Month: November 2022

Kerns, Jeffrey K. published the artcile3,5-Disubstituted-indole-7-carboxamides as IKKβ Inhibitors: Optimization of Oral Activity via the C3 Substituent, Formula: C9H6BrNO2, the publication is ACS Medicinal Chemistry Letters (2018), 9(12), 1164-1169, database is CAplus and MEDLINE.

IκB kinase β (IKKβ or IKK2) is a key regulator of nuclear factor kappa B (NF-κB) and has received attention as a therapeutic target. Herein the authors report on the optimization of a series of 3,5-disubstituted-indole-7-carboxamides for oral activity. In doing so, the authors focused attention on potency, ligand efficiency (LE), and physicochem. properties and have identified compounds I and II as having robust in vivo activity.

ACS Medicinal Chemistry Letters published new progress about 860624-90-4. 860624-90-4 belongs to indole-building-block, auxiliary class Indole,Bromide,Carboxylic acid,Indole, name is 5-Bromo-1H-indole-7-carboxylic acid, and the molecular formula is C9H6BrNO2, Formula: C9H6BrNO2.

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

Kiris, Erkan published the artcileSrc Family Kinase Inhibitors Antagonize the Toxicity of Multiple Serotypes of Botulinum Neurotoxin in Human Embryonic Stem Cell-Derived Motor Neurons, Recommanded Product: SU6656, the publication is Neurotoxicity Research (2015), 27(4), 384-398, database is CAplus and MEDLINE.

Botulinum neurotoxins (BoNTs), the causative agents of botulism, are potent inhibitors of neurotransmitter release from motor neurons. There are currently no drugs to treat BoNT intoxication after the onset of the disease symptoms. In this study, we explored how modulation of key host pathways affects the process of BoNT intoxication in human motor neurons, focusing on Src family kinase (SFK) signaling. Motor neurons derived from human embryonic stem (hES) cells were treated with a panel of SFK inhibitors and intoxicated with BoNT serotypes A, B, or E (which are responsible for >95 % of human botulism cases). Subsequently, it was found that bosutinib, dasatinib, KX2-391, PP1, PP2, Src inhibitor-1, and SU6656 significantly antagonized all three of the serotypes. Furthermore, the data indicated that the treatment of hES-derived motor neurons with multiple SFK inhibitors increased the antagonistic effect synergistically. Mechanistically, the small mols. appear to inhibit BoNTs by targeting host pathways necessary for intoxication and not by directly inhibiting the toxins’ proteolytic activity. Importantly, the identified inhibitors are all well-studied with some in clin. trials while others are FDA-approved drugs. Overall, this study emphasizes the importance of targeting host neuronal pathways, rather than the toxin’s enzymic components, to antagonize multiple BoNT serotypes in motor neurons.

Neurotoxicity 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, 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

Woudenberg-Vrenken, Titia E. published the artcileAnti-oxidants do not prevent bile acid-induced cell death in rat hepatocytes, Safety of SU6656, the publication is Liver International (2010), 30(10), 1511-1521, database is CAplus and MEDLINE.

Background: Bile acids, reactive oxygen species (ROS) and inflammatory cytokines are crucial regulators of cell death in acute and chronic liver diseases. The contribution of each factor to hepatocyte death, either apoptosis or necrosis, has not been clarified as yet. It has been suggested that the generation of oxidative stress by bile acids contributes to hepatocyte death during cholestasis and bile acid toxicity, although the beneficial role of ROS prevention in bile acid-mediated cell death is not fully understood. Aim: Study the effects of anti-oxidants in bile acid-induced cell death in vitro. Methods: Primary rat hepatocytes were exposed to the bile acids glycochenodeoxycholic acid (GCDCA) or taurolithocholic acid-3 sulfate in the absence or presence of ROS scavengers or anti-oxidants. Heme oxygenase (HO)-1 mRNA levels were analyzed by quant. polymerase chain reaction. Apoptosis was quantified by acridine orange staining and caspase-3 activity assay. Necrosis was detected by Sytox green staining. Results: Anti-oxidants do not attenuate bile acid-induced cell death. Furthermore, bile acid exposure does not enhance the mRNA expression of the oxidative stress-responsive gene HO-1. The Src-kinase inhibitor, SU6656, does reduce GCDCA-induced apoptosis and necrosis. Conclusions: In hepatocytes, bile acid-induced toxicity is not prevented by scavengers of oxidative stress. The beneficial effects observed in patients might be because of the contribution of ROS and cytokines rather than bile acid-mediated oxidative stress. However, the use of specific Src kinase inhibitors might be a useful tool to prevent bile acid-induced injury in liver diseases.

Liver International 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 C3H9ClOS, Safety 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

Ivanova, Olga A. published the artcileA Straightforward Approach to Tetrahydroindolo[3,2-b]carbazoles and 1-Indolyltetrahydrocarbazoles through [3+3] Cyclodimerization of Indole-Derived Cyclopropanes, Formula: C9H6FNO, the publication is Chemistry – A European Journal (2016), 22(4), 1223-1227, database is CAplus and MEDLINE.

A rapid new approach to produce biol. relevant bisindoles, namely indolyltetrahydrocarbazoles and indolo[3,2-b]carbazoles, was developed, based on the Ga(OTf)₃-catalyzed [3+3] cyclodimerization of indole-derived donor-acceptor cyclopropanes. Chemoselectivity of the process depends on the location of the three-membered ring at the indole core.

Chemistry – A European Journal 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, Formula: C9H6FNO.

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

Piers, E. published the artcileThe decarboxylation of ring-substituted indole-2(and 3)carboxylic acids, Safety of 6-Nitro-1H-indole-3-carboxylic acid, the publication is Canadian Journal of Chemistry (1962), 559-61, database is CAplus.

A mixture of the indole-2-carboxylic acid (0.01 mole) and its Cu salt (0.0004 mole) in 10 ml. synthetic quinoline was heated until CO₂ began to evolve and was kept at this temperature until gas evolution ceased (1.5-5 hrs.). The cooled solution was taken up in Et₂O, washed with N HCl, H₂O, Na₂CO₃, H₂O, and dried (Na₂SO₄). Removal of the Et₂O gave a solid, which was chromatographed on Al₂O₃ with CH₂Cl₂ as eluant. Thus, 6-Br 2-CO₂H analog, decarboxylated at 210-15° in 4 hrs., yield 63%, 7-Br 2-CO₂H analog, yield 74%, 4-PhCH₂S 2-CO₂H analog, yield 61%, 7-PhCH₂S 2-CO₂H analog, yield 80%, and 6-NO₂ 3-CO₂H analog, yield 85%, were prepared The Cu salt was prepared by heating a stirred mixture of the acid (0.01 mole), Na₂CO₃ (0.005 mole), and H₂O (100 ml.) until the acid dissolved. Upon addition of CuSO₄.5H₂O (0.005 mole) in 50 ml. H₂O, the blue cupric salt of the indole-2-carboxylic acid precipitated The solid was washed thoroughly with H₂O, air dried, then dried over CaCl₂ in vacuo.

Canadian Journal of 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, Safety of 6-Nitro-1H-indole-3-carboxylic 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

Walsh, Martin J. published the artcile2-Oxo-N-aryl-1,2,3,4-tetrahydroquinoline-6-sulfonamides as activators of the tumor cell specific M2 isoform of pyruvate kinase, Application In Synthesis of 166883-20-1, the publication is Bioorganic & Medicinal Chemistry Letters (2011), 21(21), 6322-6327, database is CAplus and MEDLINE.

Compared to normal differentiated cells, cancer cells have altered metabolic regulation to support biosynthesis and the expression of the M2 isoenzyme of pyruvate kinase (PKM2) plays an important role in this anabolic metabolism While the M1 isoform is a highly active enzyme, the alternatively spliced M2 variant is considerably less active and expressed in tumors. While the exact mechanism by which decreased pyruvate kinase activity contributes to anabolic metabolism remains unclear, it is hypothesized that activation of PKM2 to levels seen with PKM1 may promote a metabolic program that is not conducive to cell proliferation. Here we report the third chemotype in a series of PKM2 activators based on the 2-oxo-N-aryl-1,2,3,4-tetrahydroquinoline-6-sulfonamide scaffold. The synthesis, structure activity relationships, selectivity and notable physiochem. properties are described.

Bioorganic & Medicinal Chemistry Letters published new progress about 166883-20-1. 166883-20-1 belongs to indole-building-block, auxiliary class Indoline,Chloride,Sulfonyl chlorides,Amide, name is 1-Methyl-2-oxoindoline-5-sulfonyl chloride, and the molecular formula is C4H6O3, Application In Synthesis of 166883-20-1.

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

Velezheva, Valeriya published the artcileSynthesis and antituberculosis activity of indole-pyridine derived hydrazides, hydrazide-hydrazones, and thiosemicarbazones, Category: indole-building-block, the publication is Bioorganic & Medicinal Chemistry Letters (2016), 26(3), 978-985, database is CAplus and MEDLINE.

We describe the design, synthesis, and in vitro antimycobacterial activity of a series of novel simple hybrid hydrazides and hydrazide-hydrazones combining indole and pyridine nuclei. The compounds are derivatives of 1-acetylindoxyl or substituted indole-3-carboxaldehydes tethered via a hydrazine group by simple C-N or double C:N bonds with 3- and 4-pyridines, 1-oxide 3- and 4-pyridine carbohydrazides. The most active of the 15 compounds showed MICs values against an INH-sensitive strain of Mycobacterium tuberculosis H37Rv equal to that of INH (0.05-2 μg/mL). Five compounds demonstrated appreciable activity against the INH-resistant M. tuberculosis CN-40 clin. isolate (MICs: 2-5 μg/mL), providing justification for further in vivo studies.

Bioorganic & Medicinal Chemistry Letters 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 C15H24O2, 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

Knepper, Kerstin published the artcileBartoli Indole Synthesis on Solid Supports, Safety of Methyl 2-methyl-1H-indole-5-carboxylate, the publication is Organic Letters (2003), 5(16), 2829-2832, database is CAplus and MEDLINE.

Bartoli indole synthesis was performed on solid supports. Starting from Merrifield resin, immobilization of five nitrobenzoic acids was performed. Addition of four different alkenyl Grignard reagents and basic cleavage leads to substituted Me indolecarboxylates in excellent purities. Features of this reaction are the stability of halide groups, ester moieties, and tolerance of o,o’-unsubstituted nitro resins. Heck and Sonogashira reactions are also possible with immobilized indoles.

Organic 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, Safety of Methyl 2-methyl-1H-indole-5-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

Podevin, R. A. published the artcileConcentrative PAH transport by rabbit kidney slices in the absence of metabolic energy, Category: indole-building-block, the publication is American Journal of Physiology (1978), 235(4), F278-F285, database is CAplus and MEDLINE.

Characteristics of p-aminohippurate (PAH) transport in the absence of intracellular metabolism were studied with Na⁺,K⁺-depleted and ouabain-poisoned rabbit kidney cortex slices. The imposition of a NaCl gradient (out to in) resulted in specific stimulation of PAH uptake. PAH accumulated against its concentration gradient when cell Na⁺ concentration [Na⁺] was less than medium [Na⁺]. Conversely, renal cells extruded PAH when cell [Na⁺] exceeded medium [Na⁺]. Membrane potential measured with triphenylmethylphosphonium revealed that conditions which created an interior-pos. membrane potential inhibited the Na⁺-dependent transport of PAH but caused stimulation of the Na⁺-independent component. Characteristics of the Na⁺-dependent PAH transport system in ouabain-poisoned slices were similar to those previously described in metabolically active tissues.

American Journal of Physiology 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, 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

Shortridge, Matthew D. published the artcileCorrelation between protein function and ligand binding profiles, Quality Control of 2854-32-2, the publication is Journal of Proteome Research (2011), 10(5), 2538-2545, database is CAplus and MEDLINE.

The authors report that proteins with the same function bind the same set of small mols. from a standardized chem. library. This observation led to a quantifiable and rapidly adaptable method for protein functional anal. using exptl. derived ligand binding profiles. Ligand binding is measured using a high-throughput NMR ligand affinity screen with a structurally diverse chem. library. The method was demonstrated using a set of 19 proteins with a range of functions. A statistically significant similarity in ligand binding profiles was only observed between the two functionally identical albumins and between the five functionally similar amylases. This new approach is independent of sequence, structure, or evolutionary information and, therefore, extends the ability to analyze and functionally annotate novel genes.

Journal of Proteome Research 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 C7H6Cl2, Quality Control 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