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. Epub 2022 Oct 7.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents* / chemistry
  • Apoptosis
  • Carbon
  • Cell Line, Tumor
  • China
  • Sesquiterpenes* / chemistry

Substances

  • beta-elemene
  • Sesquiterpenes
  • Antineoplastic Agents
  • Carbon