Kaneda Masato, Kawaguchi Shinsaku, Fujii Nobutaka, Ohno Hiroaki, Oishi Shinya
Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
ACS Med Chem Lett. 2018 Mar 5;9(4):365-369. doi: 10.1021/acsmedchemlett.8b00028. eCollection 2018 Apr 12.
Odoamide is a cytotoxic peptide-polyketide hybrid molecule isolated from the Okinawan marine cyanobacterium sp. For an efficient structure-activity relationship study of the peptide part of odoamide, a facile synthetic protocol was established using a solid-phase peptide synthesis. Among a series of peptides, the d-MeAla6 isomer exhibited a more potent cytotoxicity than natural odoamide. It was also demonstrated that the 26-membered macrocyclic natural odoamide and the 24-membered isomer with comparable cytotoxicities were slowly interconvertible, and both isomers contributed to the potent cytotoxicity of odoamide. Examination of the physicochemical properties revealed that the in vitro cytotoxicity was affected by the serum protein binding of odoamide derivatives, while the differences in the macrocyclic structures had no significant effect on the membrane permeability.
奥多酰胺是一种从冲绳海洋蓝藻中分离出的细胞毒性肽 - 聚酮杂合分子。为了对奥多酰胺的肽部分进行有效的构效关系研究，采用固相肽合成法建立了一种简便的合成方案。在一系列肽中，d - MeAla6异构体表现出比天然奥多酰胺更强的细胞毒性。还证明了具有相当细胞毒性的26元大环天然奥多酰胺和24元异构体可缓慢相互转化，且两种异构体都对奥多酰胺的强效细胞毒性有贡献。对物理化学性质的研究表明，奥多酰胺衍生物的体外细胞毒性受血清蛋白结合的影响，而大环结构的差异对膜通透性没有显著影响。
