Category: indole-building-block

Chow, Amanda published the artcileDasatinib inhibits peripapillary scleral myofibroblast differentiation, HPLC of Formula: 330161-87-0, the publication is Experimental Eye Research (2020), 107999, database is CAplus and MEDLINE.

Scleral fibroblast activation occurs in glaucomatous and myopic eyes. Here we perform an unbiased screen to identify kinase inhibitors that reduce fibroblast activation to diverse stimuli in vitro and to in vivo intraocular pressure (IOP) elevation. Primary cultures of peripapillary scleral (PPS) fibroblasts from two human donors were screened using a library of 80 kinase inhibitors to identify compounds that inhibit TGFbeta-induced extracellular matrix (ECM) synthesis. Inhibition of myofibroblast differentiation was verified by alpha smooth muscle actin (aSMA) immunoblot and collagen contraction assay. Three kinase inhibitors were verified to reduce TGFbeta-induced aSMA expression and cellular contractility (rottlerin, PP2, tyrphostin 9). The effect of three Src inhibitors, bosutinib, dasatinib, and SU-6656, on myofibroblast differentiation was evaluated, with only dasatinib significantly inhibiting TGFbeta-induced ECM synthesis, aSMA expression, and cellular contractility at nanomolar dosages. Subconjunctival injection of dasatinib reduced IOP-induced scleral fibroblast proliferation compared to control (4.9 ± 11.1 ng/sclera with 0.1 muM vs. 88.7 ± 38.6 ng/sclera in control, P < 0.0001). Dasatinib inhibits scleral myofibroblast differentiation and there is pharmacol. evidence that this inhibition is not solely due to Src-kinase inhibition.

Experimental Eye 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, HPLC of Formula: 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

Axten, Jeffrey M. published the artcileDiscovery of 7-methyl-5-(1-{[3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-indol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (GSK2606414), a potent and selective first-in-class inhibitor of protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK), HPLC of Formula: 837392-67-3, the publication is Journal of Medicinal Chemistry (2012), 55(16), 7193-7207, database is CAplus and MEDLINE.

Protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) is activated in response to a variety of endoplasmic reticulum stresses implicated in numerous disease states. Evidence that PERK is implicated in tumorigenesis and cancer cell survival stimulated our search for small mol. inhibitors. Through screening and lead optimization using the human PERK crystal structure, we discovered compound I (GSK2606414), an orally available, potent, and selective PERK inhibitor. Compound I inhibits PERK activation in cells and inhibits the growth of a human tumor xenograft in mice.

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, HPLC of Formula: 837392-67-3.

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

Moraes, Eduardo Cruz published the artcileKinase inhibitor profile for human Nek1, Nek6, and Nek7 and analysis of the structural basis for inhibitor specificity, SDS of cas: 330161-87-0, the publication is Molecules (2015), 20(1), 1176-1191, 16 pp., database is CAplus and MEDLINE.

Human Neks are a conserved protein kinase family related to cell cycle progression and cell division and are considered potential drug targets for the treatment of cancer and other pathologies. We screened the activation loop mutant kinases hNek1 and hNek2, wild-type hNek7, and five hNek6 variants in different activation/phosphorylation statesand compared them against 85 compounds using thermal shift denaturation. We identified three compounds with significant Tm shifts: JNK Inhibitor II for hNek1(Δ262-1258)-(T162A), Isogranulatimide for hNek6(S206A), andGSK-3 Inhibitor XIII for hNek7wt. Each one of these compounds was also validated by reducing the kinases activity by at least 25%. The binding sites for these compounds were identified by in silico docking at the ATP-binding site of the resp. hNeks. Potential inhibitors were first screened by thermal shift assays, had their efficiency tested by a kinase assay, and were finally analyzed by mol. docking. Our findings corroborate the idea of ATP-competitive inhibition for hNek1 and hNek6 and suggest a novel non-competitive inhibition for hNek7 in regard to GSK-3 Inhibitor XIII. Our results demonstrate that our approach is useful for finding promising general and specific hNekscandidate inhibitors, which may also function as scaffolds to design more potent and selective inhibitors.

Molecules 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, 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

Chaurasiya, Narayan D. published the artcileA Combined In Vitro Assay for Evaluation of Neurotrophic Activity and Cytotoxicity, Application of SU6656, the publication is SLAS Discovery (2017), 22(6), 667-675, database is CAplus and MEDLINE.

