Day: November 21, 2022

Ross, Fiona A. published the artcileMechanisms of Paradoxical Activation of AMPK by the Kinase Inhibitors SU6656 and Sorafenib, Safety of SU6656, the publication is Cell Chemical Biology (2017), 24(7), 813-824.e4, database is CAplus and MEDLINE.

SU6656, a Src kinase inhibitor, was reported to increase fat oxidation and reduce body weight in mice, with proposed mechanisms involving AMP-activated protein kinase (AMPK) activation via inhibition of phosphorylation of either LKB1 or AMPK by the Src kinase, Fyn. However, we report that AMPK activation by SU6656 is independent of Src kinases or tyrosine phosphorylation of LKB1 or AMPK and is not due to decreased cellular energy status or binding at the ADaM site on AMPK. SU6656 is a potent AMPK inhibitor, yet binding at the catalytic site paradoxically promotes phosphorylation of Thr172 by LKB1. This would enhance phosphorylation of downstream targets provided the lifetime of Thr172 phosphorylation was sufficient to allow dissociation of the inhibitor and subsequent catalysis prior to its dephosphorylation. By contrast, sorafenib, a kinase inhibitor in clin. use, activates AMPK indirectly by inhibiting mitochondrial metabolism and increasing cellular AMP:ADP and/or ADP:ATP ratios.

Cell Chemical Biology 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, 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

Nishiyama, Takashi published the artcileConcise synthesis of carbazole-1,4-quinones and evaluation of their antiproliferative activity against HCT-116 and HL-60 cells, Related Products of indole-building-block, the publication is European Journal of Medicinal Chemistry (2016), 561-577, database is CAplus and MEDLINE.

A convenient synthesis of carbazole-1,4-quinone alkaloid koeniginequinones A and B using a tandem ring-closing metathesis with the dehydrogenation reaction sequence under an O₂ atmosphere as an important step is reported. Using this method, carbazole-1,4-quinones substituted at the 5-, 6-, 7-, and/or 8-positions I (R¹ = R² = H, CH₃; R³ = H, 6-OCH₃, 5,6-(OCH₃)₂, 7-CH₃, 6-NO₂, etc.; R⁴ = H, MOM) have been synthesized. Moreover, 24 compounds, including koeniginequinones A and B, have been evaluated for their antiproliferative activity against HCT-116 and HL-60 cells, and the 6-nitro analog exhibited the most potent activity against both tumor cell types.

European Journal of Medicinal Chemistry 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, 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

Hoque, Emdadul Md published the artcileRemarkably Efficient Iridium Catalysts for Directed C(sp²)-H and C(sp³)-H Borylation of Diverse Classes of Substrates, Application In Synthesis of 683229-62-1, the publication is Journal of the American Chemical Society (2021), 143(13), 5022-5037, database is CAplus and MEDLINE.

Here we describe the discovery of a new class of C-H borylation catalysts and their use for regioselective C-H borylation of aromatic, heteroaromatic, and aliphatic systems. The new catalysts have Ir-C(thienyl) or Ir-C(furyl) anionic ligands instead of the diamine-type neutral chelating ligands used in the standard C-H borylation conditions. It is reported that the employment of these newly discovered catalysts show excellent reactivity and ortho-selectivity for diverse classes of aromatic substrates with high isolated yields. Moreover, the catalysts proved to be efficient for a wide number of aliphatic substrates for selective C(sp³)-H bond borylations. Heterocyclic mols. are selectively borylated using the inherently elevated reactivity of the C-H bonds. A number of late-stage C-H functionalization have been described using the same catalysts. Furthermore, we show that one of the catalysts could be used even in open air for the C(sp²)-H and C(sp³)-H borylations enabling the method more general. Preliminary mechanistic studies suggest that the active catalytic intermediate is the Ir(bis)boryl complex, and the attached ligand acts as bidentate ligand. Collectively, this study underlines the discovery of new class of C-H borylation catalysts that should find wide application in the context of C-H functionalization chem.

Journal of the American Chemical Society published new progress about 683229-62-1. 683229-62-1 belongs to indole-building-block, auxiliary class Indole,Boronic acid and ester,Ether,Boronate Esters,Boronic Acids,Boronic acid and ester, name is 5-Methoxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole, and the molecular formula is C15H20BNO3, Application In Synthesis of 683229-62-1.

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

Hermanson, Daniel J. published the artcileSubstrate-selective COX-2 inhibition decreases anxiety via endocannabinoid activation, Recommanded Product: 2-(1-(4-Chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)-1-morpholinoethanone, the publication is Nature Neuroscience (2013), 16(9), 1291-1298, database is CAplus and MEDLINE.

