Day: November 21, 2022

De Martiis, F. published the artcileSynthesis and antiphlogistic properties of some indolylacetohydroxamic acids, SDS of cas: 2854-32-2, the publication is Bollettino Chimico Farmaceutico (1975), 114(6), 309-18, database is CAplus and MEDLINE.

Indoleacetates I (R = COC6H4Cl-4, R1 = Cl, NHOH, NH2, morpholino, NMe2, OMe, OEt; R = H, R1 = NHOH; R = CH2Ph, allyl, R1 = OMe, NHOH; R = CH2CO2Et, CH2CONHOH, R1 = OMe, OCMe3) were prepared from indomethacin. At 10 mg/kg orally I gave 13-62% inhibition of carrageenin edema in rats and at 5 mg/kg orally caused 12-48% increase in pain threshold in rats.

Bollettino Chimico Farmaceutico 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, SDS of cas: 2854-32-2.

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

Tuccinardi, Tiziano published the artcileCannabinoid CB2/CB1 Selectivity. Receptor Modeling and Automated Docking Analysis, Computed Properties of 2854-32-2, the publication is Journal of Medicinal Chemistry (2006), 49(3), 984-994, database is CAplus and MEDLINE.

Three-dimensional models of the CB1 and CB2 cannabinoid receptors were constructed by a mol. modeling procedure, using the x-ray structure of bovine rhodopsin as the initial template, and taking into account the available site-directed mutagenesis data. The cannabinoid system was studied by docking techniques. An anal. of the interaction of WIN55212-2 with both receptors showed that CB2/CB1 selectivity is mainly determined by the interaction in the CB2 with the nonconserved residues S3.31 and F5.46, whose importance was suggested by site-directed mutagenesis data. The authors also carried out an automated docking of several ligands into the CB2 model, using the AUTODOCK 3.0 program; the good correlation obtained between the estimated free energy binding and the exptl. binding data confirmed the authors binding hypothesis and the reliability of the model.

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 C12H14BNO2, Computed Properties of 2854-32-2.

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

Thouverey, Cyril published the artcileSelective inhibition of Src family kinases by SU6656 increases bone mass by uncoupling bone formation from resorption in mice, Recommanded Product: SU6656, the publication is Bone (New York, NY, United States) (2018), 95-104, database is CAplus and MEDLINE.

Mice deficient in the non-receptor tyrosine kinase Src exhibit high bone mass due to impaired bone resorption and increased bone formation. Although several Src family kinase inhibitors inhibit bone resorption in vivo, they display variable effects on bone formation. SU6656 is a selective Src family kinase inhibitor with weaker activity towards the non-receptor tyrosine kinase Abl and receptor tyrosine kinases which are required for appropriate osteoblast proliferation, differentiation and function. Therefore, we sought to determine whether SU6656 could increase bone mass by inhibiting bone resorption and by stimulating bone formation, and to explore its mechanisms of action. Four-month-old female C57Bl/6J mice received i.p. injections of either 25 mg/kg SU6656 or its vehicle every other day for 12 wk. SU6656-treated mice exhibited increased bone mineral d., cortical thickness, cancellous bone volume and trabecular thickness. SU6656 inhibited bone resorption in mice as shown by reduced osteoclast number, and diminished expressions of Oscar, Trap5b and CtsK. SU6656 did not affect Rankl or Opg expressions. However, it blocked c-fms signaling, osteoclastogenesis and matrix resorption, and induced osteoclast apoptosis in vitro. In addition, SU6656 stimulated bone formation rates at trabecular, endosteal and periosteal bone envelopes, and increased osteoblast number in trabecular bone. SU6656 did not affect expressions of clastokines favoring bone formation in mice. However, it stimulated osteoblast differentiation and matrix mineralization by specifically facilitating BMP-SMAD signaling pathway in vitro. Knockdown of Src and Yes mimicked the stimulatory effect of SU6656 on osteoblast differentiation. In conclusion, SU6656 uncouples bone formation from resorption by inhibiting osteoclast development, function and survival, and by enhancing BMP-mediated osteoblast differentiation.

Bone (New York, NY, 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 C6H12N2O, Recommanded Product: 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

Araldi, Dioneia published the artcileRepeated mu-opioid exposure induces a novel form of the hyperalgesic priming model for transition to chronic pain, Related Products of indole-building-block, the publication is Journal of Neuroscience (2015), 35(36), 12502-12517, database is CAplus and MEDLINE.

The primary afferent nociceptor was used as a model system to study mechanisms of pain induced by chronic opioid administration. Repeated intradermal injection of the selective mu-opioid receptor (MOR) agonist DAMGO induced mech. hyperalgesia and marked prolongation of prostaglandin E2 (PGE2) hyperalgesia, a key feature of hyperalgesic priming. However, in contrast to prior studies of priming induced by receptor-mediated (i.e., TNFα, NGF, or IL-6 receptor) or direct activation of protein kinase Cε (PKCε), the pronociceptive effects of PGE2 in DAMGO-treated rats demonstrated the following: (1) rapid induction (4 h compared with 3 d); (2) protein kinase A (PKA), rather than PKCε, dependence; (3) prolongation of hyperalgesia induced by an activator of PKA, 8-bromo cAMP; (4) failure to be reversed by a protein translation inhibitor; (5) priming in females as well as in males; and (6) lack of dependence on the isolectin B4-pos. nociceptor. These studies demonstrate a novel form of hyperalgesic priming induced by repeated administration of an agonist at the Gi-protein-coupled MOR to the peripheral terminal of the nociceptor.

Journal of Neuroscience 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, Related Products of 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

Araldi, Dioneia published the artcileMu-opioid Receptor (MOR) Biased Agonists Induce Biphasic Dose-dependent Hyperalgesia and Analgesia, and Hyperalgesic Priming in the Rat, COA of Formula: C19H21N3O3S, the publication is Neuroscience (Amsterdam, Netherlands) (2018), 60-71, database is CAplus and MEDLINE.

We investigated if local and systemic administration of biased MOR agonists (PZM21 and TRV130 [oliceridine]), which preferentially activate G-protein over beta-arrestin translocation, and have been reported to minimize some opioid side effects, also produces OIH and priming. Injected intradermally (100 ng), both biased agonists induced mech. hyperalgesia and, when injected at the same site, 5 days later, prostaglandin E₂ (PGE₂) produced prolonged hyperalgesia (priming). OIH and priming were both prevented by intrathecal treatment with an oligodeoxynucleotide (ODN) antisense (AS) for MOR mRNA. Agents that reverse Type I (the protein translation inhibitor cordycepin) and Type II (combination of Src and mitogen-activated protein kinase [MAPK] inhibitors) priming, or their combination, did not reverse priming induced by local administration of PZM21 or TRV130. While systemic PZM21 at higher doses (1 and 10 mg/kg) induced analgesia, lower doses (0.001, 0.01, 0.1, and 0.3 mg/kg) induced hyperalgesia; all doses induced priming. Hyperalgesia, analgesia and priming induced by systemic administration of PZM21 were also prevented by MOR AS-ODN. And, priming induced by systemic PZM21 was also not reversed by intradermal cordycepin or the combination of Src and MAPK inhibitors. Thus, maintenance of priming induced by biased MOR agonists, in the peripheral terminal of nociceptors, has a novel mechanism.

Neuroscience (Amsterdam, Netherlands) 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, COA of Formula: C19H21N3O3S.

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

Wang, Pingyuan published the artcileSynthesis and Pharmacological Evaluation of Noncatechol G Protein Biased and Unbiased Dopamine D1 Receptor Agonists, Product Details of C19H28BNO4, the publication is ACS Medicinal Chemistry Letters (2019), 10(5), 792-799, database is CAplus and MEDLINE.

Noncatechol heterocycles have recently been discovered as potent and selective G protein biased dopamine 1 receptor (D1R) agonists with superior pharmacokinetic properties. To determine the structure-activity relations centered on G protein or β-arrestin signaling bias, systematic medicinal chem. was employed around three aromatic pharmacophores of the lead compound PF2334, generating a series of new mols. that were evaluated at both D1R G_s-dependent cAMP signaling and β-arrestin recruitment in HEK293 cells. Here, the authors report the chem. synthesis, pharmacol. evaluation, and mol. docking studies leading to the identification of two novel noncatechol D1R agonists that are a subnanomolar potent unbiased ligand 6-(4-(Furo[3,2-c]pyridin-4-yloxy)-2-methylphenyl)-1,5-dimethylpyrimidine-2,4(1H,3H)dione (PW0441) and a nanomolar potent complete G protein biased ligand 6-(4-((3-(Difluoromethoxy)pyridin-2-yl)oxy)-2-methylphenyl)-1,5-dimethylpyrimidine-2,4(1H,3H)-dione (PW0464), resp. These novel D1R agonists provide important tools to study D1R activation and signaling bias in both health and disease.

ACS Medicinal Chemistry Letters 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 C19H21N3O, Product Details of C19H28BNO4.

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

Winski, Shannon L. published the artcileCharacterization of a Mechanism-Based Inhibitor of NAD(P)H:Quinone Oxidoreductase 1 by Biochemical, X-ray Crystallographic, and Mass Spectrometric Approaches, Application of 5-Methoxy-1,2-dimethyl-3-[(4-nitrophenoxy)methyl]indole-4,7-dione, the publication is Biochemistry (2001), 40(50), 15135-15142, database is CAplus and MEDLINE.

We report the characterization of 5-methoxy-1,2-dimethyl-3-[(4-nitrophenoxy)methyl]indole-4,7-dione (ES936) as a mechanism-based inhibitor of NQO1. Inactivation of NQO1 by ES936 was time- and concentration-dependent and required the presence of a pyridine nucleotide cofactor consistent with a need for metabolic activation. That ES936 was an efficient inhibitor was demonstrated in these studies by the low partition ratio (1.40±0.03). The orientation of ES936 in the active site of NQO1 was examined by X-ray crystallog. and found to be opposite to that observed for other indolequinones acting as substrates. ES936 was oriented in such a manner that, after enzymic reduction and loss of a nitrophenol leaving group, a reactive iminium species was located in close proximity to nucleophilic His 162 and Tyr 127 and Tyr 129 residues in the active site. To determine if ES936 was covalently modifying NQO1, ES936-treated protein was analyzed by electrospray ionization liquid chromatog./mass spectrometry (ESI-LC/MS). The control NQO1 protein had a mass of 30864 ± 6 Da (n = 20, theor., 30868.6 Da) which increased by 217 Da after ES936 treatment (31081 ± 7 Da, n = 20) in the presence of NADH. The shift in mass was consistent with adduction of NQO1 by the reactive iminium derived from ES936 (M + 218 Da). Chymotryptic digestion of the protein followed by LC/MS anal. located a tetrapeptide spanning amino acids 126-129 which was adducted with the reactive iminium species derived from ES936. LC/MS/MS anal. of the peptide fragment confirmed adduction of either Tyr 127 or Tyr 129 residues. This work demonstrates that ES936 is a potent mechanism-based inhibitor of NQO1 and may be a useful tool in defining the role of NQO1 in cellular systems and in vivo.

Biochemistry 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 C3H6O2, Application of 5-Methoxy-1,2-dimethyl-3-[(4-nitrophenoxy)methyl]indole-4,7-dione.

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

Sanz, Roberto published the artcileDioxomolybdenum(VI)-catalyzed reductive cyclization of nitroaromatics. Synthesis of carbazoles and indoles, Category: indole-building-block, the publication is Advanced Synthesis & Catalysis (2007), 349(4+5), 713-718, database is CAplus.

Reductive cyclization of nitrobiphenyls and nitrostyrenes to carbazoles and indoles, resp., is carried out by triphenylphosphine under mild conditions catalyzed by a dichlorodioxomolybdenum(VI) complex. A one-pot procedure for the synthesis of regioselectively functionalized indoles has been developed from com. available o-nitrobenzaldehydes and phosphoranes.

Advanced Synthesis & Catalysis published new progress about 20538-12-9. 20538-12-9 belongs to indole-building-block, auxiliary class Indole,Ester,Ether, name is Ethyl 7-methoxy-1H-indole-2-carboxylate, and the molecular formula is C12H13NO3, 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

Chmielarz, Piotr published the artcileGDNF/RET Signaling Pathway Activation Eliminates Lewy Body Pathology in Midbrain Dopamine Neurons, Application In Synthesis of 330161-87-0, the publication is Movement Disorders (2020), 35(12), 2279-2289, database is CAplus and MEDLINE.

Parkinson’s disease (PD) is associated with proteostasis disturbances and accumulation of misfolded α-synuclein (α-syn), a cytosolic protein present in high concentrations at pre-synaptic neuronal terminals. It is a primary constituent of intracellular protein aggregates known as Lewy neurites or Lewy bodies. Progression of Lewy pathol. caused by the prion-like self-templating properties of misfolded α-syn is a characteristic feature in the brains of PD patients. Glial cell line-derived neurotrophic factor (GDNF) promotes survival of mature dopamine (DA) neurons in vitro and in vivo. However, the data on its effect on Lewy pathol. is controversial. We studied the effects of GDNF on misfolded α-syn accumulation in DA neurons. Lewy pathol. progression was modeled by the application of α-syn preformed fibrils in cultured DA neurons and in the adult mice. We discovered that GDNF prevented accumulation of misfolded α-syn in DA neurons in culture and in vivo. These effects were abolished by deletion of receptor tyrosine kinase rearranged during transfection (RET) or by inhibitors of corresponding signaling pathway. Expression of constitutively active RET protected DA neurons from fibril-induced α-syn accumulation. For the first time, we have shown the neurotrophic factor-mediated protection against the misfolded α-syn propagation in DA neurons, uncovered underlying receptors, and investigated the involved signaling pathways. These results demonstrate that activation of GDNF/RET signaling can be an effective therapeutic approach to prevent Lewy pathol. spread at early stages of PD.

Movement Disorders 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

Taylor, Nicholas J. published the artcileDerisking the Cu-Mediated ¹⁸F-Fluorination of Heterocyclic Positron Emission Tomography Radioligands, Related Products of indole-building-block, the publication is Journal of the American Chemical Society (2017), 139(24), 8267-8276, database is CAplus and MEDLINE.

The compatibility of various heterocycles, particularly nitrogen heterocycles, towards the copper-mediated ¹⁸F-fluorination of aryl pinacolboronates with ¹⁸F-fluoride was determined using fluorination reactions of a model substrate in the presence of exogenous heterocycles and the fluorination reactions of substrates possessing heterocycles with fluorination on an attached aromatic ring or directly attached to the heterocycle of interest. Using this information, syntheses of seven ¹⁸F-labeled structurally complex pharmaceutically relevant heterocycle-containing mols. were designed and executed. The method may be useful in designing syntheses of other radiolabeled compounds and delineating the scope of utility of other radiolabeling methods.

Journal of the American Chemical Society 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 C23H43NP2, Related Products of 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