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

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

Volume: 15 Issue: 8

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

Affiliation:

• Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou 310014,China

• Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009,China

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

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.

Cite this article as:

Bai Renren *, Jie Xiaokang , Salgado Eric , Sun Jian , Zhu Yao , Pickel Thomas , Xie Yuanyuan , Chen Jichao and Xu Jinyi *, Rational Design, Synthesis and Biological Evaluation of Novel Derivatives Based on in vivo Metabolism of Natural Product β-elemene, Letters in Drug Design & Discovery 2018; 15 (8) . https://dx.doi.org/10.2174/1570180814666171108093021