polymyxin B3 | 71140-58-4

• 分子结构分类: 有机化合物 - 有机聚合物 - 多肽
• 英文名称: polymyxin B3
• 英文别名: Unii-L194hgu2LD；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-3-[(1R)-1-hydroxyethyl]-12-(2-methylpropyl)-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]octanamide
• CAS: 71140-58-4
• 化学式: C₅₅H₉₆N₁₆O₁₃
• 分子量: 1189.47
• InChiKey: MUZYEKLWXWDOOD-RUDZPDEXSA-N

物化性质

• 沸点：
  1576.2±65.0 °C(Predicted)
• 密度：
  1.28±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  -2.8
• 重原子数：
  84
• 可旋转键数：
  29
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.69
• 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 哌啶 、 水 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 48.0h， 生成 polymyxin B3
  参考文献：
  名称：

  Chemical Conversion of Natural Polymyxin B and Colistin to TheirN-Terminal Derivatives

  摘要：

  研究了天然多粘菌素 B 和秋水仙素（脂肪酰化环十肽）向多粘菌素 (2-10) 和秋水仙素 (2-10) 衍生物的化学转化。无 Nα 和侧链 Nγ 保护的非肽，即四(Nγ-三氟乙酰基)-多粘菌素 B (2-10) 和四(Nγ-三氟乙酰基)-考来霉素 (2-10)是通过对多粘菌素 B 和考来霉素进行三氟乙酰化，然后用 50% 甲磺酸进行化学裂解以去除 Nα-alkanoyl-Nγ- 三氟乙酰基-Dab-OH 而制备的。先在 Thr2 处进行选择性 Nα-酰化，然后用哌啶水溶液去除 Nγ-三氟乙酰基保护基团，Nγ-保护的非肽是半合成 N-末端衍生物的有用起始原料。此外，肉豆蔻酰基多粘菌素 B（2-10）和肉豆蔻酰基多粘菌素（2-10）对大肠杆菌、鼠伤寒沙门氏菌和铜绿假单胞菌的抗菌活性仍为 2-4 毫摩尔毫升/升。它们还保留了较高的脂聚糖（LPS）结合活性。乙酰基多粘菌素 B（2-10）和乙酰基考利司汀（2-10）的生物活性很低，但对铜绿假单胞菌具有很高的杀菌活性，其 MIC 值为 2 nmol mL-1。三种经测试的革兰氏阴性细菌对乙酰-壬肽的不同敏感性表明，脂肪酰化多粘菌素肽的 N 端疏水特性是对大肠杆菌和伤寒沙门氏菌具有杀菌活性的必要条件，但对铜绿假单胞菌却不具有杀菌活性。

  DOI：

  10.1246/bcsj.80.543

文献信息

• Synthesis of a polymyxin derivative for photolabeling studies in the gram-negative bacterium<i>Escherichia coli</i>
  作者：Benjamin van der Meijden、John A. Robinson

  DOI：10.1002/psc.2736

  日期：2015.3

  inner membrane. The work described here was prompted by the hypothesis that polymyxins might interact with proteins in the OM, as part of their self‐promoted uptake and permeabilizing effects. One way to test this is through photolabeling experiments. We describe the design and synthesis of a photoprobe based upon polymyxin B, containing photoleucine and an N‐acyl group with a terminal alkyne suitable

  多粘菌素对革兰氏阴性菌的抗菌活性已有数十​​年的历史，但导致细胞死亡的作用机理尚未得到充分研究。抗生素与细胞表面暴露的脂多糖（LPS）结合后的关键步骤是跨膜（OM）的“自我促进摄取”，其中抗生素在到达周质之前穿过不对称的LPS-磷脂双分子层。靶向并破坏细菌磷脂内膜。假说多粘菌素可能与OM中的蛋白质相互作用，这是其自我促进的摄取和通透性作用的一部分的假设，促使本文所述的工作。一种测试方法是通过光标记实验。我们描述了基于多粘菌素B的光探针的设计和合成，含有光亮氨酸和一个N-酰基基团，带有末端炔烃，适合于通过单击化学偶联到生物素标签上。所得的光探针保留了有效的抗菌活性，在最初的光标记实验中大肠杆菌ATCC25922被证明可以对几种OM蛋白进行光标记。该光探针可能是对该抗生素家族作用机理进行更详细研究的有价值的工具。版权所有©2015欧洲肽协会和John Wiley＆Sons，Ltd.
• 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。
• 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。
• Structure–activity relationships of bacterial outer-membrane permeabilizers based on polymyxin B heptapeptides
  作者：Hirotoshi Urakawa、Keiichi Yamada、Keiko Komagoe、Setsuko Ando、Hiroyuki Oku、Takashi Katsu、Ichiro Matsuo

