Journal
JOURNAL OF CELLULAR PHYSIOLOGY
Volume 234, Issue 9, Pages 16431-16446Publisher
WILEY
DOI: 10.1002/jcp.28312
Keywords
absorption; bioactivity; celastrol derivative; toxicity; zebrafish
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Funding
- Nanjing Medical Science and Technique Development Foundation [YKK18123]
- National Natural Science Foundation of China [81573833]
- National Major Scientific and Technological Special Project for Significant New Drugs Development [2017ZX09301056]
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Two series of celastrol derivatives were designed and synthesized by modifying carboxylic acid at the 28th position with amino acid, and their intermediates with isobutyrate at the third position. All compounds were evaluated for their antiproliferation activity by four human cancer cell lines (SCG7901, HGC27, HepG2, and Bel7402) and one normal cell LO2. The most promising compound, compound 8, showed superior bioactivity and lower toxicity than others including celastrol. Further underlying tests illustrated that compound 8 induced apoptosis and cell arrest at G2/M and inhibited proliferation and mobility of human hepatoma cells by suppressing the signal transducer and activator of transcription-3 signaling pathway. Besides these, a highly accurate and reproducible high performance liquid chromatography protocol was established to determine celastrol and compound 8 absorption in zebrafish, and results demonstrated that their concentration increased rapidly within 4hr in a time-dependent manner and the concentration of compound 8 was higher than that of celastrol. In addition, without detection at 12hr, compound 8 was rapidly metabolized in vivo. These findings are very helpful for the structural modification of celastrol and other bioactive compounds to improve their bioactivity, toxicity, and absorption.
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