Day: November 10, 2022

Fourches, Denis published the artcileCheminformatics Analysis of Assertions Mined from Literature that Describe Drug-Induced Liver Injury in Different Species, Recommanded Product: 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, the main research area is cheminformatics drug toxicity liver injury species difference QSAR model.

Drug-induced liver injury is one of the main causes of drug attrition. The ability to predict the liver effects of drug candidates from their chem. structures is critical to help guide exptl. drug discovery projects toward safer medicines. In this study, the authors have compiled a data set of 951 compounds reported to produce a wide range of effects in the liver in different species, comprising humans, rodents, and nonrodents. The liver effects for this data set were obtained as assertional metadata, generated from MEDLINE abstracts using a unique combination of lexical and linguistic methods and ontol. rules. The authors have analyzed this data set using conventional cheminformatics approaches and addressed several questions pertaining to cross-species concordance of liver effects, chem. determinants of liver effects in humans, and the prediction of whether a given compound is likely to cause a liver effect in humans. The authors found that the concordance of liver effects was relatively low (∼39-44%) between different species, raising the possibility that species specificity could depend on specific features of chem. structure. Compounds were clustered by their chem. similarity, and similar compounds were examined for the expected similarity of their species-dependent liver effect profiles. In most cases, similar profiles were observed for members of the same cluster, but some compounds appeared as outliers. The outliers were the subject of focused assertion regeneration from MEDLINE as well as other data sources. In some cases, addnl. biol. assertions were identified, which were in line with expectations based on compounds’ chem. similarities. The assertions were further converted to binary annotations of underlying chems. (i.e., liver effect vs. no liver effect), and binary quant. structure-activity relationship (QSAR) models were generated to predict whether a compound would be expected to produce liver effects in humans. Despite the apparent heterogeneity of data, models have shown good predictive power assessed by external 5-fold cross-validation procedures. The external predictive power of binary QSAR models was further confirmed by their application to compounds that were retrieved or studied after the model was developed. To the best of the authors’ knowledge, this is the first study for chem. toxicity prediction that applied QSAR modeling and other cheminformatics techniques to observational data generated by the means of automated text mining with limited manual curation, opening up new opportunities for generating and modeling chem. toxicol. data.

Chemical Research in Toxicology published new progress about Chemoinformatics. 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, Recommanded Product: 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Ni, Penghui published the artcileMetal-Free Three-Component Selenopheno[2,3-b]indole Formation through Double C-H Selenylation with Selenium Powder, Recommanded Product: 3-Acetylthiophene, the main research area is aromatic ketone indole selenium iodobromide regioselective selenylation heterocyclization; aryl selenophenoindole preparation.

A facile metal-free entry to novel selenopheno[2,3-b]indole motif was described. The three-component assembly of indoles, aromatic ketones and selenium powder were enabled by the IBr-promoted highly selective double C-H selenylation/annulation. This protocol provided a novel access to a diverse variety of selenopheno[2,3-b]indoles with good efficacy and broad functional group compatibility.

Advanced Synthesis & Catalysis published new progress about Heterocyclic compounds, nitrogen-selenium Role: PRP (Properties), RCT (Reactant), SPN (Synthetic Preparation), RACT (Reactant or Reagent), PREP (Preparation). 1468-83-3 belongs to class benzothiophene, name is 3-Acetylthiophene, and the molecular formula is C6H6OS, Recommanded Product: 3-Acetylthiophene.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Aleo, Michael D. published the artcileEvaluating the role of multidrug resistance protein 3 (MDR3) inhibition in predicting drug-induced liver injury using 125 pharmaceuticals, Name: 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, the main research area is MDR3 inhibition screening drug induced liver injury risk assessment; ABCB4 inhibitor screening drug induced liver injury prognosis.

The role of bile salt export protein (BSEP) inhibition in drug-induced liver injury (DILI) has been investigated widely, while inhibition of the canalicular multidrug resistant protein 3 (MDR3) has received less attention. This transporter plays a pivotal role in secretion of phospholipids into bile and functions coordinately with BSEP to mediate the formation of bile acid-containing biliary micelles. Therefore, inhibition of MDR3 in human hepatocytes was examined across 125 drugs (70 of Most-DILI-concern and 55 of No-DILI-concern). Of these tested, 41% of Most-DILI-concern and 47% of No-DILI-concern drugs had MDR3 IC50 values of <50 μM. A better distinction across DILI classifications occurred when systemic exposure was considered where safety margins of 50-fold had low sensitivity (0.29), but high specificity (0.96). Anal. of phys. chem. property space showed that basic compounds were twice as likely to be MDR3 inhibitors as acids, neutrals, and zwitterions and that inhibitors were more likely to have polar surface area (PSA) values of <100 Å2 and cPFLogD values between 1.5 and 5. These descriptors, with different cutoffs, also highlighted a group of compounds that shared dual potency as MDR3 and BSEP inhibitors. Nine drugs classified as Most-DILI-concern compounds (four withdrawn, four boxed warning, and one liver injury warning in their approved label) had intrinsic potency features of <20 μM in both assays, thereby reinforcing the notion that multiple inhibitory mechanisms governing bile formation (bile acid and phospholipid efflux) may confer addnl. risk factors that play into more severe forms of DILI as shown by others for BSEP inhibitors combined with multidrug resistance-associated protein (MRP2, MRP3, MRP4) inhibitory properties. Avoiding phys. property descriptors that highlight dual BSEP and MDR3 inhibition or testing drug candidates for inhibition of multiple efflux transporters (e.g., BSEP, MDR3, and MRPs) may be an effective strategy for prioritizing drug candidates with less likelihood of causing clin. DILI. Chemical Research in Toxicology published new progress about Bile (formation). 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, Name: 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Das, Pradipta published the artcileDramatic Effect of γ-Heteroatom Dienolate Substituents on Counterion Assisted Asymmetric Anionic Amino-Cope Reaction Cascades, Application In Synthesis of 1468-83-3, the main research area is counterion assisted anionic cascade Mannich reaction Cope rearrangement cyclization.

