Discovery of sp 3 -rich diazatricycloundecanes as lysosomotropic autophagy inhibitors

We have discovered lysosomotropic autophagy inhibitors from our compound library of sp -rich diazatricycloundecane skeletons. Compound 1u was identified as the most potent biological activity for LC3-II protein accumulation through the structure-activity relationships (SARs) for LC3-II protein accum...

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Bibliographic Details
Published inEuropean journal of medicinal chemistry Vol. 280; p. 116923
Main Authors Miura, Kazuki, Doi, Tomoya, Umedera, Kohei, Nakamura, Hiroyuki
Format Journal Article
LanguageEnglish
Published France 05.10.2024
Subjects
Lysosomotropic agent
Structure-activity relationship
sp-rich
Three-dimensional skeleton
Autophagy
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Summary:We have discovered lysosomotropic autophagy inhibitors from our compound library of sp -rich diazatricycloundecane skeletons. Compound 1u was identified as the most potent biological activity for LC3-II protein accumulation through the structure-activity relationships (SARs) for LC3-II protein accumulation and anti-proliferative activity at the three freely available substituents (R -R ) in the diazatricycloundecane skeleton. Compound 1u inhibited lysosome-dependent degradation without affecting autophagosome formation. Furthermore, compound 1u enlarged lysosomes and raised lysosomal pH similar to lysosomotropic agents such as chloroquine, resulting in inhibiting late-stage autophagy by inducing lysosomal dysfunction. Moreover, compound 1u exhibits excellent drug-like chemical properties, not previously reported for lysosomotropic agents.
ISSN:1768-3254