WP936 | 932045-57-3

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 蒽环类药物
• 英文名称: WP936
• 英文别名: N-(N-doxorubicinhexanamide)maleimide；6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-N-((2S,3S,4S,6R)-3-hydroxy-2-methyl-6-(((3S)-3,5,12-trihydroxy-3-(2-hydroxyacetyl)-10-methoxy-6,11-dioxo-1,2,3,4,6,11-hexahydrotetracen-1-yl)oxy)tetrahydro-2H-pyran-4-yl)hexanamide；6-(2,5-dioxopyrrol-1-yl)-N-[(2S,3S,4S,6R)-3-hydroxy-2-methyl-6-[[(1S,3S)-3,5,12-trihydroxy-3-(2-hydroxyacetyl)-10-methoxy-6,11-dioxo-2,4-dihydro-1H-tetracen-1-yl]oxy]oxan-4-yl]hexanamide
• CAS: 932045-57-3
• 化学式: C₃₇H₄₀N₂O₁₄
• 分子量: 736.73
• InChiKey: PXBHCOHPUSDOFP-FRTGXRTISA-N

物化性质

• 沸点：
  1011.5±65.0 °C(Predicted)
• 密度：
  1.56±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.8
• 重原子数：
  53
• 可旋转键数：
  12
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.46
• 拓扑面积：
  247
• 氢给体数：
  6
• 氢受体数：
  14

反应信息

• 作为产物：
  描述：

  6-maleimidocaproic acid sodium salt 在 N,N-二异丙基乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 1.67h， 生成 WP936
  参考文献：
  名称：

  Development of elastin-like polypeptide for thermally targeted delivery of doxorubicin

  摘要：

  The chemotherapeutic drug doxorubicin (Dox) is widely used as an antitumor agent in hematological malignancies and solid tumors. However, one of the limitations of its clinical use is that systemic administration of an effective dose of Dox results in nonselective cardiac toxicity and myelosuppression. In order to minimize this nonspecific toxicity, Elastin-like polypeptide (ELP) was examined for its ability to serve as a macromolecular carrier for thermally targeted delivery of Dox. The ELP-based doxorubicin delivery vehicle (Tat-ELP-GFLG-Dox) consists of: (1) a peptide derived from the HIV-1 Tat protein to facilitate its cellular uptake, (2) ELP to allow thermal targeting, and (3) the lysosomally degradable glycylphenylalanylleucylglycine (GFLG) spacer and a cysteine residue conjugated to a thiol reactive doxorubicin derivative. Cytotoxicity of Tat-ELP-GFLG-Dox in MES-SA uterine sarcoma cells was enhanced 20-fold when aggregation of ELP was induced with hyperthermia. The ELP delivered doxorubicin displayed a cytoplasmic distribution and induced temperature dependent caspase activation. (c) 2006 Elsevier Inc. All rights reserved.

  DOI：

  10.1016/j.bcp.2006.10.028

文献信息

• Next generation maleimides enable the controlled assembly of antibody–drug conjugates <i>via</i> native disulfide bond bridging
  作者：Felix F. Schumacher、João P. M. Nunes、Antoine Maruani、Vijay Chudasama、Mark E. B. Smith、Kerry A. Chester、James R. Baker、Stephen Caddick

  DOI：10.1039/c4ob01550a

  日期：——

  Highly homogeneous ADCs are generated by the efficient bridging of interchain disulfide bonds in trastuzumab, using next generation maleimides.

  高度均一的ADCs是通过在曲妥珠单抗中高效地连接链间二硫键，使用下一代马来酰