Day: November 18, 2022

Nishiya, Takayoshi published the artcileTienilic Acid Enhances Hyperbilirubinemia in Eisai Hyperbilirubinuria Rats through Hepatic Multidrug Resistance-Associated Protein 3 and Heme Oxygenase-1 Induction, Recommanded Product: 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, the main research area is diuretic tienilic acid hyperbilirubinemia liver MRP3 heme oxygenase hepatotoxicity.

We demonstrated that tienilic acid, a diuretic drug withdrawn from the market because of hepatic failure, enhanced hyperbilirubinemia in Eisai hyperbilirubinuria rats (EHBR) with a defect of canalicular multidrug resistance-associated protein 2 (Mrp2). In contrast, no remarkable changes were noted in Sprague-Dawley (SD) rats, the parent strain for EHBR. To investigate a mechanism underlying this enhanced hyperbilirubinemia, we focused on comprehensive effects of tienilic acid on clinicopathol. aspects and expression of hepatic transporters. Other than eventual hyperbilirubinemia with slightly increased biliary bilirubin, a single oral treatment of EHBR with tienilic acid at 300 mg/kg caused no changes in serum alanine aminotransferase and alk. phosphatase, bile flow rate and biliary bile acid secretion, or hepatic morphol. In analyses of mRNA expression of the hepatic transporters, elevated Mrp3 expression in EHBR correlated with an increase in serum total bilirubin, suggesting increased bilirubin transport from the liver into the peripheral blood flow. Hepatic heme oxygenase-1 (Ho-1) mRNA, a stress-induced isoform of the rate-limiting enzyme in the catabolism of heme to bilirubin, was markedly upregulated in EHBR at the same dose at which increased serum bilirubin was seen. A time-course study revealed that marked induction of Ho-1 occurred earlier than that of Mrp3, followed by an increase in serum bilirubin. These results suggest that hepatic Mrp3 and Ho-1 may contribute to tienilic acid-enhanced hyperbilirubinemia in EHBR by inducing increased bilirubin transport from the liver into the blood stream, preceded by potentiation of bilirubin formation in the liver.

Toxicological Sciences published new progress about Diuretics. 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

Nishiya, Takayoshi published the artcileInvolvement of cytochrome P450-mediated metabolism in tienilic acid hepatotoxicity in rats, Recommanded Product: 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, the main research area is tienilic acid glutathione adduct hepatotoxicity CYP450.

Tienilic acid is reported to be converted into electrophilic metabolites by cytochrome P 450 (CYP) in vitro. In vivo, however, the metabolites have not been detected and their effect on liver function is unknown. We previously demonstrated that tienilic acid decreased the GSH level and upregulated genes responsive to oxidative/electrophilic stresses, such as heme oxygenase-1 (Ho-1), glutamate-cysteine ligase modifier subunit (Gclm) and NAD(P)H dehydrogenase quinone 1 (Nqo1), in rat liver, as well as inducing hepatotoxicity by co-treatment with the glutathione biosynthesis inhibitor -buthionine-(S,R)-sulfoximine (BSO). In this study, for the first time, we identified a glutathione-tienilic acid adduct, a stable conjugate of putative electrophilic metabolites with glutathione (GSH), in the bile of rats given a single oral dose of tienilic acid (300 mg/kg). Furthermore, a tienilic acid-induced decrease in the GSH level and upregulation of Ho-1, Gclm and Nqo1 were completely blocked by pretreatment with the CYP inhibitor 1-aminobenzotriazole (ABT, 66 mg/kg, i.p.). The increase in the serum ALT level and hepatocyte necrosis resulting from the combined dosing of BSO and tienilic acid was prevented by ABT, despite a low hepatic GSH level. These findings suggest that the electrophilic metabolites of tienilic acid produced by CYP induce electrophilic/oxidative stresses in the rat liver and this contributes to the hepatotoxicity of tienilic acid under impaired GSH biosynthesis.

Toxicology Letters published new progress about Diuretics. 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

Koen, Yakov M. published the artcileIdentification of Protein Targets of Reactive Metabolites of Tienilic Acid in Human Hepatocytes, Related Products of benzothiophene, the main research area is tienilic acid reactive metabolite hepatotoxicity protein target.

