Day: November 21, 2022

Mosser, Eric A. published the artcileIdentification of pathways that regulate circadian rhythms using a larval zebrafish small molecule screen, SDS of cas: 330161-87-0, the publication is Scientific Reports (2019), 9(1), 1-14, database is CAplus and MEDLINE.

The circadian clock ensures that behavioral and physiol. processes occur at appropriate times during the 24-h day/night cycle, and is regulated at both the cellular and organismal levels. To identify pathways acting on intact animals, we performed a small mol. screen using a luminescent reporter of mol. circadian rhythms in zebrafish larvae. We identified both known and novel pathways that affect circadian period, amplitude and phase. Several drugs identified in the screen did not affect circadian rhythms in cultured cells derived from luminescent reporter embryos or in established zebrafish and mammalian cell lines, suggesting they act via mechanisms absent in cell culture. Strikingly, using drugs that promote or inhibit inflammation, as well as a mutant that lacks microglia, we found that inflammatory state affects circadian amplitude. These results demonstrate a benefit of performing drug screens using intact animals and provide novel targets for treating circadian rhythm disorders.

Scientific Reports published new progress about 330161-87-0. 330161-87-0 belongs to indole-building-block, auxiliary class Protein Tyrosine Kinase/RTK,Src, name is SU6656, and the molecular formula is C19H21N3O3S, SDS of cas: 330161-87-0.

Referemce:
https://www.nature.com/articles/s41429-020-0333-2,
Preparation of Indole Containing Building Blocks for the Regiospecific Construction of Indole Appended Pyrazoles and Pyrroles

Zhao, Di published the artcileFeed-forward activation of STAT3 signaling limits the efficacy of c-Met inhibitors in esophageal squamous cell carcinoma (ESCC) treatment, HPLC of Formula: 330161-87-0, the publication is Molecular Carcinogenesis (2021), 60(7), 481-496, database is CAplus and MEDLINE.

C-Hepatocyte growth factor receptor (Met) inhibitors have demonstrated clin. benefits in some types of solid tumors. However, the efficacy of c-Met inhibitors in esophageal squamous cell carcinoma (ESCC) remains unclear. In this study, we discovered that c-Met inhibitors induced “Signal Transducer and Activator of Transcription (STAT3)-addiction” in ESCC cells, and the feedback activation of STAT3 in ESCC cells limits the tumor response to c-Met inhibition. Mechanistically, c-Met inhibition increased the autocrine of several cytokines, including CCL2, interleukin 8, or leukemia inhibitory factor, and facilitated the interactions between the receptors of these cytokines and Janus Kinase1/2 (JAK1/2) to resultantly activate JAKs/STAT3 signaling. Pharmacol. inhibition of c-Met together with cytokines/JAKs/STAT3 axis enhanced cancer cells regression in vitro. Importantly, combined c-Met and STAT3 inhibitors synergistically suppressed tumor growth and promoted the apoptosis of tumor cells without producing systematic toxicity. These findings suggest that inhibition of the STAT3 feedback loop may augment the response to c-Met inhibitors via the STAT3-mediated oncogene addiction in ESCC cells.

Molecular Carcinogenesis published new progress about 330161-87-0. 330161-87-0 belongs to indole-building-block, auxiliary class Protein Tyrosine Kinase/RTK,Src, name is SU6656, and the molecular formula is C9H21NO3, HPLC of Formula: 330161-87-0.

Referemce:
https://www.nature.com/articles/s41429-020-0333-2,
Preparation of Indole Containing Building Blocks for the Regiospecific Construction of Indole Appended Pyrazoles and Pyrroles

Zhu, Wei published the artcileDesign, Synthesis, and Pharmacological Evaluation of Novel Multisubstituted Pyridin-3-amine Derivatives as Multitargeted Protein Kinase Inhibitors for the Treatment of Non-Small Cell Lung Cancer, COA of Formula: C14H18BNO3, the publication is Journal of Medicinal Chemistry (2017), 60(14), 6018-6035, database is CAplus and MEDLINE.

