXene amplification for screening serious patient in COVID-19 pandemic.

The accurate assay of cardiac troponin I (cTnI) is very important for acute myocardial infarction (AMI), it also can be employed as an effective index for screening serious patients in COVID-19 pandemic before fatal heart injury to reduce the mortality. A ratiometric sensing strategy was proposed based on electrochemiluminescent (ECL) signal of doxorubicin (Dox)-luminol or the electrochemical (EC) signal of methylene blue (MB) vs. referable EC signal of Dox. The bio-recognitive Tro4-aptamer ensures the high specificity of the sensor by affinity binding to catch cTnI, and the tetrahedral DNA (TDs) on Au/Ti3C2-MXene built an excellent sensing matrix. An in situ hybrid chain reaction (HCR) amplification greatly improved the sensitivity. The ratiometric sensing responses ECLDox-luminol/CurrentDox or CurrentMB/CurrentDox linearly regressed to cTnI concentration in the range of 0.1 fM-1 pM or 0.1 fM-500 fM with the limit of detection (LOD) as 0.04 fM or 0.1 fM, respectively. Served as the reference signal, CurrentDox reflected the variation of sensor, it is very effective to ensure the accuracy of detection to obviate the false results. The proposed biosensors show good specificity, sensitivity, reproducibility and stability, have been applied to determine cTnI in real samples with satisfactory results. They are worth looking forward to be used for screening serious patient of COVID-19 to reduce the mortality, especially in mobile cabin hospital.