[Ile⁷]-polymyxin B₁ | 811435-10-6

• 分子结构分类: 有机化合物 - 有机聚合物 - 多肽
• 英文名称: [Ile⁷]-polymyxin B₁
• 英文别名: L-Threonine, (2S)-4-amino-2-(((6S)-6-methyl-1-oxooctyl)amino)butanoyl-L-threonyl-(2S)-2,4-diaminobutanoyl-(2S)-2,4-diaminobutanoyl-(2S)-2,4-diaminobutanoyl-D-phenylalanyl-L-isoleucyl-(2S)-2,4-diaminobutanoyl-(2S)-2,4-diaminobutanoyl-, (10->4)-lactam；(6S)-N-[(2S)-4-amino-1-[[(2S,3R)-1-[[(2S)-4-amino-1-oxo-1-[[(3S,6S,9S,12S,15R,18S,21S)-6,9,18-tris(2-aminoethyl)-15-benzyl-12-[(2S)-butan-2-yl]-3-[(1R)-1-hydroxyethyl]-2,5,8,11,14,17,20-heptaoxo-1,4,7,10,13,16,19-heptazacyclotricos-21-yl]amino]butan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-1-oxobutan-2-yl]-6-methyloctanamide
• CAS: 811435-10-6
• 化学式: C₅₆H₉₈N₁₆O₁₃
• 分子量: 1203.49
• InChiKey: YAMZKVXJHUGXEM-FHUJKRKBSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -2.5
• 重原子数：
  85
• 可旋转键数：
  29
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.7
• 拓扑面积：
  491
• 氢给体数：
  18
• 氢受体数：
  18

反应信息

• 作为产物：
  描述：

  在 氢氟酸 、 苯甲醚 作用下， 反应 1.0h， 生成 [Ile⁷]-polymyxin B₁
  参考文献：
  名称：

  The Contribution of theN-Terminal Structure of Polymyxin B Peptides to Antimicrobial and Lipopolysaccharide Binding Activity

  摘要：

  为了阐明多粘菌素 B 多肽 N 端结构与活性的关系，合成了 7 种已阐明其结构的多粘菌素 B 成分肽和 7 种 N 端脂肪酸和/或氨基酸缺失类似物，并测定了它们的抗菌活性。使用[Dab(Dansyl-Gly)1]-多粘菌素 B3（Dab；l-α,γ-二氨基丁酸）作为荧光探针，评估了合成肽的脂多糖（LPS）结合活性。结果表明，脂肪酰基对于 LPS 结合并非不可或缺，但多粘菌素 B 肽的 C9 脂肪酰基对结合亲和力的贡献略大于 C8 或 C7。多粘菌素 B 的脂肪酰基对抗菌活性有很大贡献，而多粘菌素 B1-B6 不同的 N 端结构（含有正常脂肪酸、异脂肪酸、反异脂肪酸或链长在 C7 和 C9 之间的 3-羟基脂肪酸）并不影响杀菌效力。

  DOI：

  10.1246/bcsj.77.1915

文献信息

• POLYMYXIN DERIVATIVE, PREPARATION METHOD AND APPLICATION THEREOF
  申请人：Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences

  公开号：EP3556769A1

  公开（公告）日：2019-10-23

  Provided are a polymyxin derivative having a general formula I structure, and a preparation method and an application thereof. The method for preparing the polymyxin derivative comprises the following steps: (1) an Fmoc-AA-OP side chain free amino group of a protected basic amino acid reacting with a halogenated resin to obtain an Fmoc-AA-OP-resin; (2) the Fmoc-AA-OP-resin being coupled one by one to obtain a linear peptide-resin; (3) the linear peptide-resin selectively removing a protective group, and carrying out solid-phase cyclization to obtain a cyclic peptide-resin; (4) the cyclic peptide-resin undergoing acidic hydrolysis and ether precipitation to obtain a crude product of a cyclic polypeptide; (5) the crude product being purified and/or salt transferred and lyophilized to obtain a pure product of the cyclic polypeptide. The polymyxin derivative may be used for preparing an antibacterial drug, and used in particular for preparing an antibacterial drug having an expanded antibacterial spectrum, improved antibacterial activity and reduced renal toxicity, comprising preparing an antibacterial drug against a "superbugs" which carries the NDM-1 gene.

  本发明提供了一种具有通式 I 结构的多粘菌素衍生物及其制备方法和应用。该多粘菌素衍生物的制备方法包括以下步骤：(1) 受保护的碱性氨基酸的 Fmoc-AA-OP 侧链游离氨基与卤化树脂反应，得到 Fmoc-AA-OP 树脂；(2) 将 Fmoc-AA-OP 树脂逐一偶联，得到线性肽树脂；(3) 线性肽树脂选择性脱去保护基，进行固相环化，得到环状肽树脂；(4) 环肽树脂经过酸性水解和乙醚沉淀，得到环多肽的粗产品； (5) 粗产品经过纯化和/或盐转移和冻干，得到环多肽的纯产品。多粘菌素衍生物可用于制备抗菌药物，特别是用于制备抗菌谱扩大、抗菌活性提高和肾毒性降低的抗菌药物，包括制备针对携带 NDM-1 基因的 "超级细菌 "的抗菌药物。
• The Contribution of the<i>N</i>-Terminal Structure of Polymyxin B Peptides to Antimicrobial and Lipopolysaccharide Binding Activity
  作者：Naoki Sakura、Tatsuya Itoh、Yoshiki Uchida、Kazuhiro Ohki、Keiko Okimura、Kenzo Chiba、Yuki Sato、Hiroyuki Sawanishi

  DOI：10.1246/bcsj.77.1915

  日期：2004.10

  To elucidate the N-terminal structure–activity relationships of polymyxin B peptides, seven polymyxin B component peptides, the structures of which having been elucidated, and seven N-terminal fatty acid and/or amino acid deletion analogs were synthesized, and their antimicrobial activities determined. The lipopolysaccharide (LPS) binding activities of synthetic peptides were evaluated using [Dab(Dansyl-Gly)1]-polymyxin B3 (Dab; l-α,γ-diaminobutyric acid) as a fluorescent probe. The results indicated that the fatty acyl moiety was not indispensable for LPS binding, but the C9 fatty acyl groups of polymyxin B peptides contributed to the binding affinity to a slightly greater extent than C8 or C7. The fatty acyl moieties of polymyxin B contributed greatly to the antimicrobial activity, while the distinct N-terminal structures of polymyxin B1–B6, bearing normal-, iso-, or anteiso-fatty acids, or 3-hydroxy-fatty acid with chain lengths between C7 and C9, did not affect bactericidal potency.

  为了阐明多粘菌素 B 多肽 N 端结构与活性的关系，合成了 7 种已阐明其结构的多粘菌素 B 成分肽和 7 种 N 端脂肪酸和/或氨基酸缺失类似物，并测定了它们的抗菌活性。使用[Dab(Dansyl-Gly)1]-多粘菌素 B3（Dab；l-α,γ-二氨基丁酸）作为荧光探针，评估了合成肽的脂多糖（LPS）结合活性。结果表明，脂肪酰基对于 LPS 结合并非不可或缺，但多粘菌素 B 肽的 C9 脂肪酰基对结合亲和力的贡献略大于 C8 或 C7。多粘菌素 B 的脂肪酰基对抗菌活性有很大贡献，而多粘菌素 B1-B6 不同的 N 端结构（含有正常脂肪酸、异脂肪酸、反异脂肪酸或链长在 C7 和 C9 之间的 3-羟基脂肪酸）并不影响杀菌效力。