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

[ Vol. 15 , Issue. 8 ]

Author(s):

Renren Bai*, Xiaokang Jie, Eric Salgado, Jian Sun, Yao Zhu, Thomas Pickel, Yuanyuan Xie, Jichao Chen and Jinyi Xu*   Pages 905 - 912 ( 8 )

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.

Affiliation:

Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou 310014, Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou 310014, Department of Radiation Oncology, School of Medicine, Emory University, Atlanta, GA 30322, Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou 310014, Women`s Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, Department of Chemistry, Emory University, Atlanta, GA 30322, Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou 310014, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009

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