Synthesis and evaluation of novel benzotropolones as Atg4B inhibiting autophagy blockers.

Abstract:

: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.

journal_name

Bioorg Chem

journal_title

Bioorganic chemistry

authors

Tanc M,Cleenewerck M,Kurdi A,Roelandt R,Declercq W,De Meyer G,Augustyns K,Martinet W,Van der Veken P

doi

10.1016/j.bioorg.2019.03.021

subject

Has Abstract

pub_date

2019-06-01 00:00:00

pages

163-168

eissn

0045-2068

issn

1090-2120

pii

S0045-2068(18)31336-1

journal_volume

87

pub_type

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