Neurotrophic assays are phenotypic methods to identify mols. that stimulate differentiation of neuronal cells. Bioactive small mols. with neurotrophic actions hold great promise as therapeutic agents for the treatment of neurodegenerative diseases and neuronal injuries by virtue of their ability to stimulate neuritic outgrowth. A combined in vitro method, which measures neurotrophic activity and cytotoxicity in a single assay, has been described. This assay, performed in 96-well microplates with PC12 and Neuroscreen-1 (NS-1; a subclone of PC12) cells, is a simple tool for identification of new neurotrophic agents. Stimulation of neurite outgrowth was measured with NIS software by anal. of digital cell images as multiple parameters, namely, mean neurite length, neurite length/cell, nodes/cell, and number of neurites/cell. The assay has been standardized and validated with dose-response anal. for nerve growth factor (NGF) and mechanism-based inhibitors of NGF-induced neurite outgrowth, namely, SU6656 (an Src family kinase inhibitor) and PD98059 (a MEK inhibitor). The assay has been successfully applied for screening natural and synthetic compound libraries for cytotoxicity and neurotrophic activity. Screening of a set of harmala alkaloids identified harmine as a potential neurotrophic mol. that significantly stimulated NGF-induced neurite outgrowth in the NS-1 cells. Important advantages of this method are its simplicity and determination of cytotoxicity and neurotrophic activity in a single assay. This assay may be suitable for primary and cultured neuronal cells.

SLAS Discovery 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 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

Dehn, Donna L. published the artcile5-Methoxy-1,2-dimethyl-3-[(4-nitrophenoxy)methyl]indole-4,7-dione, a mechanism-based inhibitor of NAD(P)H:quinone oxidoreductase 1, exhibits activity against human pancreatic cancer in vitro and in vivo, Computed Properties of 192820-78-3, the publication is Molecular Cancer Therapeutics (2006), 5(7), 1702-1709, database is CAplus and MEDLINE.

The enzyme NAD(P)H:quinone oxidoreductase 1 (NQO1) has been found to be up-regulated in pancreatic cancer as well as many other solid tumors. A recent study showed that inhibition of NQO1 in pancreatic cancer cells using the nonselective inhibitor dicumarol suppressed the malignant phenotype. The authors suggested that inhibition of cell growth might result from an increase in intracellular superoxide production due to inhibition of NQO1. We have recently shown that NQO1 can directly scavenge superoxide and this effect may become physiol. relevant in cells containing high NQO1 levels. We therefore tested the hypothesis that 5-methoxy-1,2-dimethyl-3-[(4-nitrophenoxy)methyl]indole-4,7-dione (ES936), a specific mechanism-based inhibitor of NQO1, would be an effective agent for the treatment of pancreatic tumors. The human pancreatic tumor cell lines BxPC-3 and MIA PaCa-2 contain high levels of NQO1 activity and protein as verified by immunoblot and immunocytochem. staining of human pancreatic tumor cells. ES936 treatment inhibited NQO1 activity by >98% in MIA PaCa-2 and BxPC-3 cells. In addition, ES936 treatment induced growth inhibition [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay] in MIA PaCa-2 and BxPC-3 cells with an IC₅₀ of 108 and 365 nmol/L, resp. Treatment of MIA PaCa-2 cells with ES936 also inhibited the ability of these cells to form colonies and grow in soft agar in a dose-dependent manner. Treatment of mice carrying MIA PaCa-2 xenograft tumors with ES936 resulted in a significant difference in growth rates in ES936-treated and DMSO-treated (control) tumors. Our data did not show an increase in either intracellular superoxide production or oxygen consumption after treatment of cells with ES936, contrary to the effects seen with dicumarol. In summary, mechanism-based inhibitors of NQO1, such as ES936, may be useful therapeutic agents for the treatment of pancreatic cancer, although the underlying mechanism seems to be independent of superoxide generation.

Molecular Cancer Therapeutics 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, Computed Properties of 192820-78-3.

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

Dehn, Donna L. published the artcileBiochemical, cytotoxic, and genotoxic effects of ES936, a mechanism-based inhibitor of NAD(P)H:quinone oxidoreductase 1, in cellular systems, Product Details of C18H16N2O6, the publication is Molecular Pharmacology (2003), 64(3), 714-720, database is CAplus and MEDLINE.

