Echinomycin | 512-64-1

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 肽模拟物
• 英文名称: Echinomycin
• 英文别名: Quinomycin A；N-[(1R,4S,7R,11S,14R,17S,20R,24S)-2,4,12,15,17,25-hexamethyl-27-methylsulfanyl-3,6,10,13,16,19,23,26-octaoxo-11,24-di(propan-2-yl)-20-(quinoxaline-2-carbonylamino)-9,22-dioxa-28-thia-2,5,12,15,18,25-hexazabicyclo[12.12.3]nonacosan-7-yl]quinoxaline-2-carboxamide
• CAS: 512-64-1
• 化学式: C₅₁H₆₄N₁₂O₁₂S₂
• 分子量: 1101.27
• InChiKey: AUJXLBOHYWTPFV-VITLIGDRSA-N

物化性质

• 熔点：
  217-218℃
• 比旋光度：
  D20 -310° (c = 0.86 in chloroform)
• 沸点：
  1427.2±65.0 °C(Predicted)
• 密度：
  1.0964 (rough estimate)
• 溶解度：
  溶于DMSO（高达5mg/ml）
• 稳定性/保质期：
  Bulk: Should be stored at 5 °C or less.
• 旋光度：
  (c = 1.10, chloroform) [a]23D = -321 ± 2°

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  77
• 可旋转键数：
  7
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.49
• 拓扑面积：
  352
• 氢给体数：
  4
• 氢受体数：
  18

ADMET

毒理性

• 毒性数据

毒性数据：小鼠（腹腔注射）：LD50 400微克/千克

ToxicityData:Mouse(ip): LD50: 400 µg/kg

来源:NCI Investigational Drugs

毒理性

• 毒性数据

毒性数据：小鼠（皮下注射）：LD50 3800微克/千克

ToxicityData:Mouse(sc): LD50: 3800 µg/kg

来源:NCI Investigational Drugs

毒理性

• 毒性数据

毒性数据：小鼠（静脉注射）：LD50 629微克/千克

ToxicityData:Mouse(iv): LD50: 629 µg/kg

来源:NCI Investigational Drugs

毒理性

• 毒性数据

毒性数据：狗（静脉注射）：LDLo 89微克/千克

ToxicityData:Dog(iv): LD Lo: 89 µg/kg

来源:NCI Investigational Drugs

安全信息

• 危险等级：
  6.1(b)
• 危险品标志：
  T
• 危险类别码：
  R46
• WGK Germany：
  3
• RTECS号：
  JW5250000
• 包装等级：
  III
• 危险类别：
  6.1(b)

制备方法与用途

生物活性

Echinomycin (Quinomycin A) 是一种有效的细胞渗透性低氧诱导因子-1（HIF-1）DNA 结合活性的小分子抑制剂，能够选择性地抑制癌症干细胞，其 IC50 值为 29.4 pM。

体外研究

Echinomycin 处理 (0-10 nM; 16 小时；U251 细胞) 显著抑制了缺氧诱导的 VEGF mRNA 表达，呈剂量依赖性。在 U251-HRE 中，Echinomycin 以剂量依赖性的方式非常有效地抑制了缺氧诱导的荧光素酶表达，其半数有效浓度（EC50）为 1.2 nM。

细胞系	浓度 (nM)	孵化时间 (小时)	结果
U251 细胞	0, 0.625, 1.25, 5, 10	16	剂量依赖性地显著抑制了由缺氧诱导的 VEGF mRNA 表达

体内研究

Echinomycin (10 μg/kg；静脉注射；40 天；NOD-SCID 小鼠) 治疗有效地根除了小鼠淋巴瘤和人急性髓系白血病（AML）的小鼠异种移植模型，通过优先消除癌干细胞（CSCs）。HIF1α 维持了小鼠淋巴瘤 CSCs 的存在，通过抑制 notch 途径中的负反馈环路。

动物模型	处理方式	剂量 (μg/kg)	管理方式	结果
NOD-SCID 小鼠接受 1.8 Gy 放射线并静脉注射患者 AML-71 和 AML-150 外周血细胞	静脉注射；40 天	10	成功地根除了小鼠淋巴瘤和人 AML，通过优先消除 CSCs。

反应信息

• 作为反应物：
  描述：

  Echinomycin 在 lithium hydroxide 、 水 作用下， 反应 0.17h， 生成 、 depsiechinoserine
  参考文献：
  名称：

  Structure–activity studies of echinomycin antibiotics against drug-resistant and biofilm-forming Staphylococcus aureus and Enterococcus faecalis

  摘要：

  Four echinomycin antibiotics were isolated from the culture broth of a marine streptomycete, and their structures were determined by a combination of chemical and spectroscopic analyses. Antibiotic activities were measured against drug-resistant and biofilm-forming strains of Staphylococcus aureus and Enterococcus faecalis. Minimum inhibitory concentrations ranging from 0.01 mu M to greater than 14 mu M clearly defined structure-activity relationships for antibiotic potency. Echinomycin was the most active compound with a MIC of 0.03 mu M against methicillin-resistant S. aureus and 0.01 mu M against biofilm-forming E. faecalis. (C) 2009 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2009.01.010

文献信息

• T5 exonuclease-based method to identify DNA topoisomerase inhibitors
  申请人：Leng Fenfei

  公开号：US11268129B1

  公开（公告）日：2022-03-08

  The present invention provides assays and methods for studying DNA topology and topoisomerases. The assays and methods utilize a circular plasmid DNA comprising one or more hairpin structures and the ability of T5 exonuclease (T5E) to digest the circular plasmid DNA in a specific configuration. The assays and methods can be used as a high throughput screening for inhibitors of, for example, DNA gyrases and DNA topoisomerases I for anticancer drug and antibiotics discovery.

  本发明提供了研究DNA拓扑结构和拓扑异构酶的检测方法。这些检测方法利用包含一个或多个发夹结构的环状质粒 DNA 以及 T5 外切酶（T5E）以特定构型消化环状质粒 DNA 的能力。这些检测方法可用于高通量筛选 DNA 回旋酶和 DNA 拓扑异构酶 I 等的抑制剂，以发现抗癌药物和抗生素。
• USES OF HYPOXIA-INDUCIBLE FACTOR INHIBITORS
  申请人：Liu Yang

  公开号：US20120264697A1

  公开（公告）日：2012-10-18

  The present invention relates to treating a hematologic cancer using a Hypoxia- Inducible Factor (HIF inhibitor). The invention also relates to inducing acute myeloid leukemia remission using the HIF inhibitor. The invention further relates to inhibiting a maintenance or survival function of a cancer stem cell (CSC) using the HIF inhibitor.
• A NOVEL AFFINITY MATRIX AND DEVICES FOR ISOLATION AND PURIFICATION OF RNA AND DNA FOR POINT OF CARE MOLECULAR DEVICES
  申请人：Accudx Corporation

  公开号：US20170044519A1

  公开（公告）日：2017-02-16

  The present disclosure relates to nucleic acid extraction and purification methods and devices to accomplish the same. The present disclosure proposes a novel approach to this problem wherein cell isolation and nucleic acid purification can be integrated in a single “step,” by using the same solid phase for both cell adsorption and nucleic acid purification. This is achieved by binding the cells to a solid support as a first step. The same solid support is then used under conditions that lyse the bound cells, and then subsequently enable the nucleic acid to bind to the support. Methods of the present disclosure relate to the isolation of nucleic acid, and especially to a method for isolating DNA from cells, biological or environmental samples using antibiotics, which bind nucleic acids.
• NOVEL AFFINITY MATRIX AND DEVICES FOR ISOLATION AND PURIFICATION OF RNA AND DNA FOR POINT OF CARE MOLECULAR DEVICES
  申请人：AccuDx Corporation

  公开号：US20200199569A1

  公开（公告）日：2020-06-25

  The present disclosure relates to nucleic acid extraction and purification methods and devices to accomplish the same.
• T5 EXONUCLEASE-BASED METHOD TO IDENTIFY DNA TOPOISOMERASE INHIBITORS
  申请人：LENG Fenfei

  公开号：US20220170070A1

  公开（公告）日：2022-06-02

  The present invention provides assays and methods for studying DNA topology and topoisomerases. The assays and methods utilize a circular plasmid DNA comprising one or more hairpin structures and the ability of T5 exonuclease (T5E) to digest the circular plasmid DNA in a specific configuration. The assays and methods can be used as a high throughput screening for inhibitors of, for example, DNA gyrases and DNA topoisomerases I for anticancer drug and antibiotics discovery.