Day: November 25, 2022

Bartscht, Tobias published the artcileTGF-β Signal Transduction in Pancreatic Carcinoma Cells is Sensitive to Inhibition by the Src Tyrosine Kinase Inhibitor AZM475271, Application In Synthesis of 330161-87-0, the publication is Anti-Cancer Agents in Medicinal Chemistry (2017), 17(7), 966-972, database is CAplus and MEDLINE.

Background: Earlier results from our group have shown that in pancreatic ductal adenocarcinoma (PDAC)-derived cells transforming growth factor (TGF)-β1-dependent epithelial-mesenchymal transition (EMT) and cell motility was inhibited by the Src inhibitors PP2 and PP1 both of which targeted the TGF-β receptors for inhibition. Objective: In this study we evaluated the impact of another Src inhibitor, AZM475271, on various TGF-β responses in PDAC cells. Method: The effect of AZM475271 on TGF-β1-induced random cell migration (chemokinesis), the expression of EMT and migration/invasion-associated genes, TGF-β-induced luciferase activity, and C-terminal phosphorylation of Smad2 and Smad3 was measured in the PDAC-derived Panc-1 and Colo357 cell lines using real-time cell migration assays, quant. real-time PCR, luciferase reporter gene assays and phosphoimmunoblotting, resp. Results: AZM475271 effectively blocked TGF-β1-induced chemokinesis of Panc-1 cells in a dose-dependent fashion and inhibited the high chemokinetic activity of Panc-1 cells with ectopic expression of a constitutively active ALK5T204D mutant. AZM475271 but not another Src inhibitor, SU6656, partially relieved the suppressive effect of TGF-β1 on E-cadherin and inhibited TGF-β1-induced upregulation of the MMP2, MMP9, N-cadherin and vimentin genes, activity of a TGF-β1-dependent reporter gene, and activation of Smad2 and Smad3. Conclusion: Our data suggest that AZM475271 cross-inhibits tumor-promoting TGF-β signaling and may thus function as an inhibitor of both TGF-β and Src in both exptl. and clin. therapies against metastatic dissemination in late-stage PDAC.

Anti-Cancer Agents in Medicinal Chemistry 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, Application In Synthesis of 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

Guntur, Vamsi P. published the artcileThe potential use of tyrosine kinase inhibitors in severe asthma, Application of SU6656, the publication is Current Opinion in Allergy and Clinical Immunology (2012), 12(1), 68-75, database is CAplus and MEDLINE.

Purpose of review: Severe asthma comprises heterogeneous phenotypes that share in common a poor response to traditional therapies. Recent and ongoing work with tyrosine kinase inhibitors suggests a potential beneficial role in treatment of severe asthma. Recent findings: Various receptor and nonreceptor tyrosine kinase pathways contribute to aspects of airway inflammation, airway hyperresponsiveness, and remodeling of asthma. Selective and nonselective tyrosine kinase inhibitors may be useful to block pathways that are pathol. overactive or overexpressed in severe asthma. Recent in-vivo studies have demonstrated the utility of inhibitors against specific tyrosine kinases (epidermal growth factor receptor, c-kit/platelet derived growth factor receptor, vascular endothelial growth factor receptor, spleen tyrosine kinase, and janus kinase) in altering key aspects of severe asthma. Summary: Asthma and even severe asthma does not consist of a single phenotype. Targeting key inflammatory and remodeling pathways engaged across subphenotypes with tyrosine kinase inhibitors appears to hold promise.

Current Opinion in Allergy and Clinical 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, Application of SU6656.

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

Colucci, Marie A. published the artcileSynthesis and Evaluation of 3-Aryloxymethyl-1,2-dimethylindole-4,7-diones as Mechanism-Based Inhibitors of NAD(P)H:Quinone Oxidoreductase 1 (NQO1) Activity, HPLC of Formula: 192820-78-3, the publication is Journal of Medicinal Chemistry (2007), 50(23), 5780-5789, database is CAplus and MEDLINE.

NAD(P)H:quinone oxidoreductase 1 is a proposed target in pancreatic cancer. The synthesis of a series of indolequinones, e.g., I (H, NO₂, NH₂, CN, CF₃ or F), based on the 5- and 6-methoxy-1,2-dimethylindole-4,7-dione chromophores with a range of phenolic leaving groups at the (indol-3-yl)methyl position, is described. The ability of these indolequinones to function as mechanism-based inhibitors of purified recombinant human NQO1 was evaluated, as was their ability to inhibit both NQO1 and cell growth in human pancreatic MIA PaCa-2 tumor cells. The inhibition of rhNQO1 was related to the pK_a of the leaving group: compounds with poorer phenolic leaving groups were poor inhibitors whereas those with more acidic leaving groups were more efficient inhibitors. These inhibition data also correlated with the inhibition NQO1 in MIA PaCa-2 cells. However, the data demonstrated that NQO1 inhibition did not correlate with growth inhibitory activity, at least in the MIA PaCa-2 cell line, suggesting that targets in addition to NQO1 need to be considered to explain the potent growth inhibitory activity of this series of indolequinones in human pancreatic cancer cells.

Journal of Medicinal Chemistry published new progress about 192820-78-3. 192820-78-3 belongs to indole-building-block, auxiliary class Fused/Partially Saturated Cycles,Dihydroindoles, name is 5-Methoxy-1,2-dimethyl-3-[(4-nitrophenoxy)methyl]indole-4,7-dione, and the molecular formula is C18H16N2O6, HPLC of Formula: 192820-78-3.

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

Thadani, Avinash N. published the artcileStereospecific Synthesis of Highly Substituted Skipped Dienes through Multifunctional Palladium Catalysis, Name: (1-tosyl-1H-Indol-3-yl)boronic acid, the publication is Organic Letters (2002), 4(24), 4317-4320, database is CAplus and MEDLINE.

Skipped dienes I [R = H, Me, EtCH₂, Bu, MeO₂C; R¹ = H, EtCH₂, Ph, TBSOCH₂, HOCMe₂; R² = H, Me; R³ = Br, 4-MeOC₆H₄, 3-MeCOC₆H₄, 3-O₂NC₆H₄, Ph, 1-tosyl-3-indolyl, (E)-PhCH:CH, (E)-BuCH:CH; TBS = Me₃CSi(Me)₂] were prepared stereoselectively in one-pot processes from allyl chloride or bromide, alkynes, and boronic acids. Alkenyl bromides I (R = H, EtCH₂, Bu, Ph; R¹ = H, EtCH₂, MeO₂C; R² = Br; R³ = H) were prepared in 82-87% yields by addition of alkynes RCCR¹ dropwise to solutions of the palladium catalyst PdBr₂(PhCN)₂ with allyl bromide in DME. Under these conditions, the palladium catalyst did not decompose to palladium black, suggesting that further palladium-catalyzed processes might proceed in the same pot. Skipped alkenes I [R = H, Me, EtCH₂, Bu, MeO₂C; R¹ = H, EtCH₂, Ph, TBSOCH₂, HOCMe₂; R² = H, Me; R³ = 4-MeOC₆H₄, 3-MeCOC₆H₄, 3-O₂NC₆H₄, Ph, 1-tosyl-3-indolyl, (E)-PhCH:CH, (E)-BuCH:CH; TBS = Me₃CSi(Me)₂] were prepared in 79-86% yields by addition of alkynes RCCR¹ in THF dropwise to solutions of the palladium catalyst PdBr₂(PhCN)₂ with either allyl bromide or methallyl bromide in THF at 0° and warming to ambient temperature over 6 h followed by addition of boronic acids R²B(OH)₂, tri(tert-butyl)phosphine, and cesium carbonate to the solution and stirring for 16 h at ambient temperature Tri(tert-butyl)phosphine was the best ligand for the Suzuki coupling; 1,3-bis(2,4,6-trimethylphenyl)dihydroimidazolium chloride was also an effective ligand. Bases other than cesium carbonate were not as effective in the Suzuki coupling reaction. Dropwise addition of alkyne allowed the reactions to be conducted in the presence of. Skipped alkenes I [R = H, Me, EtCH₂, Bu, MeO₂C; R¹ = H, EtCH₂, Ph, TBSOCH₂, HOCMe₂; R² = H; R³ = 4-MeOC₆H₄, 3-MeCOC₆H₄, 3-O₂NC₆H₄, Ph; TBS = Me₃CSi(Me)₂] were also prepared in 64-73% yields using allyl chloride instead of allyl bromide; the Suzuki coupling reaction required heating at 45° to achieve good yields of product.

