抄録
Naturally occurring cyclic depsipeptides exhibit various biological activities. It would be efficient for drug discovery if a variety of their analogues can be synthesized in a high-throughput manner. Beauveriolides III, isolated from the culture broth of Beauveria sp. FO-6979, leads to a reduction in the number and size of lipid droplets in macrophages without cytotoxic effect and also inhibits cholesteryl ester (CE) synthesis, leading to suppression of foam cell formation in macrophages [1]. In order to elucidate the structure activity relationships and to discover a new drug lead, we have studied a method for rapid synthesis of beauveriolide III and its analogues. Initially, the unnatural amino acid and aliphatic acid were asymmetrically synthesized as building blocks of beauveriolide III. Solid-phase peptide synthesis by Fmoc strategy provided a linear cyclization precursor, which was allowed to undergo macrolactamization in solution phase leading to beauveriolide III.
To synthesize a variety of beauveriolide analogues, we assembled the three synthetic blocks including unnatural amino acids and aliphatic acids using a split and mix method on a polymer-support. Macrocyclization in a parallel manner, followed by preparative HPLC provided a 200-member combinatorial library of beauveriolide analogues in pure form.
The inhibitory activity of the beauveriolide analogues against CE synthesis in mouse peritoneal macrophages was evaluated. The linear cyclization precursors did not indicate the biological activity. Therefore, the macrocyclic ring structure plays a crucial role in inhibitory activity. We also found that one of the analogues exhibits 10 times more potent activity than the original natural product [2].
[1] Namatame, I.; Tomoda, H.; Ishibashi, S.; Omura, S. Proc. Natl. Acad. Sci. USA 2004, 101, 737.
[2] Nagai, K.; Doi, T.; Sekiguchi, T.; Namatame, I.; Sunazuka, T.; Tomoda, H.; Omura, S.; Takahashi, T. J. Comb. Chem. 2006, 8, 103.
