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Synthesis and evaluation of novel benzotropolones as Atg4B inhibiting autophagy blockers

(2019) BIOORGANIC CHEMISTRY. 87. p.163-168
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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.
Keywords
Autophagy, Atg4B, Benzotropolone, UAMC-2526, ENZYME

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MLA
Tanc, Muhammet et al. “Synthesis and Evaluation of Novel Benzotropolones as Atg4B Inhibiting Autophagy Blockers.” BIOORGANIC CHEMISTRY 87 (2019): 163–168. Print.
APA
Tanc, M., Cleenewerck, M., Kurdi, A., Roelandt, R., Declercq, W., De Meyer, G., Augustyns, K., et al. (2019). Synthesis and evaluation of novel benzotropolones as Atg4B inhibiting autophagy blockers. BIOORGANIC CHEMISTRY, 87, 163–168.
Chicago author-date
Tanc, Muhammet, Matthias Cleenewerck, Ammar Kurdi, Ria Roelandt, Wim Declercq, Guido De Meyer, Koen Augustyns, Wim Martinet, and Pieter Van der Veken. 2019. “Synthesis and Evaluation of Novel Benzotropolones as Atg4B Inhibiting Autophagy Blockers.” Bioorganic Chemistry 87: 163–168.
Chicago author-date (all authors)
Tanc, Muhammet, Matthias Cleenewerck, Ammar Kurdi, Ria Roelandt, Wim Declercq, Guido De Meyer, Koen Augustyns, Wim Martinet, and Pieter Van der Veken. 2019. “Synthesis and Evaluation of Novel Benzotropolones as Atg4B Inhibiting Autophagy Blockers.” Bioorganic Chemistry 87: 163–168.
Vancouver
1.
Tanc M, Cleenewerck M, Kurdi A, Roelandt R, Declercq W, De Meyer G, et al. Synthesis and evaluation of novel benzotropolones as Atg4B inhibiting autophagy blockers. BIOORGANIC CHEMISTRY. 2019;87:163–8.
IEEE
[1]
M. Tanc et al., “Synthesis and evaluation of novel benzotropolones as Atg4B inhibiting autophagy blockers,” BIOORGANIC CHEMISTRY, vol. 87, pp. 163–168, 2019.
@article{8613473,
  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.},
  author       = {Tanc, Muhammet and Cleenewerck, Matthias and Kurdi, Ammar and Roelandt, Ria and Declercq, Wim and De Meyer, Guido and Augustyns, Koen and Martinet, Wim and Van der Veken, Pieter},
  issn         = {0045-2068},
  journal      = {BIOORGANIC CHEMISTRY},
  keywords     = {Autophagy,Atg4B,Benzotropolone,UAMC-2526,ENZYME},
  language     = {eng},
  pages        = {163--168},
  title        = {Synthesis and evaluation of novel benzotropolones as Atg4B inhibiting autophagy blockers},
  url          = {http://dx.doi.org/10.1016/j.bioorg.2019.03.021},
  volume       = {87},
  year         = {2019},
}

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