Tienilic acid (TA) is a uricosuric diuretic that was withdrawn from the market only months after its introduction because of reports of serious incidents of drug-induced liver injury including some fatalities. Its hepatotoxicity is considered to be primarily immunoallergic in nature. Like other thiophene compounds, TA undergoes biotransformation to a S-oxide metabolite which then reacts covalently with cellular proteins. To identify protein targets of TA metabolites, we incubated [14C]-TA with human hepatocytes, separated cellular proteins by 2D gel electrophoresis, and analyzed proteins in 36 radioactive spots by tryptic digestion followed by LC-MS/MS. Thirty-one spots contained at least one identifiable protein. Sixteen spots contained only one of 14 nonredundant proteins which were thus considered to be targets of TA metabolites. Six of the 14 were also found in other radioactive spots that contained from 1 to 3 addnl. proteins. Eight of the 14 had not been reported to be targets for any reactive metabolite other than TA. The other 15 spots each contained from 2 to 4 identifiable proteins, many of which are known targets of other chem. reactive metabolites, but since adducted peptides were not observed, the identity of the adducted protein(s) in these spots is ambiguous. Interestingly, all the radioactive spots corresponded to proteins of low abundance, while many highly abundant proteins in the mixture showed no radioactivity. Furthermore, of approx. 16 previously reported protein targets of TA in rat liver, only one (fumarylacetoacetase) is among the 14 targets identified in this work. One reason for this difference may be statistical, given that each study identified a small number of targets from among thousands present in hepatocytes. Another may be the species difference (i.e., rat vs human), and still another may be the method of detection of adducted proteins (i.e., Western blot vs C-14). Knowledge of human target proteins is very limited. Of more than 350 known protein targets of reactive metabolites, only 42 are known from humans, and only 21 of these are known to be targets for more than one chem. Nevertheless, the demonstration that human target proteins can be identified using isolated hepatocytes in vitro should enable the question of species differences to be addressed more fully in the future.

Chemical Research in Toxicology published new progress about Diuretics. 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, Related Products of benzothiophene.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Zhu, Xiao published the artcileConstruction and analysis of a human hepatotoxicity database suitable for QSAR modeling using post-market safety data, Formula: C13H8Cl2O4S, the main research area is human hepatotoxicity database liver injury; Drug-induced liver injury; Post-market safety; Predictive toxicology; QSAR.

Drug-induced liver injury (DILI) is one of the most common drug-induced adverse events (AEs) leading to life-threatening conditions such as acute liver failure. It has also been recognized as the single most common cause of safety-related post-market withdrawals or warnings. Efforts to develop new predictive methods to assess the likelihood of a drug being a hepatotoxicant have been challenging due to the complexity and idiosyncrasy of clin. manifestations of DILI. The FDA adverse event reporting system (AERS) contains post-market data that depict the morbidity of AEs. Here, we developed a scalable approach to construct a hepatotoxicity database using post-market data for the purpose of quant. structure-activity relation (QSAR) modeling. A set of 2029 unique and modelable drug entities with 13,555 drug-AE combinations was extracted from the AERS database using 37 hepatotoxicity-related query preferred terms (PTs). To determine the optimal classification scheme to partition pos. from neg. drugs, a manually-curated DILI calibration set composed of 105 negatives and 177 positives was developed based on the published literature. The final classification scheme combines hepatotoxicity-related PT data with supporting information that optimize the predictive performance across the calibration set. Data for other toxicol. endpoints related to liver injury such as liver enzyme abnormalities, cholestasis, and bile duct disorders, were also extracted and classified. Collectively, these datasets can be used to generate a battery of QSAR models that assess a drug’s potential to cause DILI.

Toxicology published new progress about Databases. 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

Wu, Qihui published the artcileIn silico identification and mechanism exploration of hepatotoxic ingredients in traditional Chinese medicine, Name: 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, the main research area is hepatotoxic ingredient traditional Chinese medicine; consensus model; hepatotoxicity mechanism; herb induced liver injury; in silico; traditional chinese medicine.

Backgrounds and Aims: Recently, a growing number of hepatotoxicity cases aroused by Traditional Chinese Medicine (TCM) have been reported, causing increasing concern. To date, the reported predictive models for drug induced liver injury show low prediction accuracy and there are still no related reports for hepatotoxicity evaluation of TCM systematically. Addnl., the mechanism of herb induced liver injury (HILI) still remains unknown. The aim of the study was to identify potential hepatotoxic ingredients in TCM and explore the mol. mechanism of TCM against HILI. Materials and Methods: In this study, we developed consensus models for HILI prediction by integrating the best single classifiers. The consensus model with best performance was applied to identify the potential hepatotoxic ingredients from the Traditional Chinese Medicine Systems Pharmacol. database (TCMSP). Systems pharmacol. analyses, including multiple network construction and KEGG pathway enrichment, were performed to further explore the hepatotoxicity mechanism of TCM. Results: 16 single classifiers were built by combining four machine learning methods with four different sets of fingerprints. After systematic evaluation, the best four single classifiers were selected, which achieved a Matthews correlation coefficient (MCC) value of 0.702, 0.691, 0.659, and 0.717, resp. To improve the predictive capacity of single models, consensus prediction method was used to integrate the best four single classifiers. Results showed that the consensus model C-3 (MCC = 0.78) outperformed the four single classifiers and other consensus models. Subsequently, 5,666 potential hepatotoxic compounds were identified by C-3 model. We integrated the top 10 hepatotoxic herbs and discussed the hepatotoxicity mechanism of TCM via systems pharmacol. approach. Finally, Chaihu was selected as the case study for exploring the mol. mechanism of hepatotoxicity. Conclusion: Overall, this study provides a high accurate approach to predict HILI and an in silico perspective into understanding the hepatotoxicity mechanism of TCM, which might facilitate the discovery and development of new drugs.