Organic Letters published new progress about 149108-61-2. 149108-61-2 belongs to indole-building-block, auxiliary class Indole,Boronic acid and ester,Sulfamide,Benzene,Boronic Acids,Boronic Acids,Boronic acid and ester,, name is (1-tosyl-1H-Indol-3-yl)boronic acid, and the molecular formula is C9H8O4, Name: (1-tosyl-1H-Indol-3-yl)boronic acid.

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

Chauhan, Jyoti published the artcileBlue LED Mediated Intramolecular C-H Functionalization and Cyclopropanation of Tryptamines: Synthesis of Azepino[4, 5-b]indoles and Natural Product Inspired Polycyclic Indoles, Synthetic Route of 167015-84-1, the publication is Organic Letters (2020), 22(11), 4537-4541, database is CAplus and MEDLINE.

A novel blue LED mediated intramol. C-H functionalization of tryptamine derivatives to generate azepino[4, 5-b]indoles, e. g., I, in moderate to good yields is reported. By altering the substitution at the tryptamine nitrogen, intramol. cyclopropanation is achieved in high yields under the same reactions condition to provide natural product inspired polycyclic indoles, e. g., II, which are further transformed to spiropiperidino indoles, e. g., III, in decent yields. The mechanism of formation of the compounds was investigated through DFT studies.

Organic Letters published new progress about 167015-84-1. 167015-84-1 belongs to indole-building-block, auxiliary class Indols, name is tert-Butyl 3-(2-aminoethyl)-1H-indole-1-carboxylate, and the molecular formula is C15H20N2O2, Synthetic Route of 167015-84-1.

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

Cavallini, G. published the artcileSome indole derivatives presumably of biological interest. II. Synthesis of 5-bromo-3-indolaldehyde, Recommanded Product: Ethyl 5-bromo-3-formyl-1H-indole-2-carboxylate, the publication is Farmaco, Edizione Scientifica (1958), 113-16, database is CAplus.

Et pyruvate p-bromophenylhydrazone (I), m. 148-50°, was prepared in 90% yield. Heating slowly with stirring 10 g. I and 20 g. polyphosphoric acid until no heat was more developed, adding at 60° 50 cc. H₂O, filtering, washing, and drying gave 7 g. Et 5-bromo-2-indolcarboxylate (II), m. 164-5°. Refluxing II in KOH-80% EtOH and acidifying gave 90% of the free acid (III) m. 279-80° (after sublimation). Mixing 4 g. III with 0.8 g. Cu chromite, suspending in 20 cc. quinoline, and refluxing 2 hrs., pouring into H₂O acidified with HCl, extracting with Et₂O, washing, drying, and evaporating gave 2 g. 5-bromoindole, m. 85-6° (cyclohexane). Stirring 3.1 g. N-methylformanilide and 3.5 g. POCl₃ for 15 min., adding 15 g. C₂H₄Cl₂ and 5.4 g. II, refluxing 1 hr., pouring into 15 g. NaOAc in 30 cc. H₂O at 0°, decanting the H₂O, adding petr. ether, centrifuging, and drying gave 4 g. crude 5-bromo-2-carbethoxy-3-indolealdehyde (IV), m. 245° (EtOH); p-nitrophenylhydrazone, m. 360°. Adding to 0.68 g. KOH in 50 cc. 80% EtOH 2.4 g. IV refluxing 30 min., adding 0.85 g. PhNH₂, diluting the hot solution with 50 cc. H₂O, cooling to 0°, and acidifying with HCl gave 2.4 g. 5-bromo-3-(phenyliminomethyl)-2-indole-carboxylic acid (VII), m. 253°. Adding to a stirred mixture of 2 g. N-methylformanilide and 2.3 g. POCl₃ 10 g. C₂H₄Cl₂, cooling to 0°, adding dropwise 2 g. 5-bromoindole in 5 cc. C₂H₄Cl₂, avoiding a rise in temperature beyond 10°, refluxing 30 min., pouring the cooled mixture into 10 g. NaOAc in 20 cc. H₂O, removing the C₂H₄Cl₂ by steam distillation, diluting the solution to 300 cc., heating to boiling, filtering, and cooling gave 0.3 g. 5-bromo-3-indolealdehyde, m. 205° (H₂O); p-nitrophenylhydrazone, m. 273° (decomposition). The same compound is prepared in 200 mg. yield by heating to reflux 2 g. VII and 20 g. Me₂NPh until the liberation of CO₂ ceases, adding 100 cc. H₂O, distilling with steam to remove the Me₂NPh, diluting to 200 cc. with H₂O, and filtering.

