Heterocyclic Building Blocks-Benzothiophene

Bauman, Jonathon N. published the artcileCan In Vitro Metabolism-Dependent Covalent Binding Data Distinguish Hepatotoxic from Nonhepatotoxic Drugs? An Analysis Using Human Hepatocytes and Liver S-9 Fraction, Computed Properties of 40180-04-9, the main research area is hepatotoxic nonhepatotoxic drug liver covalent binding.

In vitro covalent binding studies in which xenobiotics are shown to undergo metabolism-dependent covalent binding to macromols. have been commonly used to shed light on the biochem. mechanisms of xenobiotic-induced toxicity. In this paper hepatotoxins and nonhepatotoxins were tested for their proclivity to demonstrate metabolism-dependent covalent binding to macromols. in human liver S-9 fraction (9000 g supernatant) or human hepatocytes, as an extension to previous work that used human liver microsomes published in this journal [Obachet al. (2008) Chem. Res. Toxicol.21, 1814-1822]. In the S-9 fraction, seven out of the nine drugs in each category demonstrated some level of metabolism-dependent covalent binding. Inclusion of reduced glutathione, cofactors needed by conjugating enzymes, and other parameters (total daily dose and fraction of total intrinsic clearance comprised by covalent binding) improved the ability of the system to sep. hepatotoxins from nonhepatotoxins to a limited extent. Covalent binding in human hepatocytes showed that six out of the nine hepatotoxins and four out of eight nonhepatotoxins demonstrated covalent binding. Taking into account estimates of total daily body burden of covalent binding from the hepatocyte data showed an improvement over other in vitro systems for distinguishing hepatotoxins from nonhepatotoxins; however, this metabolism system still displayed some false positives. Combined with the previous study using liver microsomes, these findings identify the limitations of in vitro covalent binding data for prospective prediction of hepatotoxicity for new drug candidates and highlight the need for a better understanding of the link between drug bioactivation, covalent adduct formation, and toxicity outcomes. Directly relating covalent binding to hepatotoxicity is likely an oversimplification of the process whereby adduct formation ultimately leads to toxicity. Understanding underlying complexities (e.g., which macromols. are important covalent binding targets, interindividual differences in susceptibility, etc.) will be essential to any understanding of the problem of metabolism-dependent hepatotoxicity and predicting toxicity from in vitro experiments

Chemical Research in Toxicology published new progress about Drug metabolism (covalent binding). 40180-04-9 belongs to class benzothiophene, name is 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, and the molecular formula is C13H8Cl2O4S, Computed Properties of 40180-04-9.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Bi, Yi-an published the artcileRole of Hepatic Organic Anion Transporter 2 in the Pharmacokinetics of R- and S-Warfarin: In Vitro Studies and Mechanistic Evaluation, Category: benzothiophene, the main research area is warfarin enantiomer liver clearance OAT2 pharmacokinetics pharmacogenomics; CYP2C9; organic anion transporter; pharmacokinetics; physiological based modeling; warfarin.

Interindividual variability in warfarin dose requirement demands personalized medicine approaches to balance its therapeutic benefits (anticoagulation) and bleeding risk. Cytochrome P 450 2C9 (CYP2C9) genotype-guided warfarin dosing is recommended in the clinic, given the more potent S-warfarin is primarily metabolized by CYP2C9. However, only about 20-30% of interpatient variability in S-warfarin clearance is associated with CYP2C9 genotype. We evaluated the role of hepatic uptake in the clearance of R- and S-warfarin. Using stably transfected HEK293 cells, both enantiomers were substrates of organic anion transporter (OAT)2 with a Michaelis-Menten constant (Km) of ∼7-12 μM but did not show substrate affinity for other major hepatic uptake transporters. Uptake of both enantiomers by primary human hepatocytes was saturable (Km ≈ 7-10 μM) and inhibitable by OAT2 inhibitors (e.g., ketoprofen) but not by OATP1B1/1B3 inhibitors (e.g., cyclosporine). To further evaluate the potential role of hepatic uptake in R- and S-warfarin pharmacokinetics, mechanistic modeling and simulations were conducted. A “”bottom-up”” PBPK model, developed assuming that OAT2-CYPs interplay, well recovered clin. pharmacokinetics, drug-drug interactions, and CYP2C9 pharmacogenomics of R- and S-warfarin. Clin. data were not available to directly verify the impact of OAT2 modulation on warfarin pharmacokinetics; however, the bottom-up PBPK model simulations suggested a proportional change in clearance of both warfarin enantiomers with inhibition of OAT2 activity. These results suggest that variable hepatic OAT2 function, in conjunction with CYP2C, may contribute to the high population variability in warfarin pharmacokinetics and possibly anticoagulation end points and thus warrant further clin. investigation.