A novel series of pyridin-3-amine derivatives were designed, synthesized, and evaluated as multitargeted protein kinase inhibitors for the treatment of non-small cell lung cancer (NSCLC). Hit 1 was first disclosed by in silico screening against fibroblast growth factor receptors (FGFR), which was subsequently validated by in vitro experiments The structure-activity relationship (SAR) of its analogs was then explored to afford novel FGFR inhibitors. Among them, I showed potent inhibition against FGFR1, 2, and 3. Interestingly, compound I not only inhibited various phosphorylation and downstream signaling across different oncogenic forms in FGFR-overactivated cancer cells but also showed nanomolar level inhibition against several other NSCLC-related oncogene kinases, including RET, EGFR, EGFR/T790M/L858R, DDR2, and ALK. Finally, in vivo pharmacol. evaluations of I showed significant antitumor activity (TGI = 66.1%) in NCI-H1581 NSCLC xenografts with a good pharmacokinetic profile.

Journal of Medicinal Chemistry published new progress about 837392-64-0. 837392-64-0 belongs to indole-building-block, auxiliary class Indoline,Boronic acid and ester,Amide,Boronate Esters, name is 5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one, and the molecular formula is C5H6N2O2, COA of Formula: C14H18BNO3.

Referemce:
https://www.nature.com/articles/s41429-020-0333-2,
Preparation of Indole Containing Building Blocks for the Regiospecific Construction of Indole Appended Pyrazoles and Pyrroles

Matsuo, Yusuke published the artcileFacile synthesis of fluorescent hetero[8]circulene analogues with tunable solubilities and optical properties, Synthetic Route of 683229-62-1, the publication is Chemical Science (2019), 10(48), 11006-11012, database is CAplus and MEDLINE.

Hetero[8]circulenes are an interesting class of polycyclic heteroaromatic mols. having rigid and planar structures, which are promising in light of their potential applications for OLEDs, OFETs and so forth. Although their synthetic methods have been developed in some specific cases, a facile synthetic protocol of novel hetero[8]circulenes with tunable properties is highly desirable. We herein report the unexpected formation of methoxy-substituted quasi-aza[8]circulene and its conversion into unprecedented triazaoxa[8]circulene. The structures and optical properties were comparatively studied. Remarkably, triazaoxa[8]circulene is highly soluble in THF, acetone and DMSO mainly because of effective hydrogen-bonding of the NH moieties to these solvents. Their highly soluble nature in various solvents enabled us to study the solvent effects of these mols. In particular, triazaoxa[8]circulene displays a high fluorescence quantum yield of 0.72 in DMSO. Furthermore, enantiomeric separation of highly distorted quasi-aza[8]circulene was successfully achieved by chiral HPLC. Thus, these novel hetero[8]circulene derivatives are practically useful fluorescent nanographene-like mols. with intriguing optical properties.

Chemical Science published new progress about 683229-62-1. 683229-62-1 belongs to indole-building-block, auxiliary class Indole,Boronic acid and ester,Ether,Boronate Esters,Boronic Acids,Boronic acid and ester, name is 5-Methoxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole, and the molecular formula is C15H20BNO3, Synthetic Route of 683229-62-1.

Referemce:
https://www.nature.com/articles/s41429-020-0333-2,
Preparation of Indole Containing Building Blocks for the Regiospecific Construction of Indole Appended Pyrazoles and Pyrroles

Matsuo, Yusuke published the artcileFacile synthesis of fluorescent hetero[8]circulene analogues with tunable solubilities and optical properties, COA of Formula: C14H17BClNO2, the publication is Chemical Science (2019), 10(48), 11006-11012, database is CAplus and MEDLINE.

