Design, synthesis, and biological evaluation of pyrido[2,3-d]pyrimidine and thieno[2,3-d]pyrimidine derivatives as novel EGFRL858R/T790M inhibitors.

EGFR mutations have been identified in 20,000 reported NSCLC (non-small cell lung cancer) samples, and exon 19 deletions and L858R mutations at position 21, known as "classical" mutations, account for 85-90% of the total EGFR (epidermal growth factor receptor) mutations. In this paper, two series of EGFR kinase inhibitors were designed and synthesised. Among them, compound B1 showed an IC50 value of 13 nM for kinase inhibitory activity against EGFRL858R/T790M and more than 76-fold selectivity for EGFRWT. Furthermore, in an in vitro anti-tumour activity test, compound B1 showed an effective anti-proliferation activity against H1975 cells with an IC50 value of 0.087 µΜ. We also verified the mechanism of action of compound B1 as a selective inhibitor of EGFRL858R/T790M by cell migration assay and apoptosis assay.

Fuc-S-A New Ultrasonic Degraded Sulfated α-l-Fucooligosaccharide-Alleviates DSS-Inflicted Colitis through Reshaping Gut Microbiota and Modulating Host-Microbe Tryptophan Metabolism.

SCOPE: The dysbiosis of intestinal microecology plays an important pathogenic role in the development of inflammatory bowel disease. METHODS AND RESULTS: A polysaccharide named Fuc-S, with a molecular weight of 156 kDa, was prepared by the ultrasonic degradation of fucoidan. Monosaccharide composition, FTIR, methylation, and NMR spectral analysis indicated that Fuc-S may have a backbone consisting of →3)-α-L-Fucp-(1→, →4)-α-L-Fucp-(1→ and →3, 4)-α-D-Glcp-(1→. Moreover, male C57BL/6 mice were fed three cycles of 1.8% dextran sulfate sodium (DSS) for 5 days and then water for 7 days to induce colitis. The longitudinal microbiome alterations were evaluated using 16S amplicon sequencing. In vivo assays showed that Fuc-S significantly improved clinical manifestations, colon shortening, colon injury, and colonic inflammatory cell infiltration associated with DSS-induced chronic colitis in mice. Further studies revealed that these beneficial effects were associated with the inhibition of Akt, p-38, ERK, and JNK phosphorylation in the colon tissues, regulating the structure and abundance of the gut microbiota, and modulating the host-microbe tryptophan metabolism of the mice with chronic colitis. CONCLUSION: Our data confirmed the presence of glucose in the backbone of fucoidan and provided useful information that Fuc-S can be applied as an effective functional food and pharmaceutical candidate for IBD treatment.

Activation of P2Y1R impedes intestinal mucosa repair during colitis.

Delayed intestinal mucosal healing is one of the pathogenic bases for the recurrence of inflammatory bowel disease (IBD), but how the IBD inflammatory environment impedes intestinal mucosa repair remains unclear. Adenosine diphosphate (ADP) is an endogenous ligand of P2Y1R that is highly produced at sites of inflammation. We herein identify a novel role of ADP to directly facilitate inflammation-induced epithelial permeability, delay wound healing, and disrupt tight junction integrity, and we found that P2Y1R, a receptor preferentially activated by ADP, was significantly upregulated in the colonic mucosa of ulcerative colitis (UC) patients and in colonic epithelial cells of colitis mice. Inhibition of P2Y1R significantly increased the epithelial permeability, decreased the wound healing capacity, and impaired the tight junction integrity in TNF-α-challenged Caco-2 cells. In parallel, the same effects in promoting intestinal mucosa repair were observed in DSS-induced colitis in P2Y1R-/- mice. Mechanistic investigation revealed that P2Y1R inhibition facilitated epithelial AMP-activated protein kinase (AMPK) phosphorylation and gut microbiota homeostasis reconstruction. Taken together, these findings highlight that P2Y1R activation plays an important role in impeding intestinal mucosa repair during colitis, and that P2Y1R is an attractive target for the therapy of IBD.

The Leaves of Cyclocarya paliurus: A Functional Tea with Preventive and Therapeutic Potential of Type 2 Diabetes.

Type 2 diabetes mellitus (T2DM) has become a universal and chronic global public health concern and causes multiple complex complications. In order to meet the rapidly growing demand for T2DM treatment, increased research has been focused on hypoglycemic drugs. Cyclocarya paliurus (Batal.) Iljinsk is the only living species of the genus Cyclocarya Iljinskaja, whose leaves have been extensively used as a functional tea to treat obesity and diabetes in China. An enormous amount of very recent pharmacological research on the leaves of C. paliurus has demonstrated that they carry out numerous biological activities, such as hypoglycemic, anti-inflammatory, and intestinal microbiota regulation. Multiple in vitro and in vivo studies have also shown that the extracts of C. paliurus leaves are innocuous and safe. This study aims to provide an up-to-date review of the botany, traditional uses, phytochemistry, pharmacological effects against diabetes, toxicology, and clinical studies of C. paliurus leaves, in hopes of promoting a better understanding of their role in the prevention and treatment of T2DM.

Design, synthesis and antibacterial activity of novel pleuromutilin derivatives with thieno[2,3-d]pyrimidine substitution.

A series of novel pleuromutilin derivatives with substituted thienopyrimidines were designed, synthesized, and evaluated for antibacterial act ivity. In this study, the activities of these compounds were investigated using the inhibition circle test, the minimum inhibitory concentration (MIC) test, real-time growth curves, time-kill kinetic assays, cytotoxicity assays, and molecular docking. Most of the tested compounds exhibited moderate antibacterial activity against Staphylococcus aureus, Streptococcus agalactiae, and Escherichia coli. Compound A11 was the most active and displayed bacteriostatic activities against methicillin-resistant S. aureus, with MIC values as low as 0.00191 µg/mL, which is 162 and 32 times lower than that of the marketed antibiotics tiamulin and retapamulin, respectively. Furthermore, the mechanism of action of A11 was confirmed by molecular docking studies.

P2Y1R Ligation Suppresses Th17 Cell Differentiation and Alleviates Colonic Inflammation in an AMPK-Dependent Manner.

P2Y1 receptor is a G-protein-coupled receptor that plays a critical role in the immune response of inflammatory bowel diseases. However, its regulatory effects on CD4+ T cell response have not been fully elucidated. The study aimed to characterize the role of P2Y1R in Th17 cell differentiation and colonic inflammation. Our results demonstrated that P2Y1R was significantly increased in the splenocytes of colitic mice, which was positively associated with the expression of RORγt and IL-17A. P2Y1R deficiency significantly ameliorated DSS-induced colitis and its Th17 responses. In parallel, P2Y1R deficiency greatly impaired the differentiation of Th17 cell, down-regulated the mRNA expression of IL-17A and RORγt, and protein expression of RORγt in vitro. More importantly, it was found that P2Y1R deficiency markedly increased AMPK phosphorylation of Th17 polarized CD4+ T cells, and antagonist of AMPK significantly reversed the inhibitory effect of P2Y1R deficiency on Th17 cell generation in vivo and in vitro. Overall, these findings demonstrated that P2Y1R deficiency could suppress Th17 cell differentiation in an AMPK-dependent manner to ameliorate colitis, and P2Y1R can act as an important regulator of Th17 cell differentiation to control colonic inflammation.

Therapeutic effects and mechanisms of Zhen-Wu-Bu-Qi Decoction on dextran sulfate sodium-induced chronic colitis in mice assessed by multi-omics approaches.

BACKGROUND: Zhen-Wu-Bu-Qi Decoction (ZWBQD), a traditional Chinese medicine formula comprising Poria, Radix Paeoniae Alba, Rhizoma Atractylodis Macrocephalae, Rhizoma Zingiberis Recens, Radix Codonopsis and Rhizoma Coptidis, is used for treating ulcerative colitis (UC). In a previous study, we have reported ZWBQD mitigates the severity of dextran sulfate sodium (DSS)-induced colitis in mice. HYPOTHESIS: In this study, we aimed to understand the systemic actions and underlying mechanisms of ZWBQD on experimental colitis in mice. METHODS: We used multi-omics techniques and immunoblotting approach to study the pharmacological actions and mechanisms of ZWBQD in DSS-induced chronic colitic mice. RESULTS: We showed that ZWBQD exhibited potent anti-inflammatory properties and significantly protected DSS-induced colitic mice against colon injury by regulating the PI3K-AKT, MAPK signaling pathway and NF-κB signaling pathways. We also revealed that ZWBQD significantly ameliorated gut microbiota dysbiosis and abnormalities of tryptophan catabolites induced by DSS. CONCLUSIONS: We demonstrated that the therapeutic effects of ZWBQD on experimental colitis are mediated by regulating multiple signaling pathways and modulation of gut microbiota. Our study employed an integrative strategy to elucidate novel mechanisms of ZWBQD, which provides new insights into the development of Chinese herbal medicine-based therapeutics for UC.

Pd-Catalyzed Rearrangement Reaction of N-Tosylhydrazones Bearing Allyl Ethers Into Trans-Olefin-Substituted Sulfonylhydrazones.

A novel and efficient rearrangement of N-tosylhydrazones bearing allyl ethers into trans-olefin-substituted sulfonylhydrazones is proposed. The reaction involves breakage of the C-O bond and formation of the C-N bond. The reaction can be extended to a wide range of substrates, and the target products can be synthesized smoothly, regardless of the presence of electron-donating and electron-withdrawing groups. The proposed strategy is a new direction in the field of rearrangement reactions.

Phytochemicals as regulators of Th17/Treg balance in inflammatory bowel diseases.

Inflammatory bowel disease (IBD) is a chronic inflammatory intestinal disorder that is difficult to cure and characterized by periods of relapse. To face the challenges of limited treatment strategies and drawbacks of conventional medications, developing new and promising strategies as well as safe and effective drugs for treatment of IBD has become an urgent demand for clinics. The imbalance of Th17/Treg is a crucial event for the development of IBD, and studies have verified that correcting the imbalance of Th17/Treg is an effective strategy for preventing and treating IBD. Recently, a growing body of studies has indicated that phytochemicals derived from natural products are potent regulators of Th17/Treg, and exert preferable protective benefits against colonic inflammation. In this review, the great potential of anti-colitis agents derived from natural products through targeting Th17/Treg cells and their action mechanisms for the treatment or prevention of IBD in recent research is summarized, which may help further the development of new drugs for IBD treatment.

Metal-Free Direct C-H Functionalization of Quinoxalin-2(1H)-Ones to Produce 3-Vinylated Quinoxalin-2(1H)-Ones in the Presence of Alkenes.

A novel and efficient C 3-H vinylation reaction with quinoxalin-2(1H)-one as the substrate, in the presence of alkenes, under metal-free conditions, is reported herein. The reaction leads to the formation of new carbon-carbon bonds that exhibit moderate to good reactivities. The vinylation of quinoxalin-2(1H)-ones, in the presence of alkenes, is an attractive process that can be potentially utilized to produce biologically active 3-vinylated quinoxalin-2(1H)-ones.

Design, synthesis and biological evaluation of aminopyrimidine derivatives bearing a 4,5,6,7-tetrahydrothieno [3,2-c]pyridine as potent EGFR inhibitors.

To resolve the problem of drug resistance caused by epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer, we used the principle of collocation to design and synthesize a series of aminopyrimidine derivatives with 4,5,6,7-tetrahydrothieno [3,2-c]pyridine side chains (according to the binding mode of AZD9291 to EGFRT790M) for use as EGFRL858R/T790M kinase inhibitors. The most promising compound A12, a non-covalently bound reversible inhibitor, showed excellent kinase inhibitory activity against EGFRL858R/T790M, with an IC50 value of 4.0 nM and more than 42-fold selectivity for EGFRWT (IC50 = 170.0 nM). Moreover, compound A12 showed strong anti-proliferative activity against H1975 cells, with IC50 value of 0.086 µΜ. Additionally, the effective inhibition of cell migration and the promotion of apoptosis by A12 verified its mechanism of action, as a selective inhibitor of EGFRL858R/T790M.

Synthesis and antifungal activities of hydrophilic cationic polymers against Rhizoctonia solani.

A series of linear hydrophilic cationic polymers with different charge density and molecular weights were synthesized by one-step polymerization process. The effect of the hydrophobicity and molecular weights on the antifungal activity against Rhizoctonia solani (R. solani) and Fusarium oxysporum f. sp. cubense race 4 (Foc4) was assessed. The biotoxicity of the cationic polymers were evaluated based on their median lethal concentration (LC50) for zebrafish and silkworm and median lethal dose (LD50) for Kunming mice. The results indicated that the balance between antifungal activity and biotoxicity could be well tuned by controlling the hydrophobic-hydrophilic balance. The minimum inhibitory concentration (MIC) of PEPB10 and PEPB25 against R. solani were 160 µg/mL and 80 µg/mL, respectively. And the LD50 for Kunming mice of PEPB10 and PEPB25 were more than 5000 mg/kg, which mean that PEPB10 and PEPB25 with high hydrophilicity show low toxicity and better selectivity for R. solani. The cationic polymers can kill the R. solani by damaging their membranes and exchanging the Ca2+ or/and Mg2+ cations of their membranes or cell wall. These results help to understand the antifungal mechanism of low-toxic polymeric quaternary ammonium salts and highlight their potential application as highly selective fungicidal agents for controlling plant diseases.