Day: November 28, 2022

Moraes, Eduardo Cruz published the artcileKinase inhibitor profile for human Nek1, Nek6, and Nek7 and analysis of the structural basis for inhibitor specificity, SDS of cas: 330161-87-0, the publication is Molecules (2015), 20(1), 1176-1191, 16 pp., database is CAplus and MEDLINE.

Human Neks are a conserved protein kinase family related to cell cycle progression and cell division and are considered potential drug targets for the treatment of cancer and other pathologies. We screened the activation loop mutant kinases hNek1 and hNek2, wild-type hNek7, and five hNek6 variants in different activation/phosphorylation statesand compared them against 85 compounds using thermal shift denaturation. We identified three compounds with significant Tm shifts: JNK Inhibitor II for hNek1(Δ262-1258)-(T162A), Isogranulatimide for hNek6(S206A), andGSK-3 Inhibitor XIII for hNek7wt. Each one of these compounds was also validated by reducing the kinases activity by at least 25%. The binding sites for these compounds were identified by in silico docking at the ATP-binding site of the resp. hNeks. Potential inhibitors were first screened by thermal shift assays, had their efficiency tested by a kinase assay, and were finally analyzed by mol. docking. Our findings corroborate the idea of ATP-competitive inhibition for hNek1 and hNek6 and suggest a novel non-competitive inhibition for hNek7 in regard to GSK-3 Inhibitor XIII. Our results demonstrate that our approach is useful for finding promising general and specific hNekscandidate inhibitors, which may also function as scaffolds to design more potent and selective inhibitors.

Molecules 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

Axten, Jeffrey M. published the artcileDiscovery of 7-methyl-5-(1-{[3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-indol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (GSK2606414), a potent and selective first-in-class inhibitor of protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK), HPLC of Formula: 837392-67-3, the publication is Journal of Medicinal Chemistry (2012), 55(16), 7193-7207, database is CAplus and MEDLINE.

Protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) is activated in response to a variety of endoplasmic reticulum stresses implicated in numerous disease states. Evidence that PERK is implicated in tumorigenesis and cancer cell survival stimulated our search for small mol. inhibitors. Through screening and lead optimization using the human PERK crystal structure, we discovered compound I (GSK2606414), an orally available, potent, and selective PERK inhibitor. Compound I inhibits PERK activation in cells and inhibits the growth of a human tumor xenograft in mice.

Journal of Medicinal Chemistry published new progress about 837392-67-3. 837392-67-3 belongs to indole-building-block, auxiliary class Indoline,Boronic acid and ester,Amide,Boronate Esters,Aliphatic Heterocyclic, name is tert-Butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indoline-1-carboxylate, and the molecular formula is C19H28BNO4, HPLC of Formula: 837392-67-3.

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

Chow, Amanda published the artcileDasatinib inhibits peripapillary scleral myofibroblast differentiation, HPLC of Formula: 330161-87-0, the publication is Experimental Eye Research (2020), 107999, database is CAplus and MEDLINE.

Scleral fibroblast activation occurs in glaucomatous and myopic eyes. Here we perform an unbiased screen to identify kinase inhibitors that reduce fibroblast activation to diverse stimuli in vitro and to in vivo intraocular pressure (IOP) elevation. Primary cultures of peripapillary scleral (PPS) fibroblasts from two human donors were screened using a library of 80 kinase inhibitors to identify compounds that inhibit TGFbeta-induced extracellular matrix (ECM) synthesis. Inhibition of myofibroblast differentiation was verified by alpha smooth muscle actin (aSMA) immunoblot and collagen contraction assay. Three kinase inhibitors were verified to reduce TGFbeta-induced aSMA expression and cellular contractility (rottlerin, PP2, tyrphostin 9). The effect of three Src inhibitors, bosutinib, dasatinib, and SU-6656, on myofibroblast differentiation was evaluated, with only dasatinib significantly inhibiting TGFbeta-induced ECM synthesis, aSMA expression, and cellular contractility at nanomolar dosages. Subconjunctival injection of dasatinib reduced IOP-induced scleral fibroblast proliferation compared to control (4.9 ± 11.1 ng/sclera with 0.1 muM vs. 88.7 ± 38.6 ng/sclera in control, P < 0.0001). Dasatinib inhibits scleral myofibroblast differentiation and there is pharmacol. evidence that this inhibition is not solely due to Src-kinase inhibition.

Experimental Eye Research 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, 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

Tanasic, Sascha published the artcileDesipramine targets astrocytes to attenuate synaptic plasticity via modulation of the ephrinA3/EphA4 signalling, Synthetic Route of 330161-87-0, the publication is Neuropharmacology (2016), 154-163, database is CAplus and MEDLINE.

