Tag: M.W=350-400

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

Al-Ali, Hassan published the artcileChemical Interrogation of the Neuronal Kinome Using a Primary Cell-Based Screening Assay, Application In Synthesis of 330161-87-0, the publication is ACS Chemical Biology (2013), 8(5), 1027-1036, database is CAplus and MEDLINE.

A fundamental impediment to functional recovery from spinal cord injury (SCI) and traumatic brain injury is the lack of sufficient axonal regeneration in the adult central nervous system. There is thus a need to develop agents that can stimulate axon growth to re-establish severed connections. Given the critical role played by protein kinases in regulating axon growth and the potential for pharmacol. intervention, small mol. protein kinase inhibitors present a promising therapeutic strategy. Here, the authors report a robust cell-based phenotypic assay, utilizing primary rat hippocampal neurons, for identifying small mol. kinase inhibitors that promote neurite growth. The assay is highly reliable and suitable for medium-throughput screening, as indicated by its Z’-factor of 0.73. A focused structurally diverse library of protein kinase inhibitors was screened, revealing several compound groups with the ability to strongly and consistently promote neurite growth. The best performing bioassay hit robustly and consistently promoted axon growth in a postnatal cortical slice culture assay. This study can serve as a jumping-off point for structure activity relationship (SAR) and other drug discovery approaches toward the development of drugs for treating SCI and related neurol. pathologies.

ACS 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, Application In Synthesis of 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

Langendorf, Christopher G. published the artcileFake Inhibitors: AMPK Activation Trumps Inhibition, Application of SU6656, the publication is Cell Chemical Biology (2017), 24(7), 775-777, database is CAplus and MEDLINE.

A review. Protein kinase inhibitors have become increasingly important therapeutic drugs for the treatment of human diseases; however, resistance and off-target effects can limit their use. In this issue of Cell Chem. Biol., Ross et al. (2017) reveal a novel off-target mechanism where the Src kinase inhibitor SU6656 paradoxically primes AMPK for phosphorylation and activation by the upstream kinase LKB1.

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, 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

Ungefroren, H. published the artcileThe Src family kinase inhibitors PP2 and PP1 block TGF-beta1-mediated cellular responses by direct and differential inhibition of type I and type II TGF-beta receptors, Safety of SU6656, the publication is Current Cancer Drug Targets (2011), 11(4), 524-535, database is CAplus and MEDLINE.

Both the nonreceptor tyrosine kinase Src and the receptors for transforming growth factor (TGF-β TβR, TβRII) play major roles during tumorigenesis by regulating cell growth, migration/invasion and metastasis. The common Src family kinase inhibitors PP2 and PP1 effectively block Src activity in vitro and in vivo, however, they may exert non-specific effects on other kinases. In this study, we have evaluated PP2 and PP1 for their ability to inhibit TGFβ1-mediated responses in the TGF-β-responsive pancreatic adenocarcinoma cell line Panc1. We show that PP2 and PP1 but not the more specific Src inhibitor SU6656 effectively relieved TGF-β1-induced growth arrest and p21^WAF1 induction, while basal growth was enhanced by PP2 and PP1, and suppressed by SU6656. PP2 and PP1 but not SU6656 also suppressed TGF-β1-induced epithelial-to-mesenchymal transition (EMT) as evidenced by their ability to inhibit downregulation of the epithelial marker E-cadherin, and upregulation of the EMT-associated transcription factor Slug. Likewise, PP2 and PP1 but not SU6656 effectively blocked TGF-β1-induced activation of Smad2 and p38 MAPK and partially suppressed Smad activation and transcriptional activity on TGF-β/Smad-responsive reporters of a kinase-active TβRI mutant ectopically expressed in Panc1 cells. Interestingly, PP2 and PP1 strongly inhibited recombinant TβRI in an in vitro kinase assay, with PP1 being more potent and PP2 being nearly as potent as the established TβR1 inhibitor SB431542. PP2 but not PP1 also weakly inhibited the TβRII kinase. Together, these data provide evidence that PP2 and PP1 are powerful inhibitors of TβR function that can block TGF-β/Smad signaling in a Src-unrelated fashion. Both agents may be useful as dual TGF-β/Src inhibitors in exptl. therapeutics of late stage metastatic disease.

Current Cancer Drug Targets 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 C9H21NO3, 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

Lian, Xiaojun published the artcileA small molecule inhibitor of Src family kinases promotes simple epithelial differentiation of human pluripotent stem cells, Category: indole-building-block, the publication is PLoS One (2013), 8(3), e60016, database is CAplus and MEDLINE.

Human pluripotent stem cells (hPSCs) provide unprecedented opportunities to study the earliest stages of human development in vitro and have the potential to provide unlimited new sources of cells for regenerative medicine. Although previous studies have reported cytokeratin 14+/p63+ keratinocyte generation from hPSCs, the multipotent progenitors of epithelial lineages have not been described and the developmental pathways regulating epithelial commitment remain largely unknown. Here we report membrane localization of β-catenin during retinoic acid (RA) – induced epithelial differentiation. In addition hPSC treatment with the Src family kinase inhibitor SU6656 modulated β-catenin localization and produced an enriched population of simple epithelial cells under defined culture conditions. SU6656 strongly upregulated expression of cytokeratins 18 and 8 (K18/K8), which are expressed in simple epithelial cells, while repressing expression of the pluripotency gene Oct4. This homogeneous population of K18+K8+Oct4- simple epithelial precursor cells can further differentiate into cells expressing keratinocyte or corneal-specific markers. These enriched hPSC-derived simple epithelial cells may provide a ready source for development and toxicol. cell models and may serve as a progenitor for epithelial cell transplantation applications.

PLoS One 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, 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

Cherubini, Fabio published the artcileSrc inhibitors modulate frataxin protein levels, Product Details of C19H21N3O3S, the publication is Human Molecular Genetics (2015), 24(15), 4296-4305, database is CAplus and MEDLINE.

Defective expression of frataxin is responsible for the inherited, progressive degenerative disease Friedreich’s Ataxia (FRDA). There is currently no effective approved treatment for FRDA and patients die prematurely. Defective frataxin expression causes critical metabolic changes, including redox imbalance and ATP deficiency. As these alterations are known to regulate the tyrosine kinase Src, we investigated whether Src might in turn affect frataxin expression. We found that frataxin can be phosphorylated by Src. Phosphorylation occurs primarily on Y118 and promotes frataxin ubiquitination, a signal for degradation Accordingly, Src inhibitors induce accumulation of frataxin but are ineffective on a non-phosphorylatable frataxin-Y118F mutant. Importantly, all the Src inhibitors tested, some of them already in the clinic, increase frataxin expression and rescue the aconitase defect in frataxin-deficient cells derived from FRDA patients. Thus, Src inhibitors emerge as a new class of drugs able to promote frataxin accumulation, suggesting their possible use as therapeutics in FRDA.

Human Molecular Genetics 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