Hetero[8]circulenes are an interesting class of polycyclic heteroaromatic mols. having rigid and planar structures, which are promising in light of their potential applications for OLEDs, OFETs and so forth. Although their synthetic methods have been developed in some specific cases, a facile synthetic protocol of novel hetero[8]circulenes with tunable properties is highly desirable. We herein report the unexpected formation of methoxy-substituted quasi-aza[8]circulene and its conversion into unprecedented triazaoxa[8]circulene. The structures and optical properties were comparatively studied. Remarkably, triazaoxa[8]circulene is highly soluble in THF, acetone and DMSO mainly because of effective hydrogen-bonding of the NH moieties to these solvents. Their highly soluble nature in various solvents enabled us to study the solvent effects of these mols. In particular, triazaoxa[8]circulene displays a high fluorescence quantum yield of 0.72 in DMSO. Furthermore, enantiomeric separation of highly distorted quasi-aza[8]circulene was successfully achieved by chiral HPLC. Thus, these novel hetero[8]circulene derivatives are practically useful fluorescent nanographene-like mols. with intriguing optical properties.

Chemical Science published new progress about 1256358-91-4. 1256358-91-4 belongs to indole-building-block, auxiliary class Indole,Chloride,Boronic acid and ester,Boronate Esters,Boronic Acids,Boronic acid and ester, name is 5-Chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole, and the molecular formula is C14H17BClNO2, COA of Formula: C14H17BClNO2.

Referemce:
https://www.nature.com/articles/s41429-020-0333-2,
Preparation of Indole Containing Building Blocks for the Regiospecific Construction of Indole Appended Pyrazoles and Pyrroles

Cheng, Hong-Gang published the artcileConvenient synthesis of tetrahydro-γ-carbolines and tetrahydroquinolines through a chemo- and regioselectivity switch by a Bronsted acid catalyzed, one-pot, multicomponent reaction, Application of 5-Fluoro-1H-indole-2-carbaldehyde, the publication is European Journal of Organic Chemistry (2010), 4976-4980, S4976/1-S4976/49, database is CAplus.

An efficient, one-pot, multicomponent reaction of aldehydes, p-methoxyaniline, and 2-vinylindoles was developed. This approach provides a practical approach to synthetically and biol. significant tetrahydro-γ-carboline and tetrahydroquinoline derivatives in good yields through a chemo- and regioselectivity switch, which can be tuned by simply changing the substituent on the indole component under identical reaction conditions.

European Journal of Organic Chemistry published new progress about 220943-23-7. 220943-23-7 belongs to indole-building-block, auxiliary class Indole,Fluoride,Aldehyde, name is 5-Fluoro-1H-indole-2-carbaldehyde, and the molecular formula is C9H6FNO, Application of 5-Fluoro-1H-indole-2-carbaldehyde.

Referemce:
https://www.nature.com/articles/s41429-020-0333-2,
Preparation of Indole Containing Building Blocks for the Regiospecific Construction of Indole Appended Pyrazoles and Pyrroles

Avanzi, Mauro P. published the artcileOptimizing megakaryocyte polyploidization by targeting multiple pathways of cytokinesis, SDS of cas: 330161-87-0, the publication is Transfusion (Malden, MA, United States) (2012), 52(11), 2406-2413, database is CAplus and MEDLINE.

BACKGROUND: Large-scale in vitro production of platelets (PLTs) from cord blood stem cells is one goal of stem cell research. One step toward this goal will be to produce polyploid megakaryocytes capable of releasing high numbers of PLTs. Megakaryocyte polyploidization requires distinct cytoskeletal and cellular mechanisms, including actin polymerization, myosin activation, microtubule formation, and increased DNA production In this study we variably combined inhibition of these principal mechanisms of cytokinesis with the goal of driving polyploidization in megakaryocytes. STUDY DESIGN AND METHODS: Megakaryocytes were derived from umbilical cord blood and cultured with reagents that inhibit distinct mechanisms of cytokinesis: Rho-Rock inhibitor (RRI), Src inhibitor (SI), nicotinamide (NIC), aurora B inhibitor (ABI), and myosin light chain kinase inhibitor (MLCKI). Combinations of reagents were used to determine their interactions and to maximize megakaryocyte ploidy. RESULTS: Treatment with RRI, NIC, SI, and ABI, but not with MLCKI, increased the final ploidy and RRI was the most effective single reagent. RRI and MLCKI, both inhibitors of MLC activation, resulted in opposite ploidy outcomes. Combinations of reagents also increased ploidy and the use of NIC, SI, and ABI was as effective as RRI alone. Addition of MLCKI to NIC, SI, and ABI reached the highest level of polyploidization. CONCLUSION: Megakaryocyte polyploidization results from modulation of a combination of distinct cytokinesis pathways. Reagents targeting distinct cytoskeletal pathways produced additive effects in final megakaryocyte ploidy. The RRI, however, showed no additive effect but produced a high final ploidy due to overlapping inhibition of multiple cytokinesis pathways.

Transfusion (Malden, MA, United States) published new progress about 330161-87-0. 330161-87-0 belongs to indole-building-block, auxiliary class Protein Tyrosine Kinase/RTK,Src, name is SU6656, and the molecular formula is C19H21N3O3S, SDS of cas: 330161-87-0.

Referemce:
https://www.nature.com/articles/s41429-020-0333-2,
Preparation of Indole Containing Building Blocks for the Regiospecific Construction of Indole Appended Pyrazoles and Pyrroles

Blomgren, Peter published the artcileDiscovery of Lanraplenib (GS-9876): A Once-Daily Spleen Tyrosine Kinase Inhibitor for Autoimmune Diseases, Product Details of C14H18BNO2, the publication is ACS Medicinal Chemistry Letters (2020), 11(4), 506-513, database is CAplus and MEDLINE.

Spleen tyrosine kinase (SYK) is a critical regulator of signaling in a variety of immune cell types such as B-cells, monocytes, and macrophages. Accordingly, there have been numerous efforts to identify compounds that selectively inhibit SYK as a means to treat autoimmune and inflammatory diseases. We previously disclosed GS-9973 (entospletinib) as a selective SYK inhibitor that is under clin. evaluation in hematol. malignancies. However, a BID dosing regimen and drug interaction with proton pump inhibitors (PPI) prevented development of entospletinib in inflammatory diseases. Herein, we report the discovery of a second-generation SYK inhibitor, GS-9876 (lanraplenib), which has human pharmacokinetic properties suitable for once-daily administration and is devoid of any interactions with PPI. Lanraplenib is currently under clin. evaluation in multiple autoimmune indications.

ACS Medicinal Chemistry Letters published new progress about 642494-36-8. 642494-36-8 belongs to indole-building-block, auxiliary class Indole,Boronic acid and ester,Indole,Boronate Esters,Boronic acid and ester, name is 6-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole, and the molecular formula is C14H18BNO2, Product Details of C14H18BNO2.

Referemce:
https://www.nature.com/articles/s41429-020-0333-2,
Preparation of Indole Containing Building Blocks for the Regiospecific Construction of Indole Appended Pyrazoles and Pyrroles

De Mauri, Andreana published the artcileProbiotics-addicted low-protein diet for microbiota modulation in patients with advanced chronic kidney disease (ProLowCKD): A protocol of placebo-controlled randomized trial, Recommanded Product: Potassium 1H-indol-3-yl sulfate, the publication is Journal of Functional Foods (2020), 104133, database is CAplus.

Microbiota is a term coined to describe the population of bacteria, viruses and fungi that inhabit in symbiosis within a living host. A connection between unbalanced microbiota and chronic kidney disease has been established. In these patients, high levels of urea reach the intestine promoting the overgrowth of bacterial species that are prone to generate uremic toxins. Due to the high morbidity and mortality of this condition, a large number of therapeutic approaches to reduce inflammation and microbial uremic toxins have been proposed, with controversial results. A low protein diet, with a protein intake of 0.6-0.8 g/kg of body weight, is a useful and historically pursued option with this regard. The aim of our study is to evaluate, among patients with advanced renal failure not on dialysis, the synergic beneficial effects of this diet and the selected probiotics Bifidobacterium longum (mix DLBL) and Lactobacillus reuteri LRE02 (DSM 23878).

