- Synthesis and evaluation of novel benzotropolones as Atg4B inhibiting autophagy blockers
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Autophagy is an intracellular degradation/recycling pathway that provides nutrients and building blocks to cellular metabolism and keeps the cytoplasm clear of obsolete proteins and organelles. During recent years, dysregulated autophagy activity has been reported to be a characteristic of many different disease types, including cancer and neurodegenerative disorders. This has created a strong case for development of autophagy modulating compounds as potential treatments for these diseases. Inhibitors of autophagy have been proposed as a therapeutic intervention in, e.g., advanced cancer, and inhibiting the cysteine protease Atg4B has been put forward as a main strategy to block autophagy. We recently identified and demonstrated -both in vitro and in vivo - that compounds with a benzotropolone basic structure targeting Atg4B, can significantly slow down tumor growth and potentiate the effect of classical chemotherapy. In this study we report the synthesis and inhibition profile of new benzotropolone derivatives with additional structural modifications at 6 different positions. To obtain a solid inhibition profile, all compounds were evaluated on three levels, including two cell-based assays to confirm autophagy and intracellular Atg4B inhibition and an SDS-PAGE-based experiment to assess in vitro Atg4B affinity. Several molecules with a promising profile were identified.
- Tanc, Muhammet,Cleenewerck, Matthias,Kurdi, Ammar,Roelandt, Ria,Declercq, Wim,De Meyer, Guido,Augustyns, Koen,Martinet, Wim,Van der Veken, Pieter
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p. 163 - 168
(2019/03/19)
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- HALOGENATED BENZOTROPOLONES AS ATG4B INHIBITORS
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The present invention relates to compounds having a benzotropolone core, and compositions containing said compounds acting as ATG4B inhibitors, thereby inhibiting autophagy. Moreover, the present invention provides processes for the preparation of the disclosed compounds, as well as methods of using them, for instance as a medicine, in particular for the treatment of cell proliferative disorders, such as cancer.
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- Method of treating hemoglobinopathies
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A therapeutic process for treating anemias in primates, including man, particularly those anemias of genetic origin including sickle-cell anemia, which comprises administering to an anemic primate an amount of a polyhydroxy benzoic, mandelic or phenylacetic acid derivative as specified at a dose level sufficient to increase fetal hemoglobin.
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