Long-term potentiation (LTP), a major cellular correlate of memory storage, depends on activation of the ERK/MAPK signalling pathway, but the cell type-specific localization of activated MAPKs remains unknown. We found that in the CA1 field of the hippocampus, shortly after LTP induction, an increase in the number of MAPK-pos. cells occurred specifically among astrocytes of the stratum radiatum, suggesting a putative role of astrocytes for LTP. Desipramine (DMI) is an antidepressant which is used to treat major depressive disorder, but also other pathologies such as neuropathic pain or attention-deficit/hyperactivity disorder. Tricyclic antidepressants such as DMI may cause memory impairment as a side effect. However, biol. underpinnings of this effect still remain unclear. Here, we show that DMI inhibited the astrocytic MAPK activation and thereby hindered synaptic potentiation. These effects correlated with a reduced neuronal activation in the stratum pyramidale, thereby prompting us to analyze a regulator of LTP located at the astrocyte-neuron interface in the stratum radiatum, namely the ephrinA3/EphA4 signalling pathway. DMI enhanced EphA4 clustering, which favored an increased ephrinA3-mediated EphA4 phosphorylation and elevated EphA4 forward signalling. The co-administration of DMI with the Src inhibitor SU6656, which blocks EphA4 forward signalling, could partially reverse the LTP attenuation, further supporting the targeting of the ephrinA3/EphA4 pathway by DMI. Thus, our findings suggest a putative novel mechanism for DMI to modulate LTP through the regulation of the ephrinA3/EphA4 signalling pathway. A further exploration of the mol. and behavioral consequences of targeting ephrinA3/EphA4 might help to improve the clin. use of DMI.

Neuropharmacology 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 C6H13NO2, Synthetic Route 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

Lamotte, Yann published the artcileSynthesis and biological activities of novel indole derivatives as potent and selective PPARγ modulators, Quality Control of 57663-18-0, the publication is Bioorganic & Medicinal Chemistry Letters (2010), 20(4), 1399-1404, database is CAplus and MEDLINE.

Starting from the structure of Telmisartan, a new series of potent and selective PPARγ modulators was identified. The synthesis, in vitro and in vivo evaluation of the most potent compounds were reported and the X-ray structure of compound I bound to the PPARγ ligand binding domain was described.

Bioorganic & Medicinal Chemistry Letters published new progress about 57663-18-0. 57663-18-0 belongs to indole-building-block, auxiliary class Indole,Ester, name is Methyl 2-methyl-1H-indole-5-carboxylate, and the molecular formula is C11H11NO2, Quality Control of 57663-18-0.

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

Kalgutkar, Amit S. published the artcileEster and Amide Derivatives of the Nonsteroidal Antiinflammatory Drug, Indomethacin, as Selective Cyclooxygenase-2 Inhibitors, COA of Formula: C23H23ClN2O4, the publication is Journal of Medicinal Chemistry (2000), 43(15), 2860-2870, database is CAplus and MEDLINE.

Recent studies from our laboratory have shown that derivatization of the carboxylate moiety in substrate analog inhibitors, such as 5,8,11,14-eicosatetraynoic acid, and in nonsteroidal antiinflammatory drugs (NSAIDs), such as indomethacin and meclofenamic acid, results in the generation of potent and selective cyclooxygenase-2 (COX-2) inhibitors (Kalgutkar et al. Proc. Natl. Acad. Sci. U.S.A. 2000, 97, 925-930). This paper summarizes details of the structure-activity studies involved in the transformation of the arylacetic acid NSAID, indomethacin, into a COX-2-selective inhibitor. Many of the structurally diverse indomethacin esters and amides inhibited purified human COX-2 with IC₅₀ values in the low-nanomolar range but did not inhibit ovine COX-1 activity at concentrations as high as 66 μM. Primary and secondary amide analogs of indomethacin were more potent as COX-2 inhibitors than the corresponding tertiary amides. Replacement of the 4-chlorobenzoyl group in indomethacin esters or amides with the 4-bromobenzyl functionality or hydrogen afforded inactive compounds Likewise, exchanging the 2-Me group on the indole ring in the ester and amide series with a hydrogen also generated inactive compounds Inhibition kinetics revealed that indomethacin amides behave as slow, tight-binding inhibitors of COX-2 and that selectivity is a function of the time-dependent step. Conversion of indomethacin into ester and amide derivatives provides a facile strategy for generating highly selective COX-2 inhibitors and eliminating the gastrointestinal side effects of the parent compound

Journal of Medicinal Chemistry published new progress about 2854-32-2. 2854-32-2 belongs to indole-building-block, auxiliary class GPCR/G Protein,Cannabinoid Receptor, name is 2-(1-(4-Chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)-1-morpholinoethanone, and the molecular formula is C23H23ClN2O4, COA of Formula: C23H23ClN2O4.