Frontiers in Pharmacology published new progress about Bupleurum. 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

Castellanos-Soriano, Jorge published the artcilePhotoredox catalysis powered by triplet fusion upconversion: arylation of heteroarenes, Related Products of benzothiophene, the main research area is furan thiophene arylation photoredox catalysis; Arylations; Furans; Photon upconversion; Photoredox catalysis; Thiophenes; Triplet fusion (triplet–triplet annihilation); Visible light.

In this work, the feasibility of triplet fusion upconversion (TFU, also named triplet-triplet annihilation upconversion) technol. for the functionalization (arylation) of furans and thiophenes has been successfully proven. Activation of aryl halides by TFU leads to generation of aryl radical intermediates; trapping of the latter by the corresponding heteroarenes, which act as nucleophiles, affords the final coupling products. Advantages of this photoredox catalytic method include the use of very mild conditions (visible light, standard conditions), employment of com. available reactants and low-loading metal-free photocatalysts, absence of any sacrificial agent (additive) in the medium and short irradiation times. The involvement of the high energetic delayed fluorescence in the reaction mechanism has been evidenced by quenching studies, whereas the two-photon nature of this photoredox arylation of furans and thiophenes has been manifested by the dependence on the energy source power. Finally, the scaling-up conditions have been gratifyingly afforded by a continuous-flow device.

Photochemical & Photobiological Sciences published new progress about Arylation. 1468-83-3 belongs to class benzothiophene, name is 3-Acetylthiophene, and the molecular formula is C6H6OS, Related Products of benzothiophene.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Whitby, Landon R. published the artcileQuantitative Chemical Proteomic Profiling of the in Vivo Targets of Reactive Drug Metabolites, Synthetic Route of 40180-04-9, the main research area is troglitazone acetaminophen clozapine tienilate hepatotoxicity proteomic profiling drug metabolite.

Idiosyncratic liver toxicity represents an important problem in drug research and pharmacotherapy. Reactive drug metabolites that modify proteins are thought to be a principal factor in drug-induced liver injury. Here, the authors describe a quant. chem. proteomic method to identify the targets of reactive drug metabolites in vivo. Treating mice with clickable analogs of four representative hepatotoxic drugs, the authors demonstrate extensive covalent binding that is confined primarily to the liver. Each drug exhibited a distinct target profile that, in certain cases, showed strong enrichment for specific metabolic pathways (e.g., lipid/sterol pathways for troglitazone). Site-specific proteomics revealed that acetaminophen reacts with high stoichiometry with several conserved, functional (seleno)cysteine residues throughout the liver proteome. The authors’ findings thus provide an advanced exptl. framework to characterize the proteomic reactivity of drug metabolites in vivo, revealing target profiles that may help to explain mechanisms and identify risk factors for drug-induced liver injury.

ACS Chemical Biology published new progress about Apoptosis. 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

Huang, Chun published the artcileI2/CuCl2-Copromoted Formal [4 + 1 + 1] Cyclization of Methyl Ketones, 2-Aminobenzonitriles and Ammonium Acetate: Direct Access to 2-Acyl-4-aminoquinazolines, Computed Properties of 1468-83-3, the main research area is aminoquinazolinyl aryl methanone preparation; aryl ethanone aminobenzonitrile ammonium acetate cyclization.

An I2/CuCl2-copromoted diamination of C(sp3)-H bonds for the preparation of 2-acyl-4-aminoquinazolines I [Ar = Ph, 1-naphthyl, 4-MeOC6H4, etc.; R = 8-Me, 6-Cl, 7-MeO, etc.] from Me ketones, 2-aminobenzonitriles, and ammonium acetate was reported. This reaction featured operational simplicity, com. available substrates, mild reaction conditions, and good functional group compatibility. Mechanistic studies indicated that CuCl2 played a pivotal role in this transformation. This study uses a Me group as a novel input to construct 2-acyl-4-aminoquinazoline derivatives for the first time.

Journal of Organic Chemistry published new progress about Amination. 1468-83-3 belongs to class benzothiophene, name is 3-Acetylthiophene, and the molecular formula is C6H6OS, Computed Properties of 1468-83-3.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Hu, Yongzhi published the artcileElectrochemical oxidative synthesis of 2-benzoylquinazolin-4(3H)-one via C(sp3)-H amination under metal-free conditions, Quality Control of 1468-83-3, the main research area is benzoylquinazolinone green preparation; aminobenzamide ketone electrochem oxidative amination TBAI catalyst.

An electrochem. induced C(sp3)-H amination of 2-aminobenzamides with ketones using TBAI as a catalyst was developed to provide 2-benzoylquinazolin-4(3H)-ones I [R1 = H, 6-F, 7-Me, etc.; R2 = Ph, 2-pyridyl, 3-MeC6H4, etc.] under metal-free conditions. The reaction proceeded using the relatively low-toxicity methanol as the solvent, employed mol. oxygen as the ideal green oxidant in a simple undivided cell and exhibited high atom economy.

Catalysis Science & Technology published new progress about Amination. 1468-83-3 belongs to class benzothiophene, name is 3-Acetylthiophene, and the molecular formula is C6H6OS, Quality Control of 1468-83-3.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem