Synlett
DOI: 10.1055/a-2325-3938
letter

Discovery of the Lysosome-Inhibiting Function of Acremolactone B

Shaonan Wang
1   School of Pharmacy, East China University of Science and Technology, Shanghai, China (Ringgold ID: RIN47860)
,
Yali Wu
1   School of Pharmacy, East China University of Science and Technology, Shanghai, China (Ringgold ID: RIN47860)
,
Mengyu Ba
2   State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Shanghai, China (Ringgold ID: RIN58309)
,
Zhou Xu
2   State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Shanghai, China (Ringgold ID: RIN58309)
,
Guoxing Gu
2   State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Shanghai, China (Ringgold ID: RIN58309)
,
William G. Whittingham
3   Jealott’s Hill International Research Centre, Syngenta UK Ltd, Bracknell, United Kingdom of Great Britain and Northern Ireland (Ringgold ID: RIN10502)
,
Cong Liu
2   State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Shanghai, China (Ringgold ID: RIN58309)
,
Ang Li
2   State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Shanghai, China (Ringgold ID: RIN58309)
,
Weiwei He
1   School of Pharmacy, East China University of Science and Technology, Shanghai, China (Ringgold ID: RIN47860)
› Institutsangaben

Lysosome inhibitors have garnered considerable interest for their utility in lysosome biology research and potential therapeutic applications. We discovered the lysosome-inhibiting function of acremolactone B (1), a scarce azaphilone-type polyketide, leveraging our previous scalable synthesis. This compound significantly reduces lysosomal acidity and impairs the maturation of the lysosomal protease cathepsin D (CTSD) in triple-negative breast cancer cells (MDA-MB-231) and human lung cancer cells (A549). Furthermore, we found that compound 1 suppresses downstream autophagy, as revealed by monitoring autophagic flux and conducting transmission electron microscopy (TEM) analysis. This study unveils the previously unrecognized biological role of 1 and introduces a new scaffold for lysosome inhibitors.



Publikationsverlauf

Eingereicht: 26. April 2024

Angenommen nach Revision: 13. Mai 2024

Accepted Manuscript online:
13. Mai 2024

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