We report a dramatic effect on product outcomes of the lithium ion enabled amino-Cope-like anionic asym. cascade when different γ-dienolate heteroatom substituents are employed. For dienolates with azide, thiomethyl, and trifluoromethylthiol substituents, a Mannich/amino-Cope/cyclization cascade ensues to form chiral cyclohexenone products with two new stereocenters in an anti-relationship. For fluoride-substituted nucleophiles, a Mannich/amino-Cope cascade proceeds to afford chiral acyclic products with two new stereocenters in a syn-relationship. Bromide- and chloride-substituted nucleophiles appear to proceed via the same pathway as the fluoride albeit with the added twist of a 3-exo-trig cyclization to yield chiral cyclopropane products with three stereocenters. When this same class of nucleophiles is substituted with a γ-nitro group, the Mannich-initiated cascade is now diverted to a β-lactam product instead of the amino-Cope pathway. These anionic asym. cascades are solvent- and counterion-dependent, with a lithium counterion being essential in combination with ethereal solvents such as MTBE and CPME. By altering the geometry of the imine double bond from E to Z, the configurations at the R1 and X stereocenters are flipped. Mechanistic, computational, substituent, and counterion studies suggest that these cascades proceed via a common Mannich-product intermediate, which then proceeds via either a chair (X = N3, SMe, or SCF3) or boat-like (X = F, Cl, or Br) transition state to afford amino-Cope-like products or β-lactam in the case of X = NO2.

Journal of the American Chemical Society published new progress about Chiral auxiliary. 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

Shin, Young G. published the artcileComparison of metabolic soft spot predictions of CYP3A4, CYP2C9 and CYP2D6 substrates using MetaSite and StarDrop, Safety of 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, the main research area is site of metabolism CYP3A4 CYP2C9 CYP2D6 substrate MetaSite StarDrop.

Metabolite identification study plays an important role in determining the sites of metabolic liability of new chem. entities (NCEs) in drug discovery for lead optimization. Here we compare the two predictive software, MetaSite and StarDrop, available for this purpose. They work very differently but are used to predict the site of oxidation by major human cytochrome P 450 (CYP) isoforms. Neither software can predict non-CYP catalyzed metabolism nor the rates of metabolism For the purpose of comparing the two software packages, we tested known probe substrate for these enzymes, which included 12 substrates of CYP3A4 and 18 substrates of CYP2C9 and CYP2D6 were analyzed by each software and the results were compared. It is possible that these known substrates were part of the training set but we are not aware of it. To assess the performance of each software we assigned a point system for each correct prediction. The total points assigned for each CYP isoform exptl. were compared as a percentage of the total points assigned theor. for the first choice prediction for all substrates for each isoform. Our results show that MetaSite and StarDrop are similar in predicting the correct site of metabolism by CYP3A4 (78% vs 83%, resp.). StarDrop appears to do slightly better in predicting the correct site of metabolism by CYP2C9 and CYP2D6 metabolism (89% and 93%, resp.) compared to MetaSite (63% and 70%, resp.). The sites of metabolism (SOM) from 34 inhouse NCEs incubated in human liver microsomes or human hepatocytes were also evaluated using two prediction software packages and the results showed comparable SOM predictions. What makes this comparison challenging is that the contribution of each isoform to the intrinsic clearance (Clint) is not known. Overall the software were comparable except for MetaSite performing better for CYP2D6 and that MetaSite has a liver model that is absent in StarDrop that predicted with 82% accuracy.

Combinatorial Chemistry & High Throughput Screening published new progress about Computer program (MetaSite). 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, Safety of 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Patel, Pitambar published the artcileWater-Mediated ortho-Carboxymethylation of Aryl Ketones under Ir(III)-Catalytic Conditions: Step Economy Total Synthesis of Cytosporones A-C, SDS of cas: 1468-83-3, the main research area is aryl ketone diazotized Meldrum’s acid iridium carboxymethylation alkylation mechanism; carboxymethyl acetophenone preparation; cytosporone total synthesis.

