Month: November 2022

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

El-Gendy, Adel A. published the artcileSynthesis and antihypertensive activity of certain Mannich bases of 2-ethoxycarbonylindoles and 5H-pyridazino[4,5-b]indoles, SDS of cas: 100123-25-9, the publication is Archives of Pharmacal Research (2001), 24(1), 21-26, database is CAplus and MEDLINE.

The synthesis of 3-(aminomethyl)-1H-indole-2-carboxylic acid Et ester derivatives and of 3-(aminomethyl)-3,5-dihydro-4H-pyridazino[4,5-b]indol-4-one derivatives was reported. Fourteen of the synthesized Mannich bases were screened as antihypertensive agents in normotensive anesthetized rats. The effect of 3-[(diethylamino)methyl]-1H-indole-2-carboxylic acid Et ester hydrochloride in normotensive anesthetized dogs was also studied.

Archives of Pharmacal Research 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, SDS of cas: 100123-25-9.

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

Anderson, Kirsty published the artcileOne-pot oxidative hydrolysis-oxidative cleavage of 7-borylindoles enables access to o-amidophenols and 4-acylbenzoxazoles, COA of Formula: C15H20BNO2, the publication is Chemical Communications (Cambridge, United Kingdom) (2020), 56(24), 3559-3562, database is CAplus and MEDLINE.

The compounds 7-borylindoles I (R¹ = H, Me, n-Pr, BPin, Ph, 4-fluorophenyl; R² = H, Me, Et, 4-methoxyphenyl; R³ = H, Me, F, Cl, Br, NO₂, BnO) undergo a one-pot oxidative-hydrolysis of the arylboronate and oxidative cleavage of the indole C2-C3 double bond to afford o-amidophenol derivatives 2-OH-4-R³-6-(R²C(O))-C₆H₂NHC(O)R¹. Subsequent cyclization delivers benzoxazoles II bearing an acyl group at C4, a substitution pattern common to fungal-derived benzoxazole alkaloids. Using 7-borylindoles I as substrates to access functionalized o-amidophenols, the difficult preparation of these compounds from arene, streamlining access to substituted 4-acylbenzoxazoles II in the process is circumvented.

Chemical Communications (Cambridge, United Kingdom) published new progress about 919119-59-8. 919119-59-8 belongs to indole-building-block, auxiliary class Indole,Boronic acid and ester,Boronate Esters,Boronic Acids,Boronic acid and ester, name is 2-Methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole, and the molecular formula is C15H20BNO2, COA of Formula: C15H20BNO2.

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

Hara, Toshiaki published the artcileProbing the Structural Requirements of Peptoids That Inhibit HDM2-p53 Interactions, Safety of tert-Butyl 3-(2-aminoethyl)-1H-indole-1-carboxylate, the publication is Journal of the American Chemical Society (2006), 128(6), 1995-2004, database is CAplus and MEDLINE.

Many cellular processes are controlled by protein-protein interactions, and selective inhibition of these interactions could lead to the development of new therapies for several diseases. For example, overexpression of the protein HDM2 (human double minute 2), which binds to and inactivates the protein p53, has been linked to tumor aggressiveness and drug resistance in cancer. In creating inhibitors of protein-protein interactions, one strategy is to recreate the three-dimensional arrangement of side chains that are involved in the binding of one protein to another, using a nonnatural scaffold as the attachment point for the side chains. Here, the authors used oligomeric peptoids as the scaffold to develop a general strategy to rationally design synthetic mols. that can be optimized for inhibition of protein-protein interactions. Structural information on the HDM2-p53 complex was used to design the first class of peptoid inhibitors, and this work provides, in detail, the strategy to modify peptoids with the appropriate side chains that are effective inhibitors of HDM2-p53 binding. While the authors initially tried to develop rigid, helical peptoids as HDM2 binders, the best inhibitors were surprisingly peptoids that lacked any helix-promoting groups. These results indicate that starting with rigid peptoid scaffolds may not always be optimal to develop new inhibitors.

Journal of the American Chemical Society 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, Safety of 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

Gallant, Michel published the artcileNew class of potent ligands for the human peripheral cannabinoid receptor, SDS of cas: 2854-32-2, the publication is Bioorganic & Medicinal Chemistry Letters (1996), 6(19), 2263-2268, database is CAplus.

Indoles, e.g. I (R¹ = morpholino, morpholinocarbonyl, CO₂Me, CO₂H, morpholinomethyl; R² = 2-, 4-ClC₆H₄, 1-, 2-naphthyl, etc.), were prepared as potent ligands for the human peripheral cannabinoid (hCB₂) receptor. Two of these indole analogs exhibited nanomolar potencies (K_i) with good selectivity for the hCB₂ receptor over the human central cannabinoid (hCB₁) receptor.

Bioorganic & Medicinal Chemistry Letters 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