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

• Published in: RSC advances 2015-01, Vol.5 (66), p.53477-53483
• Main Authors: Wang, Ping, Xia, Yang-Liu, Yu, Yang, Lu, Jun-Xia, Zou, Li-Wei, Feng, Lei, Ge, Guang-Bo, Yang, Ling
• Format: Article
• Language: English
• Subjects: Antiproliferatives; Derivatives; Drugs; Human; Human body; Liver; Perchloric acid; Stability
• ISSN: 2046-2069; 2046-2069
• DOI: 10.1039/C5RA06070B

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.