An expeditious Ir(III)-catalyzed carboxymethylation of aryl ketone with diazotized Meldrum’s acid has been developed in aqueous medium. Flavanone and chromanone were also found to be facile substrates with the developed catalytic system. Mechanistic studies revealed the active catalytic species and the role of water in the reaction process as hydroxy and proton sources. Employing the developed method, total synthesis of cytosporone A was achieved in two steps and that of cytosporones B-C was achieved in three steps starting from resorcinol.

Journal of Organic Chemistry published new progress about Alkylation. 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

Dang, Na Le published the artcileComputational Approach to Structural Alerts: Furans, Phenols, Nitroaromatics, and Thiophenes, Formula: C13H8Cl2O4S, the main research area is furan phenol nitroarom thiophene metabolism toxicity modeling toxicophore.

Structural alerts are commonly used in drug discovery to identify mols. likely to form reactive metabolites, and thereby become toxic. Unfortunately, as useful as structural alerts are, they do not effectively model if, when, and why metabolism renders safe mols. toxic. Toxicity due to a specific structural alert is highly conditional, depending on the metabolism of the alert, the reactivity of its metabolites, dosage, and competing detoxification pathways. A systems approach, which explicitly models these pathways, could more effectively assess the toxicity risk of drug candidates. In this study, the authors demonstrated that math. models of P 450 metabolism can predict the context-specific probability that a structural alert will be bioactivated in a given mol. This study focuses on the furan, phenol, nitroarom., and thiophene alerts. Each of these structural alerts can produce reactive metabolites through certain metabolic pathways, but not always. The authors tested whether the metabolism modeling approach, XenoSite, can predict when a given mol.’s alerts will be bioactivated. Specifically, the authors used models of epoxidation, quinone formation, reduction, and sulfur-oxidation to predict the bioactivation of furan-, phenol-, nitroarom.-, and thiophene-containing drugs. The authors’ models separated bioactivated and not-bioactivated furan-, phenol-, nitroarom.-, and thiophene-containing drugs with AUC performances of 100%, 73%, 93%, and 88%, resp. Metabolism models accurately predict whether alerts are bioactivated and thus serve as a practical approach to improve the interpretability and usefulness of structural alerts. The authors expect that this same computational approach can be extended to most other structural alerts and later integrated into toxicity risk models. This advance is one necessary step towards the authors’ long-term goal of building comprehensive metabolic models of bioactivation and detoxification to guide assessment and design of new therapeutic mols.

Chemical Research in Toxicology published new progress about Biological detoxification. 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

Bonierbale, Eric published the artcileOpposite Behaviors of Reactive Metabolites of Tienilic Acid and Its Isomer toward Liver Proteins: Use of Specific Anti-Tienilic Acid-Protein Adduct Antibodies and the Possible Relationship with Different Hepatotoxic Effects of the Two Compounds, Recommanded Product: 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, the main research area is tienilic acid hepatotoxicity immunity cytochrome P450.

Tienilic acid (TA) is responsible for an immune-mediated drug-induced hepatitis in humans, while its isomer (TAI) triggers a direct hepatitis in rats. In this study, we describe an immunol. approach developed for studying the specificity of the covalent binding of these two compounds For this purpose, two different coupling strategies were used to obtain TA-carrier protein conjugates. In the first strategy, the drug was linked through its carboxylic acid function to amine residues of carrier proteins (BSA-N-TA and casein-N-TA), while in the second strategy, the thiophene ring of TA was attached to proteins through a short 3-thiopropanoyl linker, the corresponding conjugates (BSA-S-5-TA and βLG-S-5-TA) thus preferentially presenting the 2,3-dichlorophenoxyacetic moiety of the drug for antibody recognition. The BSA-S-5-TA conjugate proved to be 30 times more immunogenic than BSA-N-TA. Anti-TA-protein adduct antibodies were obtained after immunization of rabbits with BSA-S-5-TA (1/35000 titer against βLG-S-5-TA in ELISA). These antibodies strongly recognized the 2,3-dichlorophenoxyacetic moiety of TA but poorly the part of the drug engaged in the covalent binding with the proteins. This powerful tool was used in immunoblots to compare TA or TAI adduct formation in human liver microsomes as well as on microsomes from yeast expressing human liver cytochrome P 450 2C9. TA displayed a highly specific covalent binding focused on P 450 2C9 which is the main cytochrome P 450 responsible for its hepatic activation in humans. On the contrary, TAI showed a nonspecific alkylation pattern, targeting many proteins upon metabolic activation. Nevertheless, this nonspecific covalent binding could be completely shifted to a thiol trapping agent like GSH. The difference in alkylation patterns for these two compounds is discussed with regard to their distinct toxicities. A relationship between the specific covalent binding of P 450 2C9 by TA and the appearance of the highly specific anti-LKM2 autoantibodies (known to specifically recognize P 450 2C9) in patients affected with TA-induced hepatitis is strongly suggested.

Chemical Research in Toxicology published new progress about Caseins Role: ADV (Adverse Effect, Including Toxicity), BUU (Biological Use, Unclassified), RCT (Reactant), BIOL (Biological Study), USES (Uses), RACT (Reactant or Reagent) (conjugate with tienilic acid). 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, Recommanded Product: 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem