N-(Methyloxycarbonyl)thiophene sulfonamides as high affinity AT2 receptor ligands

Wannberg, Johan; Gising, Johan; Lindman, Jens; Salander, Jessica; Gutiérrez‐de‐Terán, Hugo; Ablahad, Hanin; Hamid, Selin; Grönbladh, Alfhild; Spizzo, Iresha; Gaspari, Tracey; Widdop, Robert E; Hallberg, Anders; Backlund, Maria; Leśniak, Anna; Hallberg, Mathias; Larhed, Mats

doi:10.1016/j.bmc.2020.115859

Cited by 7 publications

(3 citation statements)

References 60 publications

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“…Recently, a related example of an AT 2 R ligand with a meta substitution pattern and comprising a tether between the imidazole ring and the scaffold was reported. The latter ligand acted as an agonist with a K i of 9.3 nM and caused an AT 2 R-mediated concentration-dependent vasorelaxation of precontracted mouse aorta (Wannberg et al, 2021).…”

Section: B Nonpeptide Agonistsmentioning

confidence: 99%

The Angiotensin AT₂Receptor: From a Binding Site to a Novel Therapeutic Target

et al. 2022

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NF-jB to enter the nucleus and initiate transcription. Collectively, these events lead to reduced synthesis of proinflammatory cytokines and of cyclooxygenase 2 (COX-2), the enzyme that mediates synthesis of proinflammatory prostaglandins.Key Points related to Section III.C on intracellular signaling are:• The intracellular signaling pathways coupled to this atypical GPCR are equally atypical and very different from the canonical GPCR-mediated signaling events.

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Section: B Nonpeptide Agonistsmentioning

confidence: 99%

The Angiotensin AT₂Receptor: From a Binding Site to a Novel Therapeutic Target

et al. 2022

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“…5-Cyanobenzimidazole was effectively alkylated with 2,4′-dibromoacetophenone in an NaH–THF system at reflux resulting in the mixture of regioisomers obtained in a 90% yield [ 42 ]. The alkylation of 2-methyl-, 2-ethyl-, 2-isopropyl-, and 5,6-dimethylbenzimidazole with 2,3′-dibromoacetophenone in the K 2 CO 3 –DMF system at 80 °C afforded products in moderate yields (32–55%) [ 43 ].…”

Section: Introductionmentioning

confidence: 99%

N-Phenacyldibromobenzimidazoles—Synthesis Optimization and Evaluation of Their Cytotoxic Activity

et al. 2022

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Antifungal N-phenacyl derivatives of 4,6- and 5,6-dibromobenzimidazoles are interesting substrates in the synthesis of new antimycotics. Unfortunately, their application is limited by the low synthesis yields and time-consuming separation procedure. In this paper, we present the optimization of the synthesis conditions and purification methods of N-phenacyldibromobenzimidazoles. The reactions were carried out in various base solvent-systems including K2CO3, NaH, KOH, t-BuOK, MeONa, NaHCO3, Et3N, Cs2CO3, DBU, DIPEA, or DABCO as a base, and MeCN, DMF, THF, DMSO, or dioxane as a solvent. The progress of the reaction was monitored using HPLC analysis. The best results were reached when the reactions were carried out in an NaHCO3–MeCN system at reflux for 24 h. Additionally, the cytotoxic activity of the synthesized compounds against MCF-7 (breast adenocarcinoma), A-549 (lung adenocarcinoma), CCRF-CEM (acute lymphoblastic leukemia), and MRC-5 (normal lung fibroblasts) was evaluated. We observed that the studied cell lines differed in sensitivity to the tested compounds with MCF-7 cells being the most sensitive, while A-549 cells were the least sensitive. Moreover, the cytotoxicity of the tested derivatives towards CCRF-CEM cells increased with the number of chlorine or fluorine substituents. Furthermore, some of the active compounds, i.e., 2-(5,6-dibromo-1H-benzimidazol-1-yl)-1-(3,4-dichlorophenyl)ethanone (4f), 2-(4,6-dibromo-1H-benzimidazol-1-yl)-1-(2,4,6-trichlorophenyl)ethanone (5g), and 2-(4,6-dibromo-1H-benzimidazol-1-yl)-1-(2,4,6-trifluorophenyl)ethanone (5j) demonstrated pro-apoptotic properties against leukemic cells with derivative 5g being the most effective.

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“…____________________  Shehedyn M., Barabash O., Ostapiuk M. et al, 2022 Therefore, in recent years, extensive studies of the bioactivity of compounds containing the combination of thiophene and tetrazole cycles as selective inhibitors of histone deacetylase 6 [9] and CDK8 kinase [8]. This allows it to be considered as highly effective potential anticancer agents, as well as AT2 receptor ligands [14], antiinflammatory and antibacterial agents [5]. Therefore, it is still perspective to continue studying of synthesis and reactivity of the compounds containing the thiophene and tetrazole fragments combinations.…”

Section: Introductionmentioning

confidence: 99%