Journal of Functional Foods published new progress about 2642-37-7. 2642-37-7 belongs to indole-building-block, auxiliary class Indole,Salt,Sulfonate,Inhibitor,Inhibitor, name is Potassium 1H-indol-3-yl sulfate, and the molecular formula is C8H6KNO4S, Recommanded Product: Potassium 1H-indol-3-yl sulfate.

Referemce:
https://www.nature.com/articles/s41429-020-0333-2,
Preparation of Indole Containing Building Blocks for the Regiospecific Construction of Indole Appended Pyrazoles and Pyrroles

Carroll, Daniela J. published the artcileSiglec-8 signals through a non-canonical pathway to cause human eosinophil death in vitro, Category: indole-building-block, the publication is Frontiers in Immunology (2021), 737988, database is CAplus and MEDLINE.

Sialic acid-binding Ig-like lectin (Siglec)-8 is a glycan-binding receptor bearing immunoreceptor tyrosine-based inhibitory and switch motifs (ITIM and ITSM, resp.) that is selectively expressed on eosinophils, mast cells, and, to a lesser extent, basophils. Previous work has shown that engagement of Siglec-8 on IL-5-primed eosinophils causes cell death via CD11b/CD18 integrin-mediated adhesion and NADPH oxidase activity and identified signaling mols. linking adhesion, reactive oxygen species (ROS) production, and cell death. However, the proximal signaling cascade activated directly by Siglec-8 engagement has remained elusive. Most members of the Siglec family possess similar cytoplasmic signaling motifs and recruit the protein tyrosine phosphatases SHP-1/2, consistent with ITIM-mediated signaling, to dampen cellular activation. However, the dependence of Siglec-8 function in eosinophils on these phosphatases has not been studied. Using Siglec-8 antibody engagement and pharmacol. inhibition in conjunction with assays to measure cell-surface upregulation and conformational activation of CD11b integrin, ROS production, and cell death, we sought to identify mols. involved in Siglec-8 signaling and determine the stage of the process in which each mol. plays a role. We demonstrate here that the enzymic activities of Src family kinases (SFKs), Syk, SHIP1, PAK1, MEK1, ERK1/2, PLC, PKC, acid sphingomyelinase/ceramidase, and Btk are all necessary for Siglec-8-induced eosinophil cell death, with no apparent role for SHP-1/2, SHIP2, or c-Raf. While most of these signaling mols. are necessary for Siglec-8- induced upregulation of CD11b integrin at the eosinophil cell surface, Btk is phosphorylated and activated later in the signaling cascade and is instead necessary for CD11b activation. In contrast, SFKs and ERK1/2 are phosphorylated far earlier in the process, consistent with their role in augmenting cell-surface levels of CD11b. In addition, pretreatment of eosinophils with latrunculin B or jasplakinolide revealed that actin filament disassembly is necessary and sufficient for surface CD11b integrin upregulation and that actin polymerization is necessary for downstream ROS production These results show that Siglec-8 signals through an unanticipated set of signaling mols. in IL-5-primed eosinophils to induce cell death and challenges the expectation that ITIM-bearing Siglecs signal through inhibitory pathways involving protein tyrosine phosphatases to achieve their downstream functions.

Frontiers in Immunology published new progress about 330161-87-0. 330161-87-0 belongs to indole-building-block, auxiliary class Protein Tyrosine Kinase/RTK,Src, name is SU6656, and the molecular formula is C19H21N3O3S, Category: indole-building-block.

Referemce:
https://www.nature.com/articles/s41429-020-0333-2,
Preparation of Indole Containing Building Blocks for the Regiospecific Construction of Indole Appended Pyrazoles and Pyrroles