190781-29-4Relevant articles and documents
Synthesis and evaluation of novel benzotropolones as Atg4B inhibiting autophagy blockers
Tanc, Muhammet,Cleenewerck, Matthias,Kurdi, Ammar,Roelandt, Ria,Declercq, Wim,De Meyer, Guido,Augustyns, Koen,Martinet, Wim,Van der Veken, Pieter
, p. 163 - 168 (2019/03/19)
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.
Synthesis of gallic acid analogs as histamine and pro-inflammatory cytokine inhibitors for treatment of mast cell-mediated allergic inflammation
Fei, Xiang,Je, In-Gyu,Shin, Tae-Yong,Kim, Sang-Hyun,Seo, Seung-Yong
, (2017/06/19)
Gallic acid (3,4,5-trihydroxybenzoic acid), is a natural product found in various foods and herbs that are well known as powerful antioxidants. Our previous report demonstrated that it inhibits mast cell-derived inflammatory allergic reactions by blocking histamine release and pro-inflammatory cytokine expression. In this report, various amide analogs of gallic acid have been synthesized by introducing different amines through carbodiimide-mediated amide coupling and Pd/C-catalyzed hydrogenation. These compounds showed a modest to high inhibitory effect on histamine release and pro-inflammatory cytokine expression. Among them, the amide bearing (S)-phenylglycine methyl ester 3d was found to be more active than natural gallic acid. Further optimization yielded several (S)-and (R)-phenylglycine analogs that inhibited histamine release in vitro. Our findings suggest that some gallamides could be used as a treatment for allergic inflammatory diseases.
Synthetic gallic acid derivatives as models for a comprehensive study of antioxidant activity
Belin, Florence,Barthelemy, Philippe,Ruiz, Karine,Lacombe, Jean Michel,Pucci, Bernard
, p. 247 - 265 (2007/10/03)
The synthesis and antioxidant efficiencies of amphiphilic gallic acid derivatives are reported. To specify the impact of chemical structure on the antioxidant efficiency, several structural modifications of gallic acid were performed. The following structural features were chosen: i) introduction of hydrophobic or hydrophilic residues on the gallic acid and the type of their linkage, ii) the hydrophilic and/or lipophilic character of the whole molecule. The physico-chemical studies of the different series prepared revealed that the antioxidant efficiency of this polyphenol depends clearly on the nature of the linkage with both hydrophilic and hydrophobic parts. A push-pull effect is always necessary, and ester or amide bonds seem well adapted to increase the antioxidant efficiency. Second, under the oxidation conditions applied, it was observed that the hydrophilic and/ or lipophilic character affects drastically the antioxidant activity of gallic acid derivatives. The results obtained are in accordance with the polar paradox, hydrophobic derivatives inhibit oxidation in an aqueous phase, whereas hydrophilic products are not efficient.
