多粘菌素E1 | 7722-44-3

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 中文名称: 多粘菌素E1
• 中文别名: 1,2,4,5-苯四甲酸，1,4-双[2-[((2-甲基-1-氧代-2-丙烯-1-基)氧基] -1-[[(2-甲基-1-氧代-2-丙烯-1-基)氧基]甲基]乙基]酯
• 英文名称: colistin A
• 英文别名: polymyxin E1；colistin；(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)-3-[(1R)-1-hydroxyethyl]-12,15-bis(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]-6-methyloctanamide
• CAS: 7722-44-3
• 化学式: C₅₃H₁₀₀N₁₆O₁₃
• 分子量: 1169.48
• InChiKey: XDJYMJULXQKGMM-HHAJOKTESA-N

物化性质

• 比旋光度：
  225461 -93.3° (2% acetic acid)
• 沸点：
  1536.8±65.0 °C(Predicted)
• 密度：
  1.25±0.1 g/cm3(Predicted)
• 溶解度：
  甲醇（微溶）、水（微溶）

计算性质

• 辛醇/水分配系数(LogP)：
  -2.8
• 重原子数：
  82
• 可旋转键数：
  29
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.79
• 拓扑面积：
  491
• 氢给体数：
  18
• 氢受体数：
  18

制备方法与用途

生物活性

Colistin A 是 Colistin 的主要成分，而 Colistin 则是一种多粘菌素类抗生素。它主要用于对抗由革兰氏阴性菌引起的各种感染。

反应信息

• 作为反应物：
  描述：

  乙基三氟巯基乙酯 、 多粘菌素E1 在 三乙胺 作用下， 以 二甲基亚砜 为溶剂， 反应 28.0h， 以95.6%的产率得到pentakis(Nγ-trifluoroacetyl)-colistin A
  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

• POLYMYXIN DERIVATIVE, PREPARATION METHOD AND APPLICATION THEREOF
  申请人：INSTITUTE OF MEDICINAL BIOTECHNOLOGY, CHINESE ACADEMY OF MEDICAL SCIENCES

  公开号：US20190315806A1

  公开（公告）日：2019-10-17

  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.
• 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。