Design, synthesis and antitumor efficacy evaluation of a series of novel β-elemene-based macrocycles

Bioorg Med Chem. 2022 Nov 15:74:117049. doi: 10.1016/j.bmc.2022.117049.

Xiang Qi ¹, Songwei Jiang ¹, Zi Hui ¹, Yuan Gao ², Yang Ye ¹, Frédéric Lirussi ³, Carmen Garrido ⁴, Li Xu ¹, Xingrui He ⁵, Renren Bai ⁶, Xiang-Yang Ye ⁷, Tian Xie ⁸

Affiliations

1 School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China; Key Laboratory of Elemene Class Anti-Cancer Chinese Medicine of Zhejiang Province, China; Engineering Laboratory of Development and Application of Traditional Chinese Medicine from Zhejiang Province, China; Collaborative Innovation Center of Chinese Medicines from Zhejiang Province, China.
2 Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 200000, China.
3 INSERM UMR 1231, Labex LipSTIC, Faculty of Medicine, University of Bourgogne, 21000 Dijon, France; University of Bourgogne Franche-Comté, 25056 Besançon, France; University Hospital of Besançon, PACE Platform, Dijon, France.
4 INSERM UMR 1231, Labex LipSTIC, Faculty of Medicine, University of Bourgogne, 21000 Dijon, France; University of Bourgogne Franche-Comté, 25056 Besançon, France; Cancer Center Georges François Leclerc, 21000 Dijon, France.
5 School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China; Key Laboratory of Elemene Class Anti-Cancer Chinese Medicine of Zhejiang Province, China; Engineering Laboratory of Development and Application of Traditional Chinese Medicine from Zhejiang Province, China; Collaborative Innovation Center of Chinese Medicines from Zhejiang Province, China. Electronic address: hexingrui163@163.com.
6 School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China; Key Laboratory of Elemene Class Anti-Cancer Chinese Medicine of Zhejiang Province, China; Engineering Laboratory of Development and Application of Traditional Chinese Medicine from Zhejiang Province, China; Collaborative Innovation Center of Chinese Medicines from Zhejiang Province, China. Electronic address: renrenbai@hznu.edu.cn.
7 School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China; Key Laboratory of Elemene Class Anti-Cancer Chinese Medicine of Zhejiang Province, China; Engineering Laboratory of Development and Application of Traditional Chinese Medicine from Zhejiang Province, China; Collaborative Innovation Center of Chinese Medicines from Zhejiang Province, China. Electronic address: xyye@hznu.edu.cn.
8 School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China; Key Laboratory of Elemene Class Anti-Cancer Chinese Medicine of Zhejiang Province, China; Engineering Laboratory of Development and Application of Traditional Chinese Medicine from Zhejiang Province, China; Collaborative Innovation Center of Chinese Medicines from Zhejiang Province, China. Electronic address: xbs@hznu.edu.cn.

PMID: 36240626 DOI: 10.1016/j.bmc.2022.117049

Abstract

β-Elemene is the major constituent of the antitumor drugs elemene extract approved in China. By incorporating macrocyclization strategy into the β-elemene skeleton, we designed a series of novel macrocycles retaining three key carbon-carbon double bonds. Four different methods have been successfully developed for these challenging ring systems. A total of twenty-eight 14- to 24-membered macrocycles were synthesized. Most of these macrocycles exhibited good antitumor activity against several Cancer cell lines (PC-3, A549, U87MG, U251 and HCT116), with up to 40 folds improvement of activity comparing to β-elemene. Additionally, X-ray single crystal structures of compounds Ic, IP, and IIh were successfully solved as the proof of macrocycle formation. The results warrant the further investigation of this novel class macrocycles in pharmacokinetic and pharmacodynamics studies, which will be reported in due course.

Keywords

Anti-proliferative activity; Antitumor; Macrocyclization; X-ray single crystal structure; β-elemene.

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