Augmentation of endogenous cannabinoid (eCB) signaling represents an emerging approach to the treatment of affective disorders. Cyclooxygenase-2 (COX-2) oxygenates arachidonic acid to form prostaglandins, but also inactivates eCBs in vitro. However, the viability of COX-2 as a therapeutic target for in vivo eCB augmentation has not been explored. Using medicinal chem. and in vivo anal. and behavioral pharmacol. approaches, we found that COX-2 is important for the regulation of eCB levels in vivo. We used a pharmacol. strategy involving substrate-selective inhibition of COX-2 to augment eCB signaling without affecting related non-eCB lipids or prostaglandin synthesis. Behaviorally, substrate-selective inhibition of COX-2 reduced anxiety-like behaviors in mice via increased eCB signaling. Our data suggest a key role for COX-2 in the regulation of eCB signaling and indicate that substrate-selective pharmacol. represents a viable approach for eCB augmentation with broad therapeutic potential.

Nature Neuroscience 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, Recommanded Product: 2-(1-(4-Chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)-1-morpholinoethanone.

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

Chen, Wang published the artcileSynthesis and antitumor activity of Lycogarubin C and Lycogalic acid, Computed Properties of 149108-61-2, the publication is Youji Huaxue (2014), 34(4), 797-803, database is CAplus.

Lycogarubin C and lycogalic acid were first isolated independently by Steglich and Akazawa from Lycogala epidendrum in 1994. Lycogarubin C showed a potential cytotoxic activity. Lycogalic acid is an inhibitor of Hes1 dimmer of helix-loop-helix (bHLH) transcriptional repressor factor. Lycogalic acid is also the key intermediate in the biosynthesis of indolo[2,3-a]carbazole alkaloids that exhibit broad spectrum of bioactivity. Two efficient synthetic pathways of lycogarubin C and lycogalic acid were completed in this study. The first pathway included eight steps started from the com. available indole and pyrrole to produce lycogarubin C with an overall yield of 27%. The second pathway was completed in seven steps with an overall yield of 25%. The key reactions are palladium-catalyzed Suzuki-Miyaura coupling of bis-iodo or bis-triflate derivative and indolboronic acid derivatives and Hinsberg-type synthesis of di-Me N-benzyl-3,4-dihydroxypyrrole-2,5-dicarboxylate, resp. Treatment of lycogarubin C with sodium hydroxide in ethanol under refluxing followed by acidification afforded lycogalic acid quant. Lycogarubin C and lycogalic acid showed the antiproliferative activities against four human tumor cell lines of MDA-MB-231, A549, HeLa and PC3. Further study showed that lycogarubin C inhibited the activity of DNA topoisomerase 2.

Youji Huaxue 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 C15H14BNO4S, Computed Properties of 149108-61-2.

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

Landstrom, Evan B. published the artcileEvanPhos: a ligand for ppm level Pd-catalyzed Suzuki-Miyaura couplings in either organic solvent or water, SDS of cas: 480438-51-5, the publication is Green Chemistry (2018), 20(15), 3436-3443, database is CAplus.

A new biaryl phosphine-containing palladium complex was constructed and its usefulness in Suzuki-Miyaura cross-couplings of functionalized substrates so as to yield biaryls was evaluated. By a combination of pre-activation using DIBAL and employment of uncommon solvent EtOAc, the novel catalyst proved effective with extended bench stability at loadings in the ppm (0.1-0.5 mol%) range with highly functionalized reaction partners. Similar reactions run in water containing nanomicelles were as fast or faster. This methodol. represented an attractive green synthetic advance in highly valued Suzuki-Miyaura couplings.

Green Chemistry published new progress about 480438-51-5. 480438-51-5 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-(Phenylsulfonyl)-1H-indol-5-yl)boronic acid, and the molecular formula is C14H12BNO4S, SDS of cas: 480438-51-5.

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

Landstrom, Evan B. published the artcileEvanPhos: a ligand for ppm level Pd-catalyzed Suzuki-Miyaura couplings in either organic solvent or water, COA of Formula: C15H14BNO4S, the publication is Green Chemistry (2018), 20(15), 3436-3443, database is CAplus.

A new biaryl phosphine-containing palladium complex was constructed and its usefulness in Suzuki-Miyaura cross-couplings of functionalized substrates so as to yield biaryls was evaluated. By a combination of pre-activation using DIBAL and employment of uncommon solvent EtOAc, the novel catalyst proved effective with extended bench stability at loadings in the ppm (0.1-0.5 mol%) range with highly functionalized reaction partners. Similar reactions run in water containing nanomicelles were as fast or faster. This methodol. represented an attractive green synthetic advance in highly valued Suzuki-Miyaura couplings.

Green Chemistry 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 C15H14BNO4S, COA of Formula: C15H14BNO4S.

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

Pieniazek, Anna published the artcileIndoxyl Sulfate Generates Free Radicals, Decreases Antioxidant Defense, and Leads to Damage to Mononuclear Blood Cells, Category: indole-building-block, the publication is Chemical Research in Toxicology (2018), 31(9), 869-875, database is CAplus and MEDLINE.

Indoxyl sulfate (IS) is a uremic toxin that has been associated with inflammation, oxidative stress as well as with the progression of chronic kidney disease (CKD). Indoxyl sulfate is a protein metabolite that is concentrated in the serum of CKD patients. IS is a well-known uremic toxin but there are very few reports on the effect of IS on cells including mononuclear cells (MNCs). We hypothesized that a high concentration of IS in CKD patients may induce changes in redox balance in the in vitro cells exposed. In the present study, we investigated the effect of indoxyl sulfate on free radical production, antioxidant capacity and protein damage in the mononuclear blood cells. As already determined, the concentrations (0.2 or 1 mM) of IS used in this study do not affect the survival rate of MNCs. For both the concentrations of indoxyl sulfate, there was an increase in superoxide and nitric oxide, and a release of other reactive oxygen species (ROS) inside the cells, as measured using fluorescent probes. However, an increase in other ROS as indicated by H2DCF-DA was found only for 1 mM of IS. Moreover, a decrease in the non-enzymic antioxidant capacity (NAC) and an increase in the superoxide dismutase activity after incubation of the cells with indoxyl sulfate were observed Furthermore, we found an increase in the levels of carbonyl compounds and peroxides in the cells treated with both the concentrations of IS. The obtained results show that indoxyl sulfate induces oxidative stress and a decrease in antioxidant defense in cells leading to lipids and proteins damage.

Chemical Research in Toxicology 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

McBriar, Mark D. published the artcileBicyclo[3.1.0]hexyl urea melanin concentrating hormone (MCH) receptor-1 antagonists: Impacting hERG liability via aryl modifications, Formula: C14H18BNO3, the publication is Bioorganic & Medicinal Chemistry Letters (2006), 16(16), 4262-4265, database is CAplus and MEDLINE.

Herein, we report the discovery of an effective strategy to modulate liabilities related to affinity of previously disclosed bicyclohexane MCHR-1 antagonists for the hERG channel. This paper describes one of several strategies incorporated to limit hERG binding via modifications of a terminal aryl group in an otherwise promising bicyclohexyl urea series.

Bioorganic & Medicinal Chemistry Letters published new progress about 837392-64-0. 837392-64-0 belongs to indole-building-block, auxiliary class Indoline,Boronic acid and ester,Amide,Boronate Esters, name is 5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one, and the molecular formula is C14H18BNO3, Formula: C14H18BNO3.

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

Wu, Xiaoyun published the artcileMolecular mechanism study of EGFR allosteric inhibitors using molecular dynamics simulations and free energy calculations, Recommanded Product: 2-(5-Fluoro-2-hydroxyphenyl)-2-(1-oxoisoindolin-2-yl)-N-(thiazol-2-yl)acetamide, the publication is Journal of Biomolecular Structure and Dynamics (2022), 40(13), 5848-5857, database is CAplus and MEDLINE.

The epidermal growth factor receptor (EGFR) kinase inhibitors Gefitinib, Erlotinib, Afatinib and Osimertinib have been approved for the treatments of non-small cell lung cancer patients harboring sensitive EGFR mutations, but resistance arises rapidly. To date all approved EGFR inhibitors are ATP-competitive inhibitors, highlighting the need for therapeutic agents with alternative mechanisms of action. Allosteric kinase inhibitors offer a promising new therapeutic strategy to ATP-competitive inhibitors. The mutant-selective allosteric EGFR inhibitors EAI045 exhibited higher potency for EGFRL858R&T790M compared to WT, which was also effective in EGFR-mutant models including those harboring the C797S mutation. However, it was not effective as a single-agent inhibitor, and require the co-administration of the anti-EGFR antibody Cetuximab. Further efforts produced a more potent analog JBJ-04-125-02, which can inhibit cell proliferation as a single-agent inhibitor. In the present study, mol. dynamics simulations and free energy calculations were performed and revealed the detailed inhibitory mechanism of JBJ-04-125-02 as more potent EGFR inhibitor. Moreover, the energy difference between HOMO and LUMO calculated by DFT implied the higher interaction of JBJ-04-125-02 than EAI045 in the active site of the EGFR. The identified key features obtained from the mol. modeling enabled us to design novel EGFR allosteric inhibitors.

Journal of Biomolecular Structure and Dynamics 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 C9H8F2O2, Recommanded Product: 2-(5-Fluoro-2-hydroxyphenyl)-2-(1-oxoisoindolin-2-yl)-N-(thiazol-2-yl)acetamide.

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