2. Academic Validation
  3. Synthesis and structural modification of the natural product Ivesinol to discover novel autophagy activators

Synthesis and structural modification of the natural product Ivesinol to discover novel autophagy activators

  • Eur J Med Chem. 2025 Feb 15:284:117180. doi: 10.1016/j.ejmech.2024.117180.
Zhi-Peng Wang 1,  Wenxin You 2,  Jie Peng 1,  Biao Xu 1,  Xiaohong Yang 3,  Wanyan Tang 4,  Yun He 5,  Aimin Yang 6,  Chao Yu 7,  Weiqi Nian 8
Affiliations

Affiliations

  • 1 College of Pharmacy, Chongqing Medical University, Chongqing, 400016, China.
  • 2 School of Medicine, Chongqing University, Chongqing, 400030, China.
  • 3 Chongqing Institute of Green and Intelligent Technology, Chinese Academy of Sciences, Chongqing, 400714, China.
  • 4 Department of Oncology, Chongqing Traditional Chinese Medicine Hospital, Chongqing, 400021, China.
  • 5 Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, School of Pharmaceutical Sciences, Chongqing University, Chongqing, 401331, China.
  • 6 School of Life Sciences, Chongqing University, Chongqing, 401331, China. Electronic address: aimin.yang@cqu.edu.cn.
  • 7 College of Pharmacy, Chongqing Medical University, Chongqing, 400016, China. Electronic address: yuchao@cqmu.edu.cn.
  • 8 Department of Oncology, Chongqing Traditional Chinese Medicine Hospital, Chongqing, 400021, China. Electronic address: nwqone@126.com.
PMID: 39724726 DOI: 10.1016/j.ejmech.2024.117180
Abstract

Autophagy is a lysosome-dependent cellular degradation pathway that responds to a variety of environmental and cellular stresses, which is defective in aging and age-related diseases, therefore, targeting Autophagy with small-molecule activators has potential therapeutic benefits. In this study, we successfully completed the first total synthesis of Ivesinol, an identified Antibacterial natural product, and efficiently constructed a library of its analogs. To measure the effect of Ivesinol analogs on autophagic activity, we performed cell imaging-based screening approach, and observed that several Ivesinol analogs exhibited potent autophagy-regulating activity. Specifically, the derivative B2 significantly activated Autophagy activity in concentration- and time-dependent manners, and even outperformed the commonly used activator Torin1 in activating Autophagy in MCF-7 cells at 0.5 μM. Bioinformatics analysis showed that B2 treatment significantly impacted ubiquitin mediated proteolysis and AMPK signaling pathway, with functionally related gene sets displaying strong correlations. Based on these findings, we proposed that B2 activates Autophagy by mechanisms involved in downregulation of key HSP70 family members, activation of the UPR, and ultimately leading to Autophagy. In conclusion, we suggest that B2 could be a promising and valuable Autophagy activator with significant potential for further development.

Keywords

Autophagy activator; Ivesinol; Natural product; Total synthesis.

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