Synthesis and Biological Evaluation of a Beauveriolide Analogue Library

• DOI: 10.1021/cc050084d
• Publication Date: 2006-01-09T05:29:42Z
• Authors: Kenichiro Nagai; Takayuki Doi; Takafumi Sekiguchi; Ichiji Namatame; Toshiaki Sunazuka; Hiroshi Tomoda; Satoshi Ōmura; Takashi Takahashi
• Keywords: Molecular Structure; 01 natural sciences; 0104 chemical sciences; Mice; Structure-Activity Relationship; Cyclization; Depsipeptides; Macrophages, Peritoneal; Animals; Combinatorial Chemistry Techniques; Cholesterol Esters; Chromatography, High Pressure Liquid; Hypolipidemic Agents

Synthesis of beauveriolide III (1b), which is an inhibitor of lipid droplet accumulation in macrophages, was achieved by solid-phase assembly of linear depsipeptide using a 2-chlorotrityl linker followed by solution-phase cyclization. On the basis of this strategy, a combinatorial library of beauveriolide analogues was carried out by radio frequency-encoded combinatorial chemistry. After automated purification using preparative reversed-phase HPLC, the library was tested for inhibitory activity of CE synthesis in macrophages to determine structure-activity relationships of beauveriolides. Among them, we found that diphenyl derivative 7{9,1} is 10 times more potent than 1b.