Molecular Pharmaceutics published new progress about Drug interactions, pharmacokinetic. 40180-04-9 belongs to class benzothiophene, name is 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, and the molecular formula is C13H8Cl2O4S, Category: benzothiophene.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Methogo, Ruth Menque published the artcileIdentification of liver protein targets modified by tienilic acid metabolites using a two-dimensional Western blot-mass spectrometry approach, Product Details of C13H8Cl2O4S, the main research area is liver protein tienilic acid metabolite mass spectrometry electrophoresis immunoblotting.

A combined approach based on two-dimensional electrophoresis-immuno-blotting and nanoliquid chromatog. coupled online with electrospray ionization mass spectrometry (nLC-MS/MS) was used to identify proteins modified by a reactive intermediate of tienilic acid (TA). Liver homogenates from rats exposed to TA were fractionated using ultra centrifugation; four fractions were obtained and subjected to 2D electrophoresis. Following transfer to PVDF membranes, modified proteins were visualized after India ink staining, using an anti-serum raised against TA and ECL detection. Immuno-reactive spots were localized on the PVDF membrane by superposition of the ECL image, protein spots of interest were excised, digested on the membrane with trypsin followed by nLC-MS/MS anal. and protein identification. A total of 15 proteins were identified as likely targets modified by a TA reactive metabolite. These include selenium binding protein 2, senescence marker protein SMP-30, adenosine kinase, Acy1 protein, adenosyl-homocysteinase, capping protein (actin filament), protein disulfide isomerase, fumarylacetoacetase, arginase chain A, keto-hexokinase, proteasome endopeptidase complex, triosephosphate isomerase, superoxide dismutase, DNA-type mol. chaperone hsc73 and malate dehydrogenase.

International Journal of Mass Spectrometry published new progress about Autoimmune hepatitis (drug-induced). 40180-04-9 belongs to class benzothiophene, name is 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, and the molecular formula is C13H8Cl2O4S, Product Details of C13H8Cl2O4S.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Liang, Shuang published the artcileGC-MS analysis of chemical constituents of volatile oils of the yao medicine Thunbergia grandiflora from different habitats in guangxi, Category: benzothiophene, the main research area is Thunbergia grandiflora guangxi yao medicine volatile oil GCMS.

This study was conducted to compare and anlyze the chem. constituents of the volatile oils of the Yao medicine Thunbergia grandiflora from different habitals.A quarz capillary column DB-1MS, an EI ion source a quadrupole mass analyzer were used for anal. The chromatog. and mass spectrum information obtained was automatically retrieved and analyzed by data processing system and its memory spectrum library (Nist. 08). The relative content of each chem. component in the volatile oil was determinded by the peak area normalization method.Forty nine chromatog. peaks were isolated from the sample produced in Shitun, Bailongtan Town, Mashan County, and 24 chem. constituents were identified, accounting for 88.78% of the total volatile oil. Forty nine chromatog. peaks were isolated from the sample produced in Hongdu Village, Chengjiang Town, Duan County, and 30 chem. constituents were identified, accounting for 88.38% of the total volatile oil. Forty eight chromatog. peaks were isolated from the sample produced in Longwan Township, Du’an County, and 25 chem. constituents were identified, accounting for 80.01% of the total volatile oil. Nine chem. constituents were common to the volatile oils of the samples from the three habitats. It could be seen that the main components of volatile oils from T. grandiflora produced in different areas are different.

Agricultural Biotechnology published new progress about Gas chromatography-mass spectrometry. 1468-83-3 belongs to class benzothiophene, name is 3-Acetylthiophene, and the molecular formula is C6H6OS, Category: benzothiophene.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Zhao, Guozhong published the artcileEffect of wheat bran steam explosion pretreatment on flavors of nonenzymatic browning products, HPLC of Formula: 1468-83-3, the main research area is wheat bran steam explosion flavor nonenzymic browning.

