Kuranaga Takefumi, Fukuba Atsuki, Ninomiya Akihiro, Takada Kentaro, Matsunaga Shigeki, Wakimoto Toshiyuki
Faculty of Pharmaceutical Sciences, Hokkaido University.
Graduate School of Agricultural and Life Sciences, The University of Tokyo.
Chem Pharm Bull (Tokyo). 2018;66(6):637-641. doi: 10.1248/cpb.c18-00072.
Surugamide F is a linear decapeptide (1) isolated along with the cyclic octapeptides surugamides A-E (2-6), from a marine-derived Streptomyces species. The linear peptide 1 is produced by two nonribosomal peptide synthetases (NRPSs) encoded in adjacent open reading frames, which are further flanked by an additional pair of NRPS genes responsible for the biosyntheses of the cyclic peptides 2-6. While the cyclic peptides 2-6 were identified to be cathepsin B inhibitors, the biological activity of the new metabolite 1 still remained unclear. In order to elucidate its unique biosynthetic pathway and biological activity in detail, we planned to develop an efficient synthetic route toward 1. Here we report the diastereoselective total synthesis of 1, utilizing 9-fluorenylmethyloxycarbonyl (Fmoc)-based solid-phase peptide synthesis. During this study, we found that the structural correction of 1 was required, due to the mislabeling of the commercially obtained 3-amino-2-methylpropionic acid, and the true structure of 1 was corroborated by the chemical synthesis and chromatographic comparison.
Surugamide F是一种线性十肽（1），与环八肽surugamides A - E（2 - 6）一起，从一种海洋来源的链霉菌中分离得到。线性肽1由相邻开放阅读框中编码的两种非核糖体肽合成酶（NRPSs）产生，这两个开放阅读框两侧还有另外一对负责环肽2 - 6生物合成的NRPS基因。虽然环肽2 - 6被鉴定为组织蛋白酶B抑制剂，但新代谢产物1的生物活性仍不清楚。为了详细阐明其独特的生物合成途径和生物活性，我们计划开发一条通往1的高效合成路线。在此，我们报道了利用基于9 - 芴甲氧羰基（Fmoc）的固相肽合成法对1进行非对映选择性全合成。在这项研究中，我们发现由于市售的3 - 氨基 - 2 - 甲基丙酸标记错误，需要对1的结构进行校正，并且通过化学合成和色谱比较证实了1的真实结构。
