Rational Design, Synthesis and Biological Evaluation of Novel Derivatives Based on in vivo Metabolism of Natural Product β-elemene

Author(s): Renren Bai*, Xiaokang Jie, Eric Salgado, Jian Sun, Yao Zhu, Thomas Pickel, Yuanyuan Xie, Jichao Chen, Jinyi Xu*.

Journal Name: Letters in Drug Design & Discovery

Volume 15 , Issue 8 , 2018

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Graphical Abstract:


Background: Natural products have been an exemplary source of new drugs as they have served as direct or indirect precursors for many currently available medicines. The natural product β -elemene has been used clinically in the treatment of various cancers; however, its efficacy is hampered by its poor solubility and bioavailability.

Methods: An aldehyde metabolite of β-elemene, 13-β-elemenal, was further identified and proved to exhibit significantly better anti-proliferative activity than β -elemene. A series of prodrug-like 13- and 14-substituted ester derivatives, as well as their alcohol and aldehyde intermediates, were rational designed, synthesized and biologically evaluated.

Results: The intermediates and ester derivatives of β-elemene displayed comparable to better antiproliferative activity on human cancer cell lines (A549, HepG-2 and U87). Notably, ester compounds 10d, 10m-o, 10s, 10t, 13d, 13h and 13m-o were superior over β-elemene in their antiproliferation effects, while the predicted in vivo metabolites of the designed ester compounds, 13- β-elemental (8) and 14-β-elemental (11), demonstrated the most potent anti-proliferative effect.

Conclusion: Most of the esters displayed better antitumor effects than β -elemene, which were predicted to play more significant roles in the in vivo treatment by being metabolized continuously to β -elemental. More importantly, these compounds showed better drug-like properties, such as decreased LogP values and improved solubility.

Keywords: Natural product, β-elemene, metabolism, structural modification, anti-tumor activity, cell lines.

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Article Details

Year: 2018
Page: [905 - 912]
Pages: 8
DOI: 10.2174/1570180814666171108093021
Price: $65

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