Department of Chemistry, Faculty of Pure and Applied Sciences, University of Tsukuba, 1-1-1, Tennodai, Tsukuba, Ibaraki, 305-8571, Japan.
Department of Applied Biological Chemistry, Chubu University, 1200 Matsumoto-cho, Kasugai, Aichi, 487-8501, Japan.
J Antibiot (Tokyo). 2022 Aug;75(8):420-431. doi: 10.1038/s41429-022-00540-8. Epub 2022 Jul 11.
Synthesis of various destruxin analogs was accomplished using Shiina's macrolactonization as a key reaction. Combinatorial synthesis of cyclization precursors using solid-phase peptide synthesis and macrolactonization in solution were successful. In the synthesis of destruxin E and its analogs, the hydroxyacid-proline (HA-Pro) dipeptide with an acetonide-protected diol moiety was synthesized in an asymmetric manner, and the protected diol was converted to an epoxide after macrocyclization. Destruxin E was synthesized on a gram scale using solution-phase synthesis. The structure-activity relationships of destruxins were elucidated through biological evaluation of synthetic destruxins A, B, and E and their analogs for morphological changes in osteoclast-like multinucleated cells.
使用 Shiina 的大环内酯化反应作为关键反应，合成了各种 destruxin 类似物。使用固相肽合成和溶液中环化前体的组合合成是成功的。在 destruxin E 及其类似物的合成中，通过不对称合成方法合成了具有乙酰氧基保护二醇部分的羟酸-脯氨酸 (HA-Pro) 二肽，并且在大环化后将保护二醇转化为环氧化物。使用溶液相合成在克级规模上合成了 destruxin E。通过对合成的 destruxin A、B 和 E 及其类似物进行生物评价，阐明了 destruxins 的结构-活性关系，以评估其对破骨细胞样多核细胞形态变化的影响。