Farmaco, Edizione Scientifica published new progress about 100123-25-9. 100123-25-9 belongs to indole-building-block, auxiliary class Indole,Bromide,Ester,Aldehyde, name is Ethyl 5-bromo-3-formyl-1H-indole-2-carboxylate, and the molecular formula is C12H10BrNO3, Recommanded Product: Ethyl 5-bromo-3-formyl-1H-indole-2-carboxylate.

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

Tinivella, Annachiara published the artcileInvestigating the Selectivity of Allosteric Inhibitors for Mutant T790M EGFR over Wild Type Using Molecular Dynamics and Binding Free Energy Calculations, HPLC of Formula: 1942114-09-1, the publication is ACS Omega (2018), 3(12), 16556-16562, database is CAplus.

The recent discovery of the fourth generation EAI045 allosteric inhibitor, which potently and selectively inhibits mutant EGFR, represents an important step forward for the treatment of nonsmall cell lung cancer (NSCLC). However, the structural determinants of EAI045 selectivity with respect to the wild type (weight) protein have not been fully investigated. To this aim, the authors performed a comparative anal. of long-scale mol. dynamics simulations and binding free energy calculations on weight and T790M EGFR in complex with the EAI001 and EAI045 allosteric ligands. Unexpectedly, the authors found that the observed selectivity for T790M EGFR over weight is not due to more favorable interactions of the two ligands with the mutated gatekeeper residue, as previously suggested. Rather, the allosteric ligands were engaged in a direct hydrogen bond with the Asp855 residue of the DFG motif in mutant T790M but not in weight, in which the hydrogen bond was found to be water-mediated. Per-residue decomposition of binding free energies suggest that the loss of a direct interaction with Asp855 is the main cause of inhibitor selectivity. Moreover, the possibility that the allosteric ligands and ATP may have synergistic binding effects, as previously observed in MEK allosteric inhibitors, was investigated. Altogether, the results suggest that ligand selectivity arises from direct hydrogen bonds with the Asp855 side chain, and that the design of mutant-selective inhibitors should be focused on ligands that form direct hydrogen bonds with Asp855 in T790M EGFR but not in weight EGFR. These results may provide useful hints for future structural design of mutant-selective allosteric inhibitors that spare weight EGFR, which is a highly desirable goal.

ACS Omega published new progress about 1942114-09-1. 1942114-09-1 belongs to indole-building-block, auxiliary class Indoline,Thiazole,Fluoride,Amine,Benzene,Amide,Alcohol,Protein Tyrosine Kinase/RTK, name is 2-(5-Fluoro-2-hydroxyphenyl)-2-(1-oxoisoindolin-2-yl)-N-(thiazol-2-yl)acetamide, and the molecular formula is C10H16O2, HPLC of Formula: 1942114-09-1.

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

Mayer, Patrick G. K. published the artcileRegulation of plasma membrane localization of the Na+-taurocholate co-transporting polypeptide by glycochenodeoxycholate and tauroursodeoxycholate, Category: indole-building-block, the publication is Cellular Physiology & Biochemistry (2019), 52(6), 1427-1445, database is CAplus and MEDLINE.

Background/Aims: Hydrophobic bile salts, such as glycochenodeoxycholate (GCDC) can trigger hepatocyte apoptosis, which is prevented by tauroursodesoxycholate (TUDC), but the effects of GCDC and TUDC on sinusoidal bile salt uptake via the Na+-taurocholate transporting polypeptide (Ntcp) are unclear. Methods: The effects of GCDC and TUDC on the plasma membrane localization of Ntcp were studied in perfused rat liver by means of immunofluorescence anal. and super-resolution microscopy. The underlying signaling events were investigated by Western blotting and inhibitor studies. Results: GCDC (20μmol/l) induced within 60 min a retrieval of Ntcp from the basolateral membrane into the cytosol, which was accompanied by an activating phosphorylation of the Src kinases Fyn and Yes. Both, Fyn activation and the GCDC-induced Ntcp retrieval from the plasma membrane were sensitive to the NADPH oxidase inhibitor apocynin, the antioxidant N-acetylcysteine and the Src family kinase inhibitors SU6656 and PP-2, whereas PP-2 did not inhibit GCDC-induced Yes activation. Internalization of Ntcp by GCDC was also prevented by the protein kinase C (PKC) inhibitor Gö6850. TUDC (20μmol/l) reversed the GCDC-induced retrieval of Ntcp from the plasma membrane and prevented the activation of Fyn and Yes in GCDC-perfused rat livers. Reinsertion of Ntcp into the basolateral membrane in GCDC-perfused livers by TUDC was sensitive to the protein kinase A (PKA) inhibitor H89 and the integrin-inhibitory peptide GRGDSP, whereas the control peptide GRADSP was ineffective. Exposure of cultured rat hepatocytes to GCDC (50μmol/l, 15min) increased the fluorescence intensity of the reactive oxygen fluorescent indicator DCF to about 1.6-fold of untreated controls in a TUDC (50μmol/l)-sensitive way. GCDC caused a TUDC-sensitive canalicular dilatation without evidence for Bsep retrieval from the canalicular membrane. Conclusions: The present study suggests that GCDC triggers the retrieval of Ntcp from the basolateral membrane into the cytosol through an oxidative stress-dependent activation of Fyn. TUDC prevents the GCDC-induced Fyn activation and Ntcp retrieval through integrin-dependent activation of PKA.

Cellular Physiology & Biochemistry 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

Li, Hua published the artcileModified metabolites mapping by liquid chromatography-high resolution mass spectrometry using full scan/all ion fragmentation/neutral loss acquisition, Safety of Potassium 1H-indol-3-yl sulfate, the publication is Journal of Chromatography A (2019), 80-87, database is CAplus and MEDLINE.

Modified metabolites play important roles in diagnostic monitoring, oxidative response and physiol. regulation. Comprehensive anal. methods are greatly needed for improving the coverage of modified metabolites and studying their physiol. function. Here, a novel nontargeted profiling method for mapping modified metabolites was developed by liquid chromatog.-high resolution mass spectrometry with full scan/all ion fragmentation/neutral loss (FS/AIF/NL) data acquisition. Modified metabolites were unbiasedly defined with less false pos. results by mixed standards verification. Thirteen types of modified metabolites in urine were analyzed at the same time, and 198 of 307 modified metabolites at pos. mode and 166 of 366 modified metabolites at neg. mode were putatively identified. The modified metabolites profiling method was applied for investigating the metabolic differences between the patients with breast cancer and health controls. As a result, many modified metabolites with glucuronidation, ribosylation and indole acetylation modification were significantly up-regulated in breast cancer and four modified metabolites including 7-methylguanosine, N₄-acetylcytidine, dihyroxy-1H-indole glucuronide I and indole-3-acetic acid-O-glucuronide were identified as potential biomarkers for the diagnose of breast cancer.

Journal of Chromatography A 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, Safety of 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

Bian, Jinlei published the artcileDiscovery of NAD(P)H:quinone oxidoreductase 1 (NQO1) inhibitors with novel chemical scaffolds by shape-based virtual screening combined with cascade docking, Quality Control of 192820-78-3, the publication is RSC Advances (2015), 5(61), 49471-49479, database is CAplus.

A number of novel NAD(P)H:quinone oxidoreductase 1 (NQO1) inhibitors were discovered from the ChemDiv database via a simple protocol. Based on two reference NQO1 inhibitors, dicoumarol (DIC) and ES936, a shape-based similarity search and cascade docking filtering were conducted to identify new NQO1 inhibitors. Using these techniques, 43 compounds were selected, ordered, and tested. Among them, 7 compounds with novel chem. scaffolds were confirmed to be active by in vitro assays. Determination of the ability for protecting against NQO1-mediated toxicity of β-lapachone (β-lap) confirmed that compounds 8, 10 and 13 may be pharmacol. useful for probing the function of NQO1 in cells.

RSC Advances published new progress about 192820-78-3. 192820-78-3 belongs to indole-building-block, auxiliary class Fused/Partially Saturated Cycles,Dihydroindoles, name is 5-Methoxy-1,2-dimethyl-3-[(4-nitrophenoxy)methyl]indole-4,7-dione, and the molecular formula is C18H16N2O6, Quality Control of 192820-78-3.

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