Day: November 25, 2022

Van Rheenen, D. L. published the artcileQuantitative determination of urinary indoxyl sulfate (indican) and the total content of basic compounds in the feces of cattle in relation to hypomagnesemia, Quality Control of 2642-37-7, the publication is Nature (London, United Kingdom) (1966), 212(5067), 1269-70, database is CAplus and MEDLINE.

For the determination of indican, FeCl3 in concentrated HCl was used as oxidant. The method could detect 5 γ of indican. To 1 mL. of diluted urine or standard were added 2 mL. of 20% Cl3CCO2H, 1 mL. of 0.5% thymol, and 3 mL. of 0.34% FeCl3 in concentrated HCl. After incubation in boiling water for 20 min., the tubes were centrifuged at 4000 rpm. for 10 min. The yellow supernatant (0.4 mL.) was made up to 4 mL. with CHCl3 and the color intensity determined at 540 mμ. The total amount of amines and basic amino acids in extracts of feces were determined with ninhydrin. Urinary indican increased when feed was changed from hay to grain. This was an indication of increased bacterial metabolism in the gastrointestinal tract. After treatment resulting in hypomagnesemia, the total content of basic compounds in the feces decreased. This was due to absorption during passage through the gut. Under normal conditions, indican and basic amines normally formed in the colon are partly removed in the faces, partly detoxicated in the tissues and removed in the urine. In abnormal gastrointestinal function, larger amounts are absorbed. Hypomagnesemia may affect the destruction of these compounds in the tissues.

Nature (London, United Kingdom) published new progress about 2642-37-7. 2642-37-7 belongs to indole-building-block, auxiliary class Indole,Salt,Sulfonate,Inhibitor,Inhibitor, name is Potassium 1H-indol-3-yl sulfate, and the molecular formula is C7H13NO2, Quality Control of 2642-37-7.

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

O’Reilly, Matthew C. published the artcileFurther evaluation of novel structural modifications to scaffolds that engender PLD isoform selective inhibition, Recommanded Product: 5-Fluoro-1H-indole-2-carbaldehyde, the publication is Bioorganic & Medicinal Chemistry Letters (2014), 24(24), 5553-5557, database is CAplus and MEDLINE.

This Letter describes the on-going SAR efforts based on two scaffolds, a PLD1-biased piperidinyl benzimidazolone and a PLD2-biased piperidinyl triazaspirone, with the goal of enhancing PLD inhibitory potency and isoform selectivity. Here, we found that addition of an α-Me moiety within the PLD2-biased piperidinyl triazaspirone scaffold abolished PLD2 preference, while the incorporation of substituents onto the piperidine moiety of the PLD1-biased piperidinyl benzimidazolone, or replacement with a bioisosteric [3.3.0] core, generally retained PLD1 preference, but at diminished significance. The SAR uncovered within these two allosteric PLD inhibitor series further highlights the inherent challenges of developing isoform selective PLD inhibitors.

Bioorganic & Medicinal Chemistry Letters published new progress about 220943-23-7. 220943-23-7 belongs to indole-building-block, auxiliary class Indole,Fluoride,Aldehyde, name is 5-Fluoro-1H-indole-2-carbaldehyde, and the molecular formula is C9H6FNO, Recommanded Product: 5-Fluoro-1H-indole-2-carbaldehyde.

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

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

Giacomelli, Cristiano published the artcileLoading capacity of copolymer micelles enhanced by specific interactions, Safety of 2-(1-(4-Chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)-1-morpholinoethanone, the publication is Polymer Preprints (American Chemical Society, Division of Polymer Chemistry) (2007), 48(2), 411-412, database is CAplus.

Block copolymer self-assemblies have been successfully tested in many applications as nanocarriers, especially in drug delivery. We report herein that specific interactions between hydrophobic guest mols. and core-forming segments can improve significantly the loading capacity of polymeric micelles. When selected probes exhibiting weak carboxylic acid groups in their structure were loaded into micellar nanoparticles with poly(dialkylamino)ethyl methacrylate-based cores (i.e., weak polybases), high loadings were usually achieved (> 100 % weight/weight of polymer (w/wp)). The existence of acid-base interactions between the solubilizate and the weak polybase block forming the micelle core was evidenced by 1H NMR measurements, and also through a systematic encapsulation study using structurally different probes and block copolymers.

Polymer Preprints (American Chemical Society, Division of Polymer Chemistry) 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

Giacomelli, Cristiano published the artcileSpecific Interactions Improve the Loading Capacity of Block Copolymer Micelles in Aqueous Media, Formula: C23H23ClN2O4, the publication is Langmuir (2007), 23(13), 6947-6955, database is CAplus and MEDLINE.

Block copolymer micelles find application in many fields as nanocarriers, especially in drug delivery. We report herein that specific interactions between hydrophobic guest mols. and core-forming segments can significantly improve the loading capacity of polymeric micelles. High loading capacities (>100% weight/weight of polymer (weight/weight_p)) were systematically observed for the encapsulation of probes containing weak carboxylic acid groups by micellar nanoparticles having poly[2-(dialkylamino)ethyl methacrylate] cores (i.e., particles whose cargo space exhibits antagonist weak base functions), as demonstrated by the incorporation of indomethacin (IND), ibuprofen (IBPF), and trans-3,5-bis(trifluoromethyl)cinnamic acid (F-CIN) into either poly(ethylene oxide)-b-poly[2-(diisopropylamino)ethyl methacrylate] (PEO-b-PDPA) or poly(glycerol monomethacrylate)-b-PDPA (PG2MA-b-PDPA) micelles. The esterification of IND yielding to a nonionizable IND Et ester derivative (IND-Et) caused an abrupt decrease in the micellar loading capacity down to 10-15% weight/weight_p. Similar results were also obtained when IND was combined with nonionizable block copolymers such as PEO-b-polycaprolactone (PEO-b-PCL) and PEO-b-poly(glycidyl methacrylate) (PEO-b-PGMA). The existence of acid-base interactions between the solubilizate and the weak polybase block forming the micelle core was confirmed by ¹H NMR measurements. However, the incorporation of high numbers of hydrophobic guest mols. inside polymeric micelles can provoke not only an increase in the hydrodynamic size (2R_H) of the objects but also a substantial change in the morphol. (transition from spheres to cylinders). The application of the Higuchi model showed that the probe release followed a diffusion-controlled mechanism, and diffusion coefficients (D) on the order of 10^-18-10^-17 cm²/s were determined for IND release from 1.0 mg/mL PEO₁₁₃-b-PDPA₅₀ + 100% weight/weight_p IND. Probe release from micelles with weak polybase-based cores can also be triggered by changes in the solution pH.

Langmuir 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, Formula: C23H23ClN2O4.

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

Ravula, Suchitra published the artcileLead Optimization of 5-Aryl Benzimidazolone- and Oxindole-Based AMPA Receptor Modulators Selective for TARP γ-8, Category: indole-building-block, the publication is ACS Medicinal Chemistry Letters (2018), 9(8), 821-826, database is CAplus and MEDLINE.

Glutamate mediates fast excitatory neurotransmission via ionotropic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. The trafficking and gating properties of AMPA receptors (AMPARs) can be amplified by transmembrane AMPAR regulatory proteins (TARPs), which are often expressed in localized brain regions. Herein, the authors describe the discovery, lead optimization, and preclin. characterization of 5-arylbenzimidazolone and oxindole-based neg. modulators of AMPARs associated with TARP γ-8, the primary TARP found in hippocampus. High-throughput screen lead 4 (5-(o-tolyl)indolin-2-one) was optimized for potency and brain penetration to provide benzimidazolone 3, JNJ-55511118. Replacement of the benzimidazolone core in 3 with an oxindole mitigated reactive metabolite formation and led to the identification of 18 (5-[2-chloro-6-(trifluoromethoxy)phenyl]-7-methylindolin-2-one) (GluA1/γ-8 pIC₅₀ = 9.7). Following oral dosing in rats, 18 demonstrated robust target engagement in hippocampus as assessed by ex vivo autoradiog. (ED₅₀ = 0.6 mg/kg, plasma EC₅₀ = 9 ng/mL).

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, 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

Haustein, Catherine published the artcileRoom-temperature phosphorescence of 3- and 5-substituted indoles, Safety of Potassium 1H-indol-3-yl sulfate, the publication is Talanta (1989), 36(11), 1065-8, database is CAplus and MEDLINE.

The room-temperature phosphorescence of indole and 13 substituted indoles on filter paper is reported. Cesium and iodide ions increase the emission intensity. In the presence of iodide, the excitation and emission wavelengths of indole are 279 and 440 nm, resp. The excitation and emission wavelengths of indoles with aliphatic groups in the 3-position are 288-289 and 443-449 nm, resp. Indoles with 3,5-substitution have excitation and emission wavelengths of 300-308 and 448-460 nm, resp. Indoxylsulfate and indoxyl-β-D-glucoside were the only indoles surveyed for which variations in the excitation and emission wavelengths depended on the heavy-atom ion present. These compounds had excitation wavelengths ranging from 288 to 388 nm, depending on which heavy-atom perturber was used. Emission wavelengths were 460-500 nm. Log-log plots of intensity vs. concentration were linear between 0.05 and 700 μg/mL for all the compounds studied, with detection limits in the nanogram range.

Talanta published new progress about 2642-37-7. 2642-37-7 belongs to indole-building-block, auxiliary class Indole,Salt,Sulfonate,Inhibitor,Inhibitor, name is Potassium 1H-indol-3-yl sulfate, and the molecular formula is C8H6KNO4S, Safety of Potassium 1H-indol-3-yl sulfate.

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

Garg, Neil K. published the artcileThe First Total Synthesis of Dragmacidin D, Formula: C15H14BNO4S, the publication is Journal of the American Chemical Society (2002), 124(44), 13179-13184, database is CAplus and MEDLINE.

The first total synthesis of the biol. significant bis-indole alkaloid dragmacidin D has been achieved. Thermal and electronic modulation provides the key for a series of palladium-catalyzed Suzuki cross-coupling reactions that furnished the core structure of the complex guanidine- and aminoimidazole-containing dragmacidins. Thus, 6-bromo-3-iodo-2-methoxypyrazine was coupled with bromoindole I in the presence of Pd(PPh₃)₄/MeOH/C₆H₆/Na₂CO₃/H₂O to give indolopyrazine II. II was then coupled with another indole under similar conditions to give the core silylated bisindole pyrazine III. Following this crucial sequence, a succession of meticulously controlled final events was developed leading to the completion of the natural product.

Journal of the American Chemical Society 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 C15H14BNO4S, Formula: C15H14BNO4S.

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