Selective Modification of the N-Terminal Structure of Polytheonamide B Significantly Changes its Cytotoxicity and Activity as an Ion Channel
Selective Modification of the N-Terminal Structure of Polytheonamide B Significantly Changes its Cytotoxicity and Activity as an Ion Channel
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聚酰胺 B N 端结构的选择性修饰显着改变其细胞毒性和离子通道活性
DOI：
10.1002/cmdc.201200142
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发表时间：
2012
期刊：
影响因子：
3.4
通讯作者：
Masayuki Inoue
中科院分区：
文献类型：
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作者：
Naoki Shinohara;Hiroaki Itoh;Shigeru Matsuoka;Masayuki Inoue
聚茶酰胺B（1;方案1a）是一种极具细胞毒性的天然产物（IC 50 = 0.098 nM，小鼠P388白血病细胞），也是迄今为止描述的最大的非核糖体肽（MW= 5030 Da）。[1，2]线性链多肽1由N-末端5，5-二甲基-2-氧代己酸酯基团（Ncap）和48个D-和L-手性交替的氨基酸残基形成，并且最近报道二级结构是显著的β6。3-螺旋长度约为45（图1）。[3]这种螺旋管结构被认为在生物环境中起跨膜离子通道的作用，因为直径为4的亲水孔为离子流动创造了路径。[4]平面双层实验表明，单体1形成一个单价阳离子选择性通道。[5]因此，细胞毒性肽1不仅提出了一个合成的挑战，但也提供了一个独特的结构平台，设计细胞毒性分子和合成跨膜通道。[6]我们最近报道了聚茶酰胺B的全合成，[7]以及7至37个氨基酸残基的9个亚结构的合成。我们发现，所有的子结构是至少10000倍，低于母体化合物的细胞毒性。[8，9]这些研究表明，1的整体跨膜性质对其生物活性很重要。为了进一步表征1的结构-功能关系，我们计划对合成的polytheonamide B的单体单元进行位点特异性修饰，并评估新生成的类似物的生物活性。我们假设这种类型的分子编辑[10]将使我们能够破译负责独特生物学的结构元件，
Polytheonamide B (1; Scheme1a) is an extremely cytotoxic natural product (IC50= 0.098 nM, mouse P388 leukemia cells), and it is the largest non-ribosomal peptide described to date (MW= 5030 Da).[1, 2] The linear-chain polypeptide 1 is formed of an N-terminal 5, 5-dimethyl-2-oxohexanoate group (Ncap) and 48 amino acid residues of alternating D-and L-chirality, and the secondary structure was recently reported to be a remarkable β6. 3-helix with a length of approximately 45 (Figure 1).[3]This helical tube structure is believed to function as a transmembrane ion channel in biological settings, as the hydrophilic pore, which is 4 in diameter, creates a path for ion flow.[4] Planar bilayer experiments demonstrated that monomeric 1 forms a monovalent-cation-selective channel.[5] Therefore, cytotoxic peptide 1 not only poses a synthetic challenge, but also provide a unique structural platform for designing cytotoxic molecules and synthetic transmembrane channels.[6] We recently reported the total synthesis of polytheonamide B,[7] as well as the synthesis of nine substructures of 7 to 37 amino acid residues. We found that all of the substructures are at least 10000-times less cytotoxic than the parent compound.[8, 9] These studies suggest that the overall membrane spanning property of 1 is important for its biological activity. To further characterize the structure–function relationship of 1, we planned to site-specifically modify monomer units of synthetic polytheonamide B and evaluate the biological activity of the newly generated analogues. We hypothesized that this type of molecular editing [10] would enable us to decipher the structural elements that are responsible for the unique biologi-