Day: December 6, 2022

Liu, Xiu-Fen published the artcileAntitumor Effects of Immunotoxins Are Enhanced by Lowering HCK or Treatment with Src Kinase Inhibitors, Product Details of C19H21N3O3S, the publication is Molecular Cancer Therapeutics (2014), 13(1), 82-89, database is CAplus and MEDLINE.

Recombinant immunotoxins (RIT) are agents being developed for cancer treatment. They are composed of an Fv that binds to a cancer cell, fused to a 38-kDa fragment of Pseudomonas exotoxin A. SS1P is a RIT that targets mesothelin, a protein expressed on mesothelioma as well as pancreatic, ovarian, lung, and other cancers. Because the protein tyrosine kinase family regulates a variety of cellular processes and pathways, we hypothesized that tyrosine kinases might regulate susceptibility to immunotoxin killing. To investigate their role, we used siRNAs to lower the level of expression of the 88 known tyrosine kinases. We identified five tyrosine kinases, INSR, HCK, SRC, PDGFRβ, and BMX that enhance the activity of SS1P when their level of expression is lowered by siRNAs. We further investigated the Src family member HCK in this study. Knocking down of SRC slightly increased SS1P killing in A431/H9 cells, but knocking down HCK substantially enhanced killing by SS1P. We investigated the mechanism of enhancement and found that HCK knockdown enhanced SS1P cleavage by furin and lowered levels of Mcl-1 and raised Bax. We then found that Src inhibitors mimic the stimulatory effect of HCK knockdown; both SU6656 and SKI-606 (bosutinib) enhanced immunotoxin killing of mesothelin-expressing cells by SS1P and CD22-expressing cells by HA22 (moxetumomab pasudotox). SU6656 also enhanced the antitumor effects of SS1P and HA22 in mouse xenograft tumor models. Our data suggest that the combination of immunotoxin with tyrosine kinase inhibitors may be an effective way to treat some cancers. Mol Cancer Ther; 13(1); 82-89. ©2013 AACR.

Molecular Cancer Therapeutics 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, Product Details of 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

Friedman, Adam A. published the artcileFeasibility of Ultra-High-Throughput Functional Screening of Melanoma Biopsies for Discovery of Novel Cancer Drug Combinations, Recommanded Product: SU6656, the publication is Clinical Cancer Research (2017), 23(16), 4680-4692, database is CAplus and MEDLINE.

Purpose: Successful development of targeted therapy combinations for cancer patients depends on first discovering such combinations in predictive preclin. models. Stable cell lines and mouse xenograft models can have genetic and phenotypic drift and may take too long to generate to be useful as a personalized medicine tool. Exptl. Design: To overcome these limitations, we have used a platform of ultra-high-throughput functional screening of primary biopsies preserving both cancer and stroma cell populations from melanoma patients to nominate such novel combinations from a library of thousands of drug combinations in a patient-specific manner within days of biopsy. In parallel, patient-derived xenograft (PDX) mouse models were created and novel combinations tested for their ability to shrink matched PDXs. Results: The screening method identifies specific drug combinations in tumor cells with patterns that are distinct from those obtained from stable cell lines. Screening results were highly specific to individual patients. For patients with matched PDX models, we confirmed that individualized novel targeted therapy combinations could inhibit tumor growth. In particular, a combination of multi-kinase and PI3K/Akt inhibitors was effective in some BRAF-wild-type melanomas, and the addition of cediranib to the BRAF inhibitor PLX4720 was effective in a PDX model with BRAF mutation. Conclusions: This proof-of-concept study demonstrates the feasibility of using primary biopsies directly for combinatorial drug discovery, complementing stable cell lines and xenografts, but with much greater speed and efficiency. This process could potentially be used in a clin. setting to rapidly identify therapeutic strategies for individual patients. Clin Cancer Res; 23(16); 4680-92. ©2017 AACR.

Clinical Cancer 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

Wu, Cheng-Jun published the artcileDesign, synthesis and biological evaluation of indole-based [1,2,4]triazolo[4,3-a] pyridine derivatives as novel microtubule polymerization inhibitors, Application of 6-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole, the publication is European Journal of Medicinal Chemistry (2021), 113629, database is CAplus and MEDLINE.

A series of indole-based [1,2,4]triazolo [4,3-a]pyridine derivatives was designed and synthesized as novel microtubulin polymerization inhibitors by using a conformational restriction strategy. These compounds exhibited moderate to potent anti-proliferative activities against a panel of cancer cell lines (HeLa, A549, MCF-7 and HCT116). Among them, compound I featuring a N-methyl-5-indolyl substituent at the C-6 position of the [1,2,4]triazolo [4,3-a]pyridine core exhibited the highest antiproliferative activity with the IC₅₀ values ranging from 15 to 69 nM, and remarkable inhibitory effect on tubulin polymerization with an IC₅₀ value of 1.64μM. Mechanistic studies revealed that compound I induced cellular apoptosis and cell cycle arrest at the G₂/M phase in a dose-dependent fashion. Moreover, compound I significantly suppressed wound closure and disturbed microtubule networks.