Wheat bran, which contains a large amount of cellulose, is used as a raw material to produce soy sauce, but it is hard to degrade during fermentation Steam explosion (SE) is efficient in hydrolyzing the cellulose for enhancing enzymic digestion and solvent accessibility. In this study, we applied a SE at a sufficiently high pressure to damage the integrity of the wheat bran structure and modify it to assume a layered form. We found that cellulose, hemicellulose, and lignin structures were collapsed by SE pretreatment, which was indicated by their changes in Fourier transform IR spectroscopy (FTIR). The amounts of cellulose, hemicellulose, and lignin decreased by 5.8%, 21.4%, and 43.4%, resp., under 1.5 MPa, resulting in the significant reduction of sugar and amino acid nitrogen. The co-reaction of nonenzymic browning after SE pretreatment resulted in an intense increase in flavor (overall feeling), as determined by electronic nose anal. and sensory evaluation. In conclusion, SE pretreatment under 1.0 MPa was proven to be the most optimal state for the production of aroma compounds (volatile compounds), which are essential for soy sauce production

LWT–Food Science and Technology published new progress about Browning (food) (nonenzymic browning). 1468-83-3 belongs to class benzothiophene, name is 3-Acetylthiophene, and the molecular formula is C6H6OS, HPLC of Formula: 1468-83-3.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Xiao, Miao published the artcileTransition-Metal-Free Hydrogen Autotransfer: Diastereoselective N-Alkylation of Amines with Racemic Alcohols, Application In Synthesis of 1468-83-3, the main research area is diastereoselective alkylation amines alc chiral amine synthesis; alcohols; alkylation; amines; deuterium; reaction mechanisms.

A practical method for the synthesis of α-chiral amines by alkylation of amines with alcs. in the absence of any transition-metal catalysts has been developed. Under the co-catalysis of a ketone and NaOH, racemic secondary alcs. reacted with Ellman’s chiral tert-butanesulfinamide by a hydrogen autotransfer process to afford chiral amines with high diastereoselectivities (up to >99:1) [e.g., 1-phenylethanol + (R)-(+)-tert-butanesulfinamide → I (70%, > 95:5 d.r.) in presence of acetophenone and NaOH in toluene]. Broad substrate scope and up to a 10 g scale production of chiral amines were demonstrated. The method was applied to the synthesis of chiral deuterium-labeled amines with high deuterium incorporation and optical purity, including examples of chiral deuterated drugs. The configuration of amine products is found to be determined solely by the configuration of the chiral tert-butanesulfinamide regardless of that of alcs., and this is corroborated by DFT calculations Further mechanistic studies showed that the reaction is initiated by the ketone catalyst and involves a transition state similar to that proposed for the Meerwein-Ponndorf-Verley (MPV) reduction, and importantly, it is the interaction of the sodium cation of the base with both the nitrogen and oxygen atoms of the sulfinamide moiety that makes feasible, and determines the diastereoselectivity of, the reaction.

Angewandte Chemie, International Edition published new progress about Alkylation catalysts, stereoselective. 1468-83-3 belongs to class benzothiophene, name is 3-Acetylthiophene, and the molecular formula is C6H6OS, Application In Synthesis of 1468-83-3.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Zhang, Fangming published the artcileRh(III)-catalyzed regioselective C-H activation dialkenylation/annulation cascade for rapid access to 6H-isoindolo[2,1-a]indole, Category: benzothiophene, the main research area is isoindoloindole preparation regioselective diastereoselective; aryl indole acrylate dialkenylation cyclization tandem rhodium catalyst.

The 6H-isoindolo[2,1-a]indoles I [R = H, 2-Br, 2-NO2, 1,3-(CH3)2; R1 = H, 9-Me, 8-OMe, 8-F, etc.; R2 = Et, Me, n-Bu, t-Bu, Bn] and II were accessed via a Rh(III)-catalyzed N-H free indole directed C-H activation dialkenylation/annulation cascade in moderate to excellent yields. This protocol also features: reaction procedures that are insensitive to air and moisture, excellent regioselectivity and good functional group tolerance.

RSC Advances published new progress about Alkenylation (stereo-, regioselective). 1468-83-3 belongs to class benzothiophene, name is 3-Acetylthiophene, and the molecular formula is C6H6OS, Category: benzothiophene.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Takakusa, Hideo published the artcileQuantitative assessment of reactive metabolite formation using 35S-labeled glutathione, Synthetic Route of 40180-04-9, the main research area is drug metabolism reactive metabolite determination radiolabeled glutathione.

The metabolic bioactivation of a drug to a reactive metabolite (RM) and its covalent binding to cellular macromols. is believed to be involved in clin. adverse events, including idiosyncratic drug toxicities. Therefore, it is important to assess the potential of drug candidates to generate RMs and form drug-protein covalent adducts during lead optimization processes. In this study, the RM formation of some marketed drugs were quant. assessed by means of a sensitive and robust detection method that we have established using 35S-glutathione (35S-GSH) as a trapping agent. Problematic drugs well-known to generate RMs exhibited a relatively high rate of 35S-GS-adducts to RM (RM-GS) formation, which contrasted with safe drugs. For practical use in lead optimization processes, a series of new chem. entities were tested and hints on the structural modifications needed in order to minimize their RM formation were provided. Furthermore, the RM-GS formation rates of a number of compounds were compared using their in vitro covalent binding yields to liver proteins determined with 14C-labeled compounds, demonstrating that the RM-GS formation rate could be a substitute for the covalent binding yield within the same series of compounds

Drug Metabolism and Pharmacokinetics published new progress about Drug metabolism (metabolic bioactivation). 40180-04-9 belongs to class benzothiophene, name is 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, and the molecular formula is C13H8Cl2O4S, Synthetic Route of 40180-04-9.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Bauer, John H. published the artcileEffects of diuretic and propranolol on plasma lipoprotein lipids, Formula: C13H8Cl2O4S, the main research area is diuretic propranolol plasma lipoprotein.

To define the effects of diuretics on plasma lipoproteins, experiments were performed in hypertensive subjects after placebo therapy, 4 wk after therapy with either hydrochlorothiazide (HCTZ)(I) [58-93-5] or ticrynafen (TCNF)(II) [40180-04-9], 3 mo after diuretic with propranolol (III) [525-66-6], and 1 mo after therapy with propranolol alone. Plasma lipoproteins were separated by ultracentrifugation and the lipid fractions isolated by extraction and silicic acid thin-layer chromatog. Plasma low-d. lipoprotein (LDL) total cholesterol fell and high-d. lipoprotein (HDL) total cholesterol rose in subjects receiving TCNF. TCNF had no effect on plasma very low-d. lipoprotein (VLDL) triglyceride or phospholipid. There were no significant changes in LDL or HDL total cholesterol in subjects on HCTZ. HCTZ tended to increase plasma VLDL triglyceride and phospholipid. The addition of propranolol to either diuretic had no effect on LDL or HDL total cholesterol but increased VLDL triglyceride, especially in subjects on HCTZ. Propranolol alone had no effect on any of the lipids measured.

Clinical Pharmacology & Therapeutics (St. Louis, MO, United States) published new progress about Lipoproteins Role: BIOL (Biological Study). 40180-04-9 belongs to class benzothiophene, name is 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, and the molecular formula is C13H8Cl2O4S, Formula: C13H8Cl2O4S.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Luo, Wenjun published the artcileSynthesis of W-Phos Ligand and Its Application in the Copper-Catalyzed Enantioselective Addition of Linear Grignard Reagents to Ketones, SDS of cas: 1468-83-3, the main research area is ketone Grignard reagent copper phosphine enantioselective regioselective addition; chiral tertiary alc preparation; Alcohols; Asymmetric Catalysis; Copper; Grignard Reagents; Ketones.

A novel family of PNP ligands (W-Phos) was designed and applied in copper-catalyzed asym. addition of linear Grignard reagents to aryl alkyl ketones, allowing facile access to versatile chiral tertiary alcs. in good to high yields with excellent enantioselectivities (up to 94% yield, 96% ee). The process was also used to synthesize chiral allylic tertiary alcs. from more challenging α,β-unsaturated ketones. Notably, the potential utility of this method was demonstrated in the gram-scale synthesis and modification of various densely functionalized medicinally relevant mols.

Angewandte Chemie, International Edition published new progress about Addition reaction catalysts, regioselective. 1468-83-3 belongs to class benzothiophene, name is 3-Acetylthiophene, and the molecular formula is C6H6OS, SDS of cas: 1468-83-3.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem