Discovery of tetrasubstituted thiophenes as Cisd2 activators : A potential novel therapeutic option in nonalcoholic fatty liver disease
Copyright © 2023 Elsevier Masson SAS. All rights reserved..
Down-regulation of Cisd2 in the liver has been implicated in the development of nonalcoholic fatty liver disease (NAFLD) and increasing the level of Cisd2 is therefore a potential therapeutic approach to this group of diseases. Herein, we describe the design, synthesis, and biological evaluation of a series of Cisd2 activators, all thiophene analogs, based on a hit obtained using two-stage screening and prepared via either the Gewald reaction or by intramolecular aldol-type condensation of an N,S-acetal. Metabolic stability studies of the resulting potent Cisd2 activators suggest that thiophenes 4q and 6 are suitable for in vivo studies. The results from studies on 4q-treated and 6-treated Cisd2hKO-het mice, which carry a heterozygous hepatocyte-specific Cisd2 knockout, confirm that (1) there is a correlation between Cisd2 levels and NAFLD and (2) these compounds have the ability to prevent, without detectable toxicity, the development and progression of NAFLD.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:258 |
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| Enthalten in: |
European journal of medicinal chemistry - 258(2023) vom: 05. Okt., Seite 115583 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Yao, Chun-Hsu [VerfasserIn] |
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| Links: |
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| Themen: |
CISD2 protein, human |
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| Anmerkungen: |
Date Completed 28.07.2023 Date Revised 28.07.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.ejmech.2023.115583 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
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| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2023 Elsevier Masson SAS. All rights reserved. | ||
| 520 | |a Down-regulation of Cisd2 in the liver has been implicated in the development of nonalcoholic fatty liver disease (NAFLD) and increasing the level of Cisd2 is therefore a potential therapeutic approach to this group of diseases. Herein, we describe the design, synthesis, and biological evaluation of a series of Cisd2 activators, all thiophene analogs, based on a hit obtained using two-stage screening and prepared via either the Gewald reaction or by intramolecular aldol-type condensation of an N,S-acetal. Metabolic stability studies of the resulting potent Cisd2 activators suggest that thiophenes 4q and 6 are suitable for in vivo studies. The results from studies on 4q-treated and 6-treated Cisd2hKO-het mice, which carry a heterozygous hepatocyte-specific Cisd2 knockout, confirm that (1) there is a correlation between Cisd2 levels and NAFLD and (2) these compounds have the ability to prevent, without detectable toxicity, the development and progression of NAFLD | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Cisd2 activator | |
| 650 | 4 | |a Nonalcoholic fatty liver disease | |
| 650 | 4 | |a Tetrasubstituted thiophene | |
| 650 | 7 | |a Thiophenes |2 NLM | |
| 650 | 7 | |a CISD2 protein, human |2 NLM | |
| 700 | 1 | |a Shen, Zhao-Qing |e verfasserin |4 aut | |
| 700 | 1 | |a Rajan, Yesudoss Christu |e verfasserin |4 aut | |
| 700 | 1 | |a Huang, Yu-Wen |e verfasserin |4 aut | |
| 700 | 1 | |a Lin, Chin-Yu |e verfasserin |4 aut | |
| 700 | 1 | |a Song, Jen-Shin |e verfasserin |4 aut | |
| 700 | 1 | |a Shiao, Hui-Yi |e verfasserin |4 aut | |
| 700 | 1 | |a Ke, Yi-Yu |e verfasserin |4 aut | |
| 700 | 1 | |a Fan, Yu-Shiou |e verfasserin |4 aut | |
| 700 | 1 | |a Tsai, Chi-Hui |e verfasserin |4 aut | |
| 700 | 1 | |a Yeh, Teng-Kuang |e verfasserin |4 aut | |
| 700 | 1 | |a Tsai, Ting-Fen |e verfasserin |4 aut | |
| 700 | 1 | |a Lee, Jinq-Chyi |e verfasserin |4 aut | |
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