Identification of a Privileged Scaffold for Induction of Lysosomal Biogenesis through Synthesis of the Scaffold of Cipadonoid A
This study presents a streamlined stereoselective synthesis strategy for constructing the highly congested cage-like tetracyclic core of cipadonoid A, employing visible-light photoredox catalysis to enable intramolecular Giese-type radical cyclization as a key step. Density Functional Theory (DFT) analysis revealed that the selective formation of the <i>cis</i>-fused AB bicyclic framework is controlled by intramolecular hydrogen bonding-mediated conformational stabilization. Notably, the synthesized B,D-seco-limonoid scaffold exhibited lysosomal biogenesis enhancing activity on par with its natural counterpart, with comparative bioassays demonstrating equivalent efficacy between the synthetic derivative and native cipadonoid A (<b>1</b>) in promoting lysosomal biogenesis.
Authors
- Zuwei Song (ORCID: https://orcid.org/0009-0009-7524-4898)
- Ying‐Tong Di (ORCID: https://orcid.org/0000-0001-5766-0198)
- Xiao Ding (ORCID: https://orcid.org/0000-0002-5512-2131)
- Xiao‐Jiang Hao (ORCID: https://orcid.org/0000-0001-9496-2152)
- Xinyu Tan (ORCID: https://orcid.org/0000-0001-9338-6608)
- Hong Liang (ORCID: https://orcid.org/0000-0002-0579-8651)
- Zhen Jun Yang (ORCID: https://orcid.org/0000-0001-8036-934X)
- Zhongchao Zhang (ORCID: https://orcid.org/0000-0001-5017-5691)
- Lili Xu (ORCID: https://orcid.org/0000-0001-8759-1568)
- Hao‐Jing Zang
Institutions
- Nanjing Agricultural University (CN)
- Academy of Medical Sciences (GB)
- Kunming Institute of Botany (CN)
- Kunming University (CN)
- Chinese Academy of Sciences (CN)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Peking University (CN)
- Institute of Organic Chemistry with Centre of Phytochemistry (BG)
- Shenzhen Bay Laboratory (CN)
- Beijing National Laboratory for Molecular Sciences (CN)
- Peking University Shenzhen Hospital (CN)
- State Key Laboratory of Chemical Engineering (CN)
- University of Chinese Academy of Sciences (CN)
Publication Details
- Journal
- Organic Letters
- Published
- 2025-06-02
- DOI
- https://doi.org/10.1021/acs.orglett.5c01602
- Primary Topic
- Phytochemical compounds biological activities
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Natural Science Foundation of China
- Natural Science Foundation of Guangdong Province
- Chinese Academy of Medical Sciences
- Science, Technology and Innovation Commission of Shenzhen Municipality
- Yunnan Key Research and Development Program
- West Light Foundation of the Chinese Academy of Sciences
- Shenzhen-Hong Kong Institute of Brain Science
- Shenzhen Bay Laboratory