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Issue 66, 2015
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Design, synthesis and biological evaluation of esculetin derivatives as anti-tumour agents

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Abstract

Esculetin, a naturally catecholic coumarin, possess multiple pharmacological activities including anti-tumour, anti-inflammatory and anti-oxidant. However, the extensive phase II metabolism and rapid elimination from the human body significantly hinder esculetin and its derivatives as drug leads/candidates. To improve both the metabolic stability and the anti-tumour activity of esculetin via rational modification, a series of C-4 and C-8 substituted derivatives were designed and synthesized by perchloric acid catalysed von Pechmann reaction and Mannich reaction, respectively. The in vitro metabolic half-life in human liver S9 and anti-tumour activities in A549 and B16 cell lines of the newly synthesized compounds were assayed. Of these compounds, 8-(pyrrolidin-1-ylmethyl)-4-trifluoromethyl esculetin 15 was the most potent candidate compound, with almost a 20-fold increase in antiproliferative activity and a 3-fold prolonged half-life in human liver S9 compared with the parent compound 1. In addition, the potential structure–activity relationship and structure–metabolic stability relationship were discussed. Notably, the introduction of a nitrogen containing group as a hydrogen bond acceptor at the C-8 position of esculetin can improve both the metabolic stability and anti-tumour activity. All of these findings are very helpful for the structural modification of esculetin and other bioactive phenolic compounds to improve their phase II metabolic stability and bioactivity synchronously.

Graphical abstract: Design, synthesis and biological evaluation of esculetin derivatives as anti-tumour agents

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Supplementary files

Article information


Submitted
05 Apr 2015
Accepted
02 Jun 2015
First published
02 Jun 2015

RSC Adv., 2015,5, 53477-53483
Article type
Paper

Design, synthesis and biological evaluation of esculetin derivatives as anti-tumour agents

P. Wang, Y. Xia, Y. Yu, J. Lu, L. Zou, L. Feng, G. Ge and L. Yang, RSC Adv., 2015, 5, 53477
DOI: 10.1039/C5RA06070B

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