European Journal of Medicinal Chemistry 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 C14H10O4, Application of 6-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole.

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, Cong-Shuai published the artcileDesign of C3-Alkenyl-Substituted 2-Indolylmethanols for Catalytic Asymmetric Interrupted Nazarov-Type Cyclization, HPLC of Formula: 100123-25-9, the publication is Advanced Synthesis & Catalysis (2018), 360(5), 846-851, database is CAplus.

The C3-alkenyl-substituted 2-indolylmethanols were designed as a new class of substrates for catalytic asym. interrupted Nazarov-type cyclizations. In the presence of a chiral phosphoric acid as a mild chiral Bronsted acid, the interrupted Nazarov-type cyclization of C3-alkenyl-substituted 2-indolylmethanols I (R¹ = Ph, 4-ClC₆H₄, 2-FC₆H₄, etc.; R² = Ph, 3-FC₆H₄, 3-MeC₆H₄; R³ = H, Cl, Br, MeO) with nucleophiles R⁴H (R⁴ = 3-indolyl, 2-hydroxy-1-naphthyl, etc.) occurred smoothly to construct cyclopenta[b]indole frameworks II with generally excellent diastereo- and enantioselectivities (up to >95:5 dr, >99% ee).

Advanced Synthesis & Catalysis 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 C6H5F4NO3S, HPLC of Formula: 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

Savall, Brad M. published the artcileDiscovery of Imidazo[1,2-a]pyrazines and Pyrazolo[1,5-c]pyrimidines as TARP γ-8 Selective AMPAR Negative Modulators, Formula: C14H18BNO3, the publication is ACS Medicinal Chemistry Letters (2019), 10(3), 267-272, database is CAplus and MEDLINE.

This report discloses the discovery and characterization of imidazo[1,2-a]pyrazines and pyrazolo[1,5-c]pyrimidines as selective neg. modulators of α-amino-3-hydroxy-5-methylisoxazole-4-propionate receptors (AMPARs) associated with transmembrane AMPAR regulatory protein γ-8. Imidazopyrazine 5 was initially identified as a promising γ-8 selective high-throughput screening hit, and subsequent structure-activity relationship optimization yielded subnanomolar, brain penetrant leads. Replacement of the imidazopyrazine core with an isosteric pyrazolopyrimidine scaffold improved microsomal stability and efflux liabilities to provide 26(I), JNJ-61432059. Following oral administration, 26 exhibited time- and dose-dependent AMPAR/γ-8 receptor occupancy in mouse hippocampus, which resulted in robust seizure protection in corneal kindling and pentylenetetrazole (PTZ) anticonvulsant models.

ACS 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

Kim, Jina published the artcileInsights of a Lead Optimization Study and Biological Evaluation of Novel 4-Hydroxytamoxifen Analogs as Estrogen-Related Receptor γ (ERRγ) Inverse Agonists, Product Details of C19H28BNO4, the publication is Journal of Medicinal Chemistry (2016), 59(22), 10209-10227, database is CAplus and MEDLINE.

We evaluated the in vitro pharmacol. as well as the absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties of chem. entities that have not only shown to be highly selective agonists for ERRγ, but also exhibited enhanced pharmacokinetic profile than 3 (GSK5182). 6G and 10b had comparable potency to 3 and were far more selective for ERRγ over the ERRα, -β, and ERα. The in vivo pharmacokinetic profiles of 6g and 10b were further evaluated as they possessed superior in vitro ADMET profiles compared to the other compounds Addnl., we observed a significant increase of fully-glycosylated NIS protein, key protein for radioiodine therapy in anaplastic thyroid cancer (ATC), in 6g- or 10b-treated CAL62 cells, which indicated that these compounds could be promising enhancers for restoring NIS protein function in ATC cells. Thus, 6g and 10b possess advantageous drug-like properties and can be used to potentially treat various ERRγ-related disorders.

Journal of Medicinal Chemistry 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 C19H28BNO4, 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

New, David C. published the artcileBML-190 and AM251 act as inverse agonists at the human cannabinoid CB₂ receptor: signalling via cAMP and inositol phosphates, Safety of 2-(1-(4-Chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)-1-morpholinoethanone, the publication is FEBS Letters (2003), 536(1-3), 157-160, database is CAplus and MEDLINE.

The aminoalkylindole BML-190 and diarylpyrazole AM251 ligands have previously been shown to bind to cannabinoid CB₂ and CB₁ receptors, resp. In HEK-293 cells stably expressing the human CB₂ receptor, BML-190 and AM251 potentiated the forskolin-stimulated accumulation of cAMP. Moreover, the CB₂ receptor can interact productively with 16z44, a promiscuous Gα_16/z chimera. BML-190 and AM251 reduce the basal levels of inositol phosphate production in cells expressing the CB₂ receptor and 16z44. These results demonstrate that BML-190 and AM251 act as inverse agonists at the human CB₂ receptor acting via Gα_i/o and Gα_q family-coupled pathways.

FEBS 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, Safety of 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

Yeyeodu, Susan T. published the artcileA rapid, inexpensive high throughput screen method for neurite outgrowth, SDS of cas: 330161-87-0, the publication is Current Chemical Genomics (2010), 74-83, database is CAplus and MEDLINE.

Neurite outgrowth assays are the most common phenotypic screen to assess chem. effects on neuronal cells. Current automated assays involve expensive equipment, lengthy sample preparation and handling, costly reagents and slow rates of data acquisition and anal. We have developed a high throughput screen (HTS) for neurite outgrowth using a robust neuronal cell model coupled to fast and inexpensive visualization methods, reduced data volume and rapid data anal. Neuroscreen-1 (NS-1) cell, a subclone of PC12, possessing rapid growth and enhanced sensitivity to NGF was used as a model neuron. This method reduces preparation time by using cells expressing GFP or native cells stained with HCS CellMask Red in a multiplexed 30 min fixation and staining step. A 2 × 2 camera binning process reduced both image data files and anal. times by 75% and 60% resp., compared to current protocols. In addition, eliminating autofocus steps during montage generation reduced data collection time. Pharmacol. profiles for stimulation and inhibition of neurite outgrowth by NGF and SU6656 were comparable to current standard method utilizing immunofluorescence detection of tubulin. Potentiation of NGF-induced neurite outgrowth by members of a 1,120-member Prestwick compound library as assayed using this method identified six mols., including etoposide, isoflupredone acetate, fludrocortisone acetate, thioguanosine, oxyphenbutazone and gibberellic acid, that more than doubled the neurite mass primed by 2 ng/mL NGF. This simple procedure represents an important routine approach in high throughput screening of large chem. libraries using the neurite outgrowth phenotype as a measure of the effects of chem. mols. on neuronal cells.

Current Chemical Genomics 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 C10H18BNO2, SDS of cas: 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

Beall, Howard D. published the artcileIndolequinone Antitumor Agents: Correlation between Quinone Structure, Rate of Metabolism by Recombinant Human NAD(P)H:Quinone Oxidoreductase, and in Vitro Cytotoxicity, Category: indole-building-block, the publication is Journal of Medicinal Chemistry (1998), 41(24), 4755-4766, database is CAplus and MEDLINE.

A series of indolequinones bearing various functional groups has been synthesized, and the effects of substituents on the metabolism of the quinones by recombinant human NAD(P)H:quinone oxidoreductase (NQO1) were studied. Thus 5-methoxyindolequinones were prepared by the Nenitzescu reaction, followed by functional group interconversions. The methoxy group was subsequently displaced by amine nucleophiles to give a series of amine-substituted quinones. Metabolism of the quinones by NQO1 revealed that, in general, compounds with electron-withdrawing groups at the indole 3-position were among the best substrates, whereas those with amine groups at the 5-position were poor substrates. Compounds with a leaving group at the 3-indolyl Me position generally inactivated the enzyme. The toxicity toward non-small-cell lung cancer cells with either high NQO1 activity (H460) or no detectable activity (H596) was also studied in representative quinones. Compounds which were good substrates for NQO1 showed the highest selectivity between the two cell lines.

Journal of Medicinal Chemistry 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, 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

Wilkinson, Jonathan D. published the artcileCannabinoids inhibit human keratinocyte proliferation through a non-CB1/CB2 mechanism and have a potential therapeutic value in the treatment of psoriasis, HPLC of Formula: 2854-32-2, the publication is Journal of Dermatological Science (2007), 45(2), 87-92, database is CAplus and MEDLINE.

Cannabinoids from cannabis (Cannabis sativa) are anti-inflammatory and have inhibitory effects on the proliferation of a number of tumorigenic cell lines, some of which are mediated via cannabinoid receptors. Cannabinoid (CB) receptors are present in human skin and anandamide, an endogenous CB receptor ligand, inhibits epidermal keratinocyte differentiation. Psoriasis is an inflammatory disease also characterized in part by epidermal keratinocyte hyper-proliferation. We investigated the plant cannabinoids Δ-9 tetrahydrocannabinol, cannabidiol, cannabinol and cannabigerol for their ability to inhibit the proliferation of a hyper-proliferating human keratinocyte cell line and for any involvement of cannabinoid receptors. A keratinocyte proliferation assay was used to assess the effect of treatment with cannabinoids. Cell integrity and metabolic competence confirmed using lactate-dehydrogenase and adenosine tri-phosphate assays. To determine the involvement of the receptors, specific agonist and antagonist were used in conjunction with some phytocannabinoids. Western blot and RT-PCR anal. confirmed presence of CB1 and CB2 receptors. The cannabinoids tested all inhibited keratinocyte proliferation in a concentration-dependent manner. The selective CB2 receptor agonists JWH015 and BML190 elicited only partial inhibition, the non-selective CB agonist HU210 produced a concentration-dependent response, the activity of theses agonists were not blocked by either CB1/CB2 antagonists. The results indicate that while CB receptors may have a circumstantial role in keratinocyte proliferation, they do not contribute significantly to this process. Our results show that cannabinoids inhibit keratinocyte proliferation, and therefore support a potential role for cannabinoids in the treatment of psoriasis.

Journal of Dermatological Science 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 C19H14N2, HPLC of Formula: 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