Indole Building Blocks

Tan, Lun published the artcileDevelopment of Dual Inhibitors Targeting Epidermal Growth Factor Receptor in Cancer Therapy, COA of Formula: C19H14FN3O3S, the publication is Journal of Medicinal Chemistry (2022), 65(7), 5149-5183, database is CAplus and MEDLINE.

A review. Epidermal growth factor receptor (EGFR) is of great significance in mediating cell signaling transduction and tumor behaviors. Currently, third-generation inhibitors of EGFR, especially osimertinib, are at the clin. frontier for the treatment of EGFR-mutant non-small-cell lung cancer (NSCLC). Regrettably, the rapidly developing drug resistance caused by EGFR mutations and the compensatory mechanism have largely limited their clin. efficacy. Given the synergistic effect between EGFR and other compensatory targets during tumorigenesis and tumor development, EGFR dual-target inhibitors are promising for their reduced risk of drug resistance, higher efficacy, lower dosage, and fewer adverse events than those of single-target inhibitors. Hence, we present the synergistic mechanism underlying the role of EGFR dual-target inhibitors against drug resistance, their structure-activity relationships, and their therapeutic potential. Most importantly, we emphasize the optimal target combinations and design strategies for EGFR dual-target inhibitors and provide some perspectives on new challenges and future directions in this field.

Journal of Medicinal Chemistry 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 C14H10N2O, COA of Formula: C19H14FN3O3S.

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, Huiying published the artcileSrc family tyrosine kinase inhibitors suppress Nav1.1 expression in cultured rat spiral ganglion neurons, Formula: C19H21N3O3S, the publication is Journal of Comparative Physiology, A: Neuroethology, Sensory, Neural, and Behavioral Physiology (2016), 202(3), 185-193, database is CAplus and MEDLINE.

Src family kinases regulate neuronal voltage-gated Na⁺ channels, which generate action potentials. The mechanisms of action, however, remain poorly understood. The aim of the present study was to further elucidate the effects of Src family kinases on Nav1.1 mRNA and protein expression in spiral ganglion neurons. Immunofluorescence staining techniques detected Nav1.1 expression in the spiral ganglion neurons. Addnl., quant. PCR and western blot techniques were used to analyze Nav1.1 mRNA and protein expression, resp., in spiral ganglion neurons following exposure to Src family kinase inhibitors PP2 (1 and 10 μM) and SU6656 (0.1 and 1 μM) for different lengths of time (6 and 24 h). In the spiral ganglion neurons, Nav1.1 protein expression was detected in the somas and axons. The Src family kinase inhibitors PP2 and SU6665 significantly decreased Nav1.1 mRNA and protein expression (p < 0.05), resp., in the spiral ganglion neurons, and changes in expression were not dependent on time or dose (p > 0.05).

Journal of Comparative Physiology, A: Neuroethology, Sensory, Neural, and Behavioral Physiology 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, 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

Mertins, Kristin published the artcileCatalytic borylation of o-xylene and heteroarenes via C-H activation, SDS of cas: 683229-62-1, the publication is Journal of Molecular Catalysis A: Chemical (2004), 207(1), 21-25, database is CAplus.

Ir and Rh complexes catalyze the borylation of xylene and different heteroarenes using pinacolborane via C-H activation. Various five-membered heterocycles such as thiophene, pyrrole, thionaphthene, and indole derivatives yield the borylated products in moderate to good yields. In general, the reactions proceed with high selectivity to give borylation ortho to the heteroatom.

Journal of Molecular Catalysis A: Chemical 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, SDS of cas: 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

Jia, Yong published the artcileOvercoming EGFR(T790M) and EGFR(C797S) resistance with mutant-selective allosteric inhibitors, Related Products of indole-building-block, the publication is Nature (London, United Kingdom) (2016), 534(7605), 129-132, database is CAplus and MEDLINE.

The epidermal growth factor receptor (EGFR)-directed tyrosine kinase inhibitors (TKIs) gefitinib, erlotinib and afatinib are approved treatments for non-small cell lung cancers harbouring activating mutations in the EGFR kinase, but resistance arises rapidly, most frequently owing to the secondary T790M mutation within the ATP site of the receptor. Recently developed mutant-selective irreversible inhibitors are highly active against the T790M mutant, but their efficacy can be compromised by acquired mutation of C797, the cysteine residue with which they form a key covalent bond. All current EGFR TKIs target the ATP-site of the kinase, highlighting the need for therapeutic agents with alternative mechanisms of action. Here we describe the rational discovery of EAI045, an allosteric inhibitor that targets selected drug-resistant EGFR mutants but spares the wild-type receptor. The crystal structure shows that the compound binds an allosteric site created by the displacement of the regulatory C-helix in an inactive conformation of the kinase. The compound inhibits L858R/T790M-mutant EGFR with low-nanomolar potency in biochem. assays. However, as a single agent it is not effective in blocking EGFR-driven proliferation in cells owing to differential potency on the two subunits of the dimeric receptor, which interact in an asym. manner in the active state. We observe marked synergy of EAI045 with cetuximab, an antibody therapeutic that blocks EGFR dimerization, rendering the kinase uniformly susceptible to the allosteric agent. EAI045 in combination with cetuximab is effective in mouse models of lung cancer driven by EGFR(L858R/T790M) and by EGFR(L858R/T790M/C797S), a mutant that is resistant to all currently available EGFR TKIs. More generally, our findings illustrate the utility of purposefully targeting allosteric sites to obtain mutant-selective inhibitors.

Nature (London, United Kingdom) 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 C19H14FN3O3S, 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

Race, Nicholas J. published the artcileEnantioselective C2-Alkylation of Indoles through a Redox-Relay Heck Reaction of 2-Indole Triflates, Application of 5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one, the publication is Chemistry – A European Journal (2019), 25(2), 512-515, database is CAplus and MEDLINE.

A palladium-catalyzed enantioselective redox-relay Heck reaction of 2-indole triflates and disubstituted alkenes is reported. This process combines readily available indole triflates with a variety of alkenes to afford a range of indole derivatives bearing a stereocenter adjacent to C2. Enantioselectivity is achieved through use of a simple pyridine-oxazoline ligand. Tuning the electronics of the indole, through judicious choice of N-protecting group, is required to ensure selective β-hydride elimination away from the indole core. Utility of this method is highlighted in a modular formal synthesis of an S1P₁ agonist precursor developed by Merck.

Chemistry – A European Journal 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, Application of 5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one.

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, Anthony published the artcileEstrogens and androgens inhibit association of RANKL with the pre-osteoblast membrane through post-translational mechanisms, Recommanded Product: SU6656, the publication is Journal of Cellular Physiology (2017), 232(12), 3798-3807, database is CAplus and MEDLINE.

We have recently demonstrated that RUNX2 promoted, and 17β-Estradiol (E2) diminished, association of RANKL with the cell membrane in pre-osteoblast cultures. Here we show that, similar to E2, dihydrotestosterone (DHT) diminishes association of RANKL, and transiently transfected GFP-RANKL with the pre-osteoblast membrane without decreasing total RANKL mRNA or protein levels. Diminution of membrane-associated RANKL was accompanied with marked suppression of osteoclast differentiation from co-cultured pre-osteoclasts, even though DHT increased, not decreased, RANKL concentrations in pre-osteoblast conditioned media. A marked decrease in membrane-associated RANKL was observed after 30 min of either E2 or DHT treatment, and near-complete inhibition was observed by 1 h, suggesting that the diminution of RANKL membrane association was mediated through non-genomic mechanisms. Further indicating dispensability of nuclear action of estrogen receptor, E2-mediated inhibition of RANKL membrane association was mimicked by an estrogen dendrimer conjugate (EDC) that cannot enter the cell nucleus. Finally, the inhibitory effect of E2 and DHT on RANKL membrane association was counteracted by the MMP inhibitor NNGH, and the effect of E2 (and not DHT) was antagonized by the Src inhibitor SU6656. Taken together, these results suggest that estrogens and androgens inhibit osteoblast-driven osteoclastogenesis through non-genomic mechanism(s) that entail, MMP-mediated RANKL dissociation from the cell membrane.

Journal of Cellular Physiology 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

Lin, Shu-Yu published the artcilePhenyl Benzenesulfonylhydrazides Exhibit Selective Indoleamine 2,3-Dioxygenase Inhibition with Potent in Vivo Pharmacodynamic Activity and Antitumor Efficacy, Product Details of C9H8ClNO3S, the publication is Journal of Medicinal Chemistry (2016), 59(1), 419-430, database is CAplus and MEDLINE.

Tryptophan metabolism has been recognized as an important mechanism in immune tolerance. Indoleamine 2,3-dioxygenase plays a key role in local tryptophan metabolism via the kynurenine pathway and has emerged as a therapeutic target for cancer immunotherapy. The prior study identified Ph benzenesulfonyl hydrazide as a potent in vitro (though not in vivo) inhibitor of indoleamine 2,3-dioxygenase. Further lead optimization to improve in vitro potencies and pharmacokinetic profiles resulted in N’-(4-bromophenyl)-2-oxo-2,3-dihydro-1H-indole-5-sulfonyl hydrazide (I), which demonstrated 59% oral bioavailability and 73% of tumor growth delay without apparent body weight loss in the murine CT26 syngeneic model, after oral administration of 400 mg/kg. Accordingly, I is proposed as a potential drug lead worthy of advanced preclin. evaluation.

Journal of Medicinal Chemistry 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 C9H8ClNO3S, Product Details of C9H8ClNO3S.

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

Okubo, Ayaka published the artcileNAD(P)H dehydrogenase, quinone 1 (NQO1), protects melanin-producing cells from cytotoxicity of rhododendrol, Safety of 5-Methoxy-1,2-dimethyl-3-[(4-nitrophenoxy)methyl]indole-4,7-dione, the publication is Pigment Cell & Melanoma Research (2016), 29(3), 309-316, database is CAplus and MEDLINE.

Summary : Rhododendrol (RD) is a potent tyrosinase inhibitor that is metabolized to RD-quinone by tyrosinase, which may underlie the cytotoxicity of RD and leukoderma of the skin that may result. We have examined how forced expression of the NAD(P)H quinone dehydrogenase, quinone 1 (NQO1), a major quinone-reducing enzyme in cytosol, affects the survival of RD-treated cells. We found that treatment of the mouse melanoma cell line B16BL6 or normal human melanocytes with carnosic acid, a transcriptional inducer of the NQO1 gene, notably suppressed the cell killing effect of RD. This effect was mostly abolished by ES936, a highly specific NQO1 inhibitor. Moreover, conditional overexpression of the human NQO1 transgene in B16BL6 led to an expression-dependent increase of cell survival after RD treatment. Our results suggest that NQO1 attenuates the cytotoxicity of RD and/or its metabolites.

Pigment Cell & Melanoma Research 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 C18H16N2O6, Safety 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

Zhao, Peng published the artcileCrystal structure of EGFR T790M/C797S/V948R in complex with EAI045, Recommanded Product: 2-(5-Fluoro-2-hydroxyphenyl)-2-(1-oxoisoindolin-2-yl)-N-(thiazol-2-yl)acetamide, the publication is Biochemical and Biophysical Research Communications (2018), 502(3), 332-337, database is CAplus and MEDLINE.

Lung cancer is the leading cause of cancer deaths. Epidermal growth factor receptor (EGFR) kinase domain mutations are a common cause of non-small cell lung cancers (NSCLCs), a major subtype of lung cancers. Patients harboring most of these mutations respond well to the anti-EGFR tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib initially, but soon develop resistance to them in about half of the cases due to the emergence of the gatekeeper mutation T790M. The third-generation TKIs such as AZD9291, HM61713, CO-1686 and WZ4002 can overcome T790M through covalent binding to the EGFR kinase through Cys 797, but ultimately lose their efficacy upon emergence of the C797S mutation that abolishes the covalent bonding. Therefore to develop new TKIs to overcome EGFR drug-resistant mutants harboring T790M/C797S is urgently demanded. EAI001 and EAI045 are a new type of EGFR TKIs that bind to EGFR reversibly and not relying on Cys 797. EAI045 in combination with cetuximab is effective in mouse models of lung cancer driven by EGFR L858R/T790M and L858R/T790M/C797S. Here we report the crystal structure of EGFR T790M/C797S/V948R in complex with EAI045, and compare it to EGFR T790M/V948R in complex with EAI001. The complex structure reveals why EAI045 binds tighter to EGFR than does EAI001, and why EAI001 and EAI045 prefer binding to EGFR T790M. The knowledge may facilitate future drug development studies targeting this very important cancer target.

Biochemical and Biophysical Research Communications 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 C14H22O2, 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

Zheng, Qi published the artcilePalladium-catalyzed cross-coupling reaction between 3-indoleboronic acids and tetrahydropyridine triflates, Application In Synthesis of 149108-61-2, the publication is Tetrahedron Letters (1993), 34(14), 2235-8, database is CAplus.

The palladium catalyzed cross-coupling reactions between 3-indoleboronic acids and vinyl triflates is a good method to introduce vinyl groups into the indole 3-position, e.g. I. The regioselectivity of the enolization of N-substituted-3-piperidones is far greater than previously reported. N-tosyl-3-indole boronic acids can be easily synthesized via mercuration-boronation method.

Tetrahedron Letters 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 C8H5F3O3, Application In Synthesis 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