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

Yang, Qing-Qing published the artcileVisible-Light-Induced Direct Photocatalytic Carboxylation of Indoles with CBr₄/MeOH, Recommanded Product: tert-Butyl 3-(2-aminoethyl)-1H-indole-1-carboxylate, the publication is Chemistry – A European Journal (2015), 21(50), 18052-18056, database is CAplus and MEDLINE.

Photocatalysis enables the cascade reactions of indoles and CBr₄ in MeOH through a C(sp²)-H functionalization/methanolysis sequence. The title reaction provides an efficient access to indole-2- and 3-carboxylates in a single operation (no preinstallation of protecting or directing groups was required) with good yields under mild reaction conditions.

Chemistry – A European Journal 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 C40H35N7O8, Recommanded Product: tert-Butyl 3-(2-aminoethyl)-1H-indole-1-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

Douat-Casassus, Celine published the artcileSynthetic anticancer vaccine candidates: rational design of antigenic peptide mimetics that activate tumor-specific T-cells, Synthetic Route of 167015-84-1, the publication is Journal of Medicinal Chemistry (2007), 50(7), 1598-1609, database is CAplus and MEDLINE.

A rational design approach was followed to develop peptidomimetic analogs of a cytotoxic T-cell epitope capable of stimulating T-cell responses as strong as or stronger (heteroclytic) than those of parental antigenic peptides. The work described herein focused on structural alterations of the central amino acids of the melanoma tumor-associated antigenic peptide Melan-A/MART-1_26-35 using nonpeptidic units. A screening was first realized in silico to select altered peptides potentially capable of fitting at the interface between the major histocompatibilty complex (MHC) class-I HLA-A2 mol. and T-cell receptors (TCRs). Two compounds appeared to be high-affinity ligands to the HLA-A2 mol. and stimulated several Melan-A/MART-1 specific T-cell clones. Most remarkably, one of them even managed to amplify the response of one clone. Together, these results indicate that central TCR-contact residues of antigenic peptides can be replaced by nonpeptidic motifs without loss of binding affinity to MHC class-I mols. and T-cell triggering capacity.

Journal of Medicinal Chemistry 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

Davies, Huw M. L. published the artcileC-H Activation as a Strategic Reaction: Enantioselective Synthesis of 4-Substituted Indoles, Category: indole-building-block, the publication is Journal of the American Chemical Society (2006), 128(4), 1060-1061, database is CAplus and MEDLINE.

A method is described for the asym. synthesis of 4-substituted indoles, e.g., I, from the Rh₂(S-DOSP)₄-catalyzed decomposition of vinyldiazoacetates in the presence of N-Boc-4-acetoxy-6,7-dihydroindole. The reaction proceeds via a combined C-H activation/Cope rearrangement-elimination mechanism resulting in good yields and very high asym. induction. The absolute configuration of I was determined by X-ray crystallog. of its reduced analog.

Journal of the American Chemical Society published new progress about 27784-79-8. 27784-79-8 belongs to indole-building-block, auxiliary class Other Aromatic Heterocyclic,Bromide,Ketone, name is 2-Bromo-6,7-dihydro-1H-indol-4(5H)-one, and the molecular formula is C8H8BrNO, 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

Martin, James S. published the artcileSynthesis of a Series of Diaminoindoles, HPLC of Formula: 10242-03-2, the publication is Journal of Organic Chemistry (2021), 86(17), 11333-11340, database is CAplus and MEDLINE.

A selection of 3,4-diaminoindoles were required for a recent drug discovery project. To this end, a 10-step synthesis was developed from 4-nitroindole. This synthesis was subsequently adapted and used to synthesize 3,5-; 3,6-; and 3,7-diaminoindoles from the corresponding 5-, 6-, or 7-nitroindole. These novel intermediates feature orthogonal protecting groups that allow them to be further diversified. This is the first reported synthesis of these types of compounds

Journal of Organic Chemistry published new progress about 10242-03-2. 10242-03-2 belongs to indole-building-block, auxiliary class Indole,Nitro Compound,Carboxylic acid,Indole, name is 6-Nitro-1H-indole-3-carboxylic acid, and the molecular formula is C9H6N2O4, HPLC of Formula: 10242-03-2.

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