The specific involvement of NAD(P)H:quinone oxidoreductase 1 (NQO1) in the bioactivation of quinone prodrugs has been shown through the use of the inhibitor of NQO1, dicoumarol. Disadvantages of using dicoumarol to inhibit NQO1 include its lack of specificity and its competitive mechanism of inhibition. The concentration of dicoumarol required for inhibition of NQO1 varies according to the substrate under evaluation, which may lead to either false conclusions of the involvement of NQO1 or the alteration of other cellular processes. We have reported previously on the chem. and biochem. properties of ES936, a mechanism-based inhibitor of NQO1 in cell-free systems. In this study, we investigated the effects of ES936 in cellular systems. ES936 (100 nM) inhibits more than 95% of NQO1 activity within 30 min and is stable in complete media at this concentration for a min. of 2 h. The duration of inhibition is cell line-specific because a new protein must be generated for resumption of activity. ES936 abrogates the toxicity of streptonigrin, with greater effects seen in cell lines expressing higher levels of NQO1. ES936 does not inhibit other cellular reductases, nor does it alter cellular levels of acid-soluble thiols. Some evidence of DNA strand breaks was observed at the concentrations of ES936 required for the inhibition of NQO1 activity. From our studies, we propose the use of ES936 (100 nM) as a mechanism-based inhibitor of NQO1 in cellular systems and for use as a component of the routine activity assay for NQO1.

Molecular Pharmacology 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, Product Details of C18H16N2O6.

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

Gustafson, Daniel L. published the artcileKinetics of NAD(P)H:quinone oxidoreductase I (NQO1) inhibition by mitomycin C in vitro and in vivo, Name: 5-Methoxy-1,2-dimethyl-3-[(4-nitrophenoxy)methyl]indole-4,7-dione, the publication is Journal of Pharmacology and Experimental Therapeutics (2003), 305(3), 1079-1086, database is CAplus and MEDLINE.

The bioreductive activation of the antitumor quinone mitomycin C (MMC) by NAD(P)H: quinone oxidoreductase 1 (NQO1) is complicated by the ability of MMC to also act as a mechanism-based inhibitor of NQO1 in a pH dependent manner. Inhibition of NQO1 by MMC has been studied in purified enzyme preparations and in cultured cells but has not determined in vivo. In the studies presented here, NQO1 activity was measured in mouse tissues following treatment with MMC or the potent mechanism-based human NQO1 inhibitor 5-methoxy-1,2-dimethyl-[(4-nitrophenoxy)methyl]indole-4,7-dione (ES936). NQO1 activity was significantly decreased at 1, 2, and 4 h following MMC (10 or 20 mg/kg) treatment in kidney and lung but was unchanged in brain, heart, liver, and bladder. ES936 (1 mg/kg) treatment led to a significant and much more potent inhibition of NQO1 in all murine tissues analyzed except for bladder. To extrapolate these in vivo results from mice to humans, the species-specific kinetics of NQO1 inactivation by MMC was determined in vitro using mouse, rat, and human recombinant NQO1 proteins. Results showed the inactivation kinetics of mouse and human proteins by MMC were similar. Treatment of human and murine endothelial cells with MMC or ES936 showed similar inhibition of NQO1 activity. The aforementioned results clearly demonstrate that MMC can serve as a substrate for NQO1 in vivo; however, the metabolism resulting in enzyme inactivation is possibly tissue-specific. Furthermore, the kinetic similarities for inactivation between murine and human forms of NQO1 show these results are apropos to clin. use of MMC.

Journal of Pharmacology and Experimental Therapeutics 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, Name: 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

Khandelwal, Ravina published the artcileStructure-based Virtual Screening for the Identification of High-affinity Small Molecule Towards STAT3 for the Clinical Treatment of Osteosarcoma, Safety of SU6656, the publication is Current Topics in Medicinal Chemistry (Sharjah, United Arab Emirates) (2018), 18(29), 2511-2526, database is CAplus and MEDLINE.

Background: According to DCEG investigation, the compared results of the osteosarcoma incidences in different continents, reported it to be the most diagnosed in adolescents and adults above 60 yrs. old. Indubitably, new drugs and new therapeutic targets are required to improve the outcome as well as to diminish the long-term toxicities associated with the current benchmark of treatment. STAT3 appears to be an important mediator of chemoresistance in osteosarcoma. Results: Exptl. evidence clearly demonstrate the disruption of STAT3 signaling which inhibits the survival and proliferation of osteosarcoma and decreases the growth of disease. This prevailing study approach is by mol. docking, virtual screening to elucidate inhibitor with superior affinity against STAT3 to have a cautious pharma profile. The compound Sorafenib (Pub CID 216239) having high-affinity scores is subjected to another similarity search to retrieve the drugs with similar properties. The virtual screened compound with PubChem CID-44815014 as per BOILED-Egg plot reveals its high affinity. Conclusion: Comparative study and ADMET study both showed the compounds to have equivalent properties, whereas interestingly the virtual screened compound having PubChem CID-44815014 is seen to have the lowest rerank score. These drugs are identified to have high potential to act as STAT3 inhibitors and probably can be considered for further studies in wet lab anal.

Current Topics in Medicinal Chemistry (Sharjah, United Arab Emirates) 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

Rehni, Ashish K. published the artcileModulation of src-kinase attenuates naloxone-precipitated opioid withdrawal syndrome in mice, Related Products of indole-building-block, the publication is Behavioural Pharmacology (2011), 22(2), 182-190, database is CAplus and MEDLINE.

This study was designed to investigate the effect of 2,3-dihydro-N, N-dimethyl-2-oxo-3-[(4,5,6,7-tetrahydro-1H-indol-2-yl)methylene]-1H-indole-5-sulfonamide (SU-6656), a selective inhibitor of src family kinase, on the development of naloxone-induced opioid withdrawal syndrome in mice. Subacute morphine administration followed by a single injection of naloxone (8 mg/kg, i.p.) was used to precipitate the opioid withdrawal syndrome in mice. Behavioral observations were made immediately after naloxone treatment. The withdrawal syndrome was quant. assessed in terms of withdrawal severity score and frequency of jumping, rearing, forepaw licking, and circling. Daily single administration of SU-6656 was continued during the morphine treatment procedure. Injection of naloxone precipitated severe withdrawal in morphine-dependent mice. However, once-daily administration of SU-6656 (1.5, 3, and 6 mg/kg, i.p.) markedly and dose-dependently attenuated the naloxone-induced morphine withdrawal syndrome. Therefore, it seems that an src family-kinase-linked mechanism is involved in the development of physiol. opioid dependence; thus, src family kinase may serve as a potential target to address the pathol. condition of physiol. dependence and abstinence associated with continuous opioid usage.

Behavioural Pharmacology 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, 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

Rehni, Ashish K. published the artcileSU-6656, a Selective Src Kinase Inhibitor, Attenuates Mecamylamine-Precipitated Nicotine Withdrawal Syndrome in Mice, COA of Formula: C19H21N3O3S, the publication is Nicotine & Tobacco Research (2012), 14(4), 407-414, database is CAplus and MEDLINE.

Introduction: Src kinase is reported to regulate neuronal nicotinic acetylcholine receptor activity, which is among the principal receptor systems acted upon by nicotine. Src kinase is documented to mediate the pathogenesis of substance dependence. Therefore, the present study has been designed to investigate the effect of SU-6656, selective src kinase inhibitor, on the development of nicotine dependence in a mouse model of mecamylamine-induced nicotine withdrawal syndrome. Methods: Our exptl. protocol consisted of administration of nicotine (2.5 mg/kg, s.c.), 4 times daily for 7 days. In order to precipitate nicotine withdrawal, mice were given 1 injection of mecamylamine (3 mg/kg, i.p.), 1 h after the last nicotine injection on the test day (Day 8). Behavioral observations were made for a period of 30 min immediately after mecamylamine treatment. Withdrawal syndrome was quantitated in terms of a composite withdrawal severity score (WSS), and withdrawal syndrome-related anxiety was assessed by elevated plus maze test results. Results: SU-6656 markedly and dose dependently (p < .01) attenuated mecamylamine-induced exptl. nicotine withdrawal syndrome in mice measured in terms of WSS and anxiety score. Conclusions: Thus, it is suggested that src kinase is involved in the development of nicotine dependence-induced precipitation of its withdrawal syndrome and thus may serve as a viable pharmacol. target to tackle the problem of nicotine addiction.

Nicotine & Tobacco 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, 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