2. Academic Validation
  3. Discovery of tetrasubstituted thiophenes as Cisd2 activators: A potential novel therapeutic option in nonalcoholic fatty liver disease

Discovery of tetrasubstituted thiophenes as Cisd2 activators: A potential novel therapeutic option in nonalcoholic fatty liver disease

  • Eur J Med Chem. 2023 Oct 5;258:115583. doi: 10.1016/j.ejmech.2023.115583.
Chun-Hsu Yao 1,  Zhao-Qing Shen 2,  Yesudoss Christu Rajan 1,  Yu-Wen Huang 1,  Chin-Yu Lin 1,  Jen-Shin Song 1,  Hui-Yi Shiao 1,  Yi-Yu Ke 1,  Yu-Shiou Fan 1,  Chi-Hui Tsai 1,  Teng-Kuang Yeh 3,  Ting-Fen Tsai 4,  Jinq-Chyi Lee 5
Affiliations

Affiliations

  • 1 Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli, 350, Taiwan.
  • 2 Department of Life Sciences and Institute of Genome Sciences, National Yang Ming Chiao Tung University, Taipei, 11221, Taiwan.
  • 3 Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli, 350, Taiwan. Electronic address: tkyeh@nhri.edu.tw.
  • 4 Department of Life Sciences and Institute of Genome Sciences, National Yang Ming Chiao Tung University, Taipei, 11221, Taiwan; Institute of Molecular and Genomic Medicine, National Health Research Institutes, Miaoli, 350, Taiwan; Center for Healthy Longevity and Aging Sciences, National Yang Ming Chiao Tung University, Taipei, 11221, Taiwan. Electronic address: tftsai@nycu.edu.tw.
  • 5 Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli, 350, Taiwan. Electronic address: jinqchyi@nhri.edu.tw.
PMID: 37393792 DOI: 10.1016/j.ejmech.2023.115583
Abstract

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.

Keywords

Cisd2 activator; Nonalcoholic fatty liver disease; Tetrasubstituted thiophene.

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