Tag: M.W=350-400

Mashkani, Baratali published the artcileColony stimulating factor-1 receptor as a target for small molecule inhibitors, Related Products of indole-building-block, the publication is Bioorganic & Medicinal Chemistry (2010), 18(5), 1789-1797, database is CAplus and MEDLINE.

Imatinib, dasatinib, sunitinib, CEP-701, and PKC-412, ATP-competitive small mol. inhibitors of type III receptor tyrosine kinases c-KIT and/or FLT3, were evaluated for binding to the closely related receptor, FMS, by docking into models of inactive and active conformations of the FMS kinase domain. To confirm the docking predictions, the drugs were tested for their activity and selectivity in inhibiting cell proliferation and FMS phosphorylation upon stimulation by the FMS ligand, CSF-1. All five drugs inhibited FMS activity. Imatinib, dasatinib and CEP-701 represent three different types of interactions determining drug potency and selectivity.

Bioorganic & Medicinal Chemistry 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

Gindi, Natalie published the artcileFyn and argonaute 2 participate in maternal-mRNA degradation during mouse oocyte maturation, Related Products of indole-building-block, the publication is Cell Cycle (2022), 21(8), 792-804, database is CAplus and MEDLINE.

Fertilization triggers physiol. degradation of maternal-mRNAs, which are then replaced by embryonic transcripts. Ample evidence suggests that Argonaut 2 (AGO2) is a possible post-fertilization regulator of maternal-mRNAs degradation; but its role in degradation of maternal-mRNAs during oocyte maturation remains obscure. Fyn, a member of the Src family kinases (SFKs), and an essential factor in oocyte maturation, was reported to inhibit AGO2 activity in oligodendrocytes. Our aim was to examine the role of Fyn and AGO2 in degradation of maternal-mRNAs during oocyte maturation by either suppressing their activity with SU6656 – an SFKs inhibitor; or by microinjecting DN-Fyn RNA for suppression of Fyn and BCl-137 for suppression of AGO2. Batches of fifteen mouse oocytes or embryos were analyzed by qPCR to measure the expression level of nine maternal-mRNAs that were selected for their known role in oocyte growth, maturation and early embryogenesis. We found that Fyn/SFKs are involved in maintaining the stability of at least four pre-transcribed mRNAs in oocytes at the germinal vesicle (GV) stage, whereas AGO2 had no role at this stage. During in-vivo oocyte maturation, eight maternal-mRNAs were significantly degraded. Inhibition of AGO2 prevented the degreadation of at least five maternal-mRNAs, whereas inhibition of Fyn/SFK prevented degradation of at least five Fyn maternal-mRNAs and two SFKs maternal-mRNAs; pointing at their role in promoting the physiol. degradation which occurs during in-vivo oocyte maturation. Our findings imply the involvement of Fyn/SFKs in stabilization of maternal-mRNA at the GV stage and the involvement of Fyn, SFKs and AGO2 in degradation of maternal mRNAs during oocyte maturation.

Cell Cycle 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

Hao, Lu published the artcileDevelopment of Kilogram-Scale Synthesis of EGFR Inhibitor EAI045, COA of Formula: C19H14FN3O3S, the publication is Organic Process Research & Development (2019), 23(3), 397-402, database is CAplus.

Herein, we report a synthetic route for an EGFR inhibitor, 2-(5-fluoro-2-hydroxyphenyl)-2-(1-oxoisoindolin-2-yl) acetic acid (EAI045), using a three-step approach. This short and efficient route is the first report of a scalable process for EAI045, which employs a convergent three-component coupling strategy as the key step, producing EAI045 in good yield on kilogram scale.

Organic Process Research & Development 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, 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

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

Shreevatsa, Bhargav published the artcileVirtual Screening for Potential Phytobioactives as Therapeutic Leads to Inhibit NQO1 for Selective Anticancer Therapy, Application of 5-Methoxy-1,2-dimethyl-3-[(4-nitrophenoxy)methyl]indole-4,7-dione, the publication is Molecules (2021), 26(22), 6863, database is CAplus and MEDLINE.

NAD(P)H:quinone acceptor oxidoreductase-1 (NQO1) is a ubiquitous FAD-dependent flavoprotein that promotes obligatory two-electron reductions of quinones, quinonimines, nitroaroms., and azo dyes. NQO1 is a multifunctional antioxidant enzyme whose expression and deletion are linked to reduced and increased oxidative stress susceptibilities. NQO1 acts as both a tumor suppressor and tumor promoter; thus, the inhibition of NQO1 results in less tumor burden. In addition, the high expression of NQO1 is associated with a shorter survival time of cancer patients. Inhibiting NQO1 also enables certain anticancer agents to evade the detoxification process. In this study, a series of phytobioactives were screened based on their chem. classes such as coumarins, flavonoids, and triterpenoids for their action on NQO1. The in silico evaluations were conducted using PyRx virtual screening tools, where the flavone compound, Orientin showed a better binding affinity score of -8.18 when compared with standard inhibitor Dicumarol with favorable ADME properties. An MD simulation study found that the Orientin binding to NQO1 away from the substrate-binding site induces a potential conformational change in the substrate-binding site, thereby inhibiting substrate accessibility towards the FAD-binding domain. Furthermore, with this computational approach we are offering a scope for validation of the new therapeutic components for their in vitro and in vivo efficacy against NQO1.

Molecules 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 C28H41N2P, Application 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

Sadaie, Mahito published the artcileCell-based screen for altered nuclear phenotypes reveals senescence progression in polyploid cells after Aurora kinase B inhibition, COA of Formula: C19H21N3O3S, the publication is Molecular Biology of the Cell (2015), 26(17), 2971-2985, database is CAplus and MEDLINE.

Cellular senescence is a widespread stress response and is widely considered to be an alternative cancer therapeutic goal. Unlike apoptosis, senescence is composed of a diverse set of subphenotypes, depending on which of its associated effector programs are engaged. Here we establish a simple and sensitive cell-based prosenescence screen with detailed validation assays. We characterize the screen using a focused tool compound kinase inhibitor library. We identify a series of compounds that induce different types of senescence, including a unique phenotype associated with irregularly shaped nuclei and the progressive accumulation of G1 tetraploidy in human diploid fibroblasts. Downstream analyses show that all of the compounds that induce tetraploid senescence inhibit Aurora kinase B (AURKB). AURKB is the catalytic component of the chromosome passenger complex, which is involved in correct chromosome alignment and segregation, the spindle assembly checkpoint, and cytokinesis. Although aberrant mitosis and senescence have been linked, a specific characterization of AURKB in the context of senescence is still required. This proof-of-principle study suggests that our protocol is capable of amplifying tetraploid senescence, which can be observed in only a small population of oncogenic RAS-induced senescence, and provides addnl. justification for AURKB as a cancer therapeutic target.

Molecular Biology of the Cell 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

Chmielarz, Piotr published the artcileGDNF/RET Signaling Pathway Activation Eliminates Lewy Body Pathology in Midbrain Dopamine Neurons, Application In Synthesis of 330161-87-0, the publication is Movement Disorders (2020), 35(12), 2279-2289, database is CAplus and MEDLINE.

Parkinson’s disease (PD) is associated with proteostasis disturbances and accumulation of misfolded α-synuclein (α-syn), a cytosolic protein present in high concentrations at pre-synaptic neuronal terminals. It is a primary constituent of intracellular protein aggregates known as Lewy neurites or Lewy bodies. Progression of Lewy pathol. caused by the prion-like self-templating properties of misfolded α-syn is a characteristic feature in the brains of PD patients. Glial cell line-derived neurotrophic factor (GDNF) promotes survival of mature dopamine (DA) neurons in vitro and in vivo. However, the data on its effect on Lewy pathol. is controversial. We studied the effects of GDNF on misfolded α-syn accumulation in DA neurons. Lewy pathol. progression was modeled by the application of α-syn preformed fibrils in cultured DA neurons and in the adult mice. We discovered that GDNF prevented accumulation of misfolded α-syn in DA neurons in culture and in vivo. These effects were abolished by deletion of receptor tyrosine kinase rearranged during transfection (RET) or by inhibitors of corresponding signaling pathway. Expression of constitutively active RET protected DA neurons from fibril-induced α-syn accumulation. For the first time, we have shown the neurotrophic factor-mediated protection against the misfolded α-syn propagation in DA neurons, uncovered underlying receptors, and investigated the involved signaling pathways. These results demonstrate that activation of GDNF/RET signaling can be an effective therapeutic approach to prevent Lewy pathol. spread at early stages of PD.

Movement Disorders 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

Winski, Shannon L. published the artcileCharacterization of a Mechanism-Based Inhibitor of NAD(P)H:Quinone Oxidoreductase 1 by Biochemical, X-ray Crystallographic, and Mass Spectrometric Approaches, Application of 5-Methoxy-1,2-dimethyl-3-[(4-nitrophenoxy)methyl]indole-4,7-dione, the publication is Biochemistry (2001), 40(50), 15135-15142, database is CAplus and MEDLINE.

We report the characterization of 5-methoxy-1,2-dimethyl-3-[(4-nitrophenoxy)methyl]indole-4,7-dione (ES936) as a mechanism-based inhibitor of NQO1. Inactivation of NQO1 by ES936 was time- and concentration-dependent and required the presence of a pyridine nucleotide cofactor consistent with a need for metabolic activation. That ES936 was an efficient inhibitor was demonstrated in these studies by the low partition ratio (1.40±0.03). The orientation of ES936 in the active site of NQO1 was examined by X-ray crystallog. and found to be opposite to that observed for other indolequinones acting as substrates. ES936 was oriented in such a manner that, after enzymic reduction and loss of a nitrophenol leaving group, a reactive iminium species was located in close proximity to nucleophilic His 162 and Tyr 127 and Tyr 129 residues in the active site. To determine if ES936 was covalently modifying NQO1, ES936-treated protein was analyzed by electrospray ionization liquid chromatog./mass spectrometry (ESI-LC/MS). The control NQO1 protein had a mass of 30864 ± 6 Da (n = 20, theor., 30868.6 Da) which increased by 217 Da after ES936 treatment (31081 ± 7 Da, n = 20) in the presence of NADH. The shift in mass was consistent with adduction of NQO1 by the reactive iminium derived from ES936 (M + 218 Da). Chymotryptic digestion of the protein followed by LC/MS anal. located a tetrapeptide spanning amino acids 126-129 which was adducted with the reactive iminium species derived from ES936. LC/MS/MS anal. of the peptide fragment confirmed adduction of either Tyr 127 or Tyr 129 residues. This work demonstrates that ES936 is a potent mechanism-based inhibitor of NQO1 and may be a useful tool in defining the role of NQO1 in cellular systems and in vivo.

Biochemistry 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 C3H6O2, Application 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

Araldi, Dioneia published the artcileMu-opioid Receptor (MOR) Biased Agonists Induce Biphasic Dose-dependent Hyperalgesia and Analgesia, and Hyperalgesic Priming in the Rat, COA of Formula: C19H21N3O3S, the publication is Neuroscience (Amsterdam, Netherlands) (2018), 60-71, database is CAplus and MEDLINE.

We investigated if local and systemic administration of biased MOR agonists (PZM21 and TRV130 [oliceridine]), which preferentially activate G-protein over beta-arrestin translocation, and have been reported to minimize some opioid side effects, also produces OIH and priming. Injected intradermally (100 ng), both biased agonists induced mech. hyperalgesia and, when injected at the same site, 5 days later, prostaglandin E₂ (PGE₂) produced prolonged hyperalgesia (priming). OIH and priming were both prevented by intrathecal treatment with an oligodeoxynucleotide (ODN) antisense (AS) for MOR mRNA. Agents that reverse Type I (the protein translation inhibitor cordycepin) and Type II (combination of Src and mitogen-activated protein kinase [MAPK] inhibitors) priming, or their combination, did not reverse priming induced by local administration of PZM21 or TRV130. While systemic PZM21 at higher doses (1 and 10 mg/kg) induced analgesia, lower doses (0.001, 0.01, 0.1, and 0.3 mg/kg) induced hyperalgesia; all doses induced priming. Hyperalgesia, analgesia and priming induced by systemic administration of PZM21 were also prevented by MOR AS-ODN. And, priming induced by systemic PZM21 was also not reversed by intradermal cordycepin or the combination of Src and MAPK inhibitors. Thus, maintenance of priming induced by biased MOR agonists, in the peripheral terminal of nociceptors, has a novel mechanism.

Neuroscience (Amsterdam, Netherlands) 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

Araldi, Dioneia published the artcileRepeated mu-opioid exposure induces a novel form of the hyperalgesic priming model for transition to chronic pain, Related Products of indole-building-block, the publication is Journal of Neuroscience (2015), 35(36), 12502-12517, database is CAplus and MEDLINE.

The primary afferent nociceptor was used as a model system to study mechanisms of pain induced by chronic opioid administration. Repeated intradermal injection of the selective mu-opioid receptor (MOR) agonist DAMGO induced mech. hyperalgesia and marked prolongation of prostaglandin E2 (PGE2) hyperalgesia, a key feature of hyperalgesic priming. However, in contrast to prior studies of priming induced by receptor-mediated (i.e., TNFα, NGF, or IL-6 receptor) or direct activation of protein kinase Cε (PKCε), the pronociceptive effects of PGE2 in DAMGO-treated rats demonstrated the following: (1) rapid induction (4 h compared with 3 d); (2) protein kinase A (PKA), rather than PKCε, dependence; (3) prolongation of hyperalgesia induced by an activator of PKA, 8-bromo cAMP; (4) failure to be reversed by a protein translation inhibitor; (5) priming in females as well as in males; and (6) lack of dependence on the isolectin B4-pos. nociceptor. These studies demonstrate a novel form of hyperalgesic priming induced by repeated administration of an agonist at the Gi-protein-coupled MOR to the peripheral terminal of the nociceptor.

Journal of Neuroscience 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