  DOI：10.1016/j.bmcl.2010.01.040

  日期：2010.3

  A series of cationic cyclic heptapeptides based on polymyxin B have been synthesized for use as permeabilizers of the outer membrane of Gram-negative bacteria. Only analogs with the Dab(2)-D-Phe(3)-Leu(4)-Xxx(5) sequence (Xxx = Dab or Orn) showed a synergistic bactericidal effect when combined with conventional antibiotics, indicating that the Dab(2) residue plays a critical role in permeation of the outer membrane of Gram-negative bacteria. (C) 2010 Elsevier Ltd. All rights reserved.
• Chemical Conversion of Natural Polymyxin B and Colistin to Their<i>N</i>-Terminal Derivatives
  作者：Keiko Okimura、Kazuhiro Ohki、Yuki Sato、Kuniharu Ohnishi、Yoshiki Uchida、Naoki Sakura

  DOI：10.1246/bcsj.80.543

  日期：2007.3.15

  The chemical conversions of natural polymyxin B and colistin, which are fatty-acylated cyclic decapeptides, to polymyxin (2–10) and colistin (2–10) derivatives were examined. The Nα-free and side chain Nγ-protected nonapeptides, i.e., tetrakis(Nγ-trifluoroacetyl)–polymyxin B (2–10) and tetrakis(Nγ-trifluoroacetyl)–colistin (2–10), were prepared by trifluoroacetylation of polymyxin B and colistin, followed by chemical cleavage with 50% methanesulfonic acid to remove Nα-alkanoyl–Nγ-trifluoroacetyl–Dab–OH. The Nγ-protected nonapeptides were useful starting materials for the semi-synthesis of N-terminal derivatives by selective Nα-acylation at Thr2, followed by the removal of the Nγ-trifluoroacetyl protecting group with aqueous piperidine. Further, myristoyl–polymyxin B (2–10) and myristoyl–colistin (2–10) retained their antimicrobial activity with an MIC of 2–4 nmol mL−1 against Escherichia coli, Salmonella Typhimurium, and Pseudomonas aeruginosa. They also retained their high lipopolysaccahride (LPS) binding activity. Acetyl–polymyxin B (2–10) and acetyl–colistin (2–10) exhibited very low biological activities, except for a high bactericidal activity specifically against Pseudomonas aeruginosa with an MIC of 2 nmol mL−1. The distinct sensitivity of three Gram-negative bacteria tested toward acetyl-nonapeptides suggested that the N-terminal hydrophobic character of the fatty-acylated polymyxin peptides was necessary for the bactericidal activity against Escherichia coli and Salmonella Typhimurium, but not against Pseudomonas aeruginosa.

  研究了天然多粘菌素 B 和秋水仙素（脂肪酰化环十肽）向多粘菌素 (2-10) 和秋水仙素 (2-10) 衍生物的化学转化。无 Nα 和侧链 Nγ 保护的非肽，即四(Nγ-三氟乙酰基)-多粘菌素 B (2-10) 和四(Nγ-三氟乙酰基)-考来霉素 (2-10)是通过对多粘菌素 B 和考来霉素进行三氟乙酰化，然后用 50% 甲磺酸进行化学裂解以去除 Nα-alkanoyl-Nγ- 三氟乙酰基-Dab-OH 而制备的。先在 Thr2 处进行选择性 Nα-酰化，然后用哌啶水溶液去除 Nγ-三氟乙酰基保护基团，Nγ-保护的非肽是半合成 N-末端衍生物的有用起始原料。此外，肉豆蔻酰基多粘菌素 B（2-10）和肉豆蔻酰基多粘菌素（2-10）对大肠杆菌、鼠伤寒沙门氏菌和铜绿假单胞菌的抗菌活性仍为 2-4 毫摩尔毫升/升。它们还保留了较高的脂聚糖（LPS）结合活性。乙酰基多粘菌素 B（2-10）和乙酰基考利司汀（2-10）的生物活性很低，但对铜绿假单胞菌具有很高的杀菌活性，其 MIC 值为 2 nmol mL-1。三种经测试的革兰氏阴性细菌对乙酰-壬肽的不同敏感性表明，脂肪酰化多粘菌素肽的 N 端疏水特性是对大肠杆菌和伤寒沙门氏菌具有杀菌活性的必要条件，但对铜绿假单胞菌却不具有杀菌活性。