Brötz, Elke, Herrmann, Jennifer, Wiese, Jutta , Zinecker, Heidi, Maier, Armin, Kelter, Gerhardt, Imhoff, Johannes F. , Müller, Rolf and Paululat, Thomas (2014) Synthesis and Cytotoxic Activity of a Small Naphthoquinone Library: First Synthesis of Juglonbutin. European Journal of Organic Chemistry, 2014 (24). pp. 5318-5330. DOI 10.1002/ejoc.201402272.

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Abstract

A synthetic protocol has been designed to synthesize grecoketidone (2k), 5-hydroxylapachol (2g), and the recently discovered natural products juglonbutin (2o) and its derivatives, leading to a small library of different 1,4-naphthoquinones with the intention of finding new active compounds. Within our collection, 2-O-alkylated naphthoquinones with an ester functionality in the side-chain and a free OH group at C-5 showed the best activities. Compounds 2f, 2m, and 2n showed GI50 values against 12 tumor cell lines in the lower micromolar range and juglonbutin (2o) showed remarkably efficient inhibition of the glycogen synthase kinase 3β with an IC50 value of 2.03 μM. Furthermore, studies on the mode of action of the most active cytotoxic compounds have been carried out. To the best of our knowledge, this is the first report on the synthesis of juglonbutin (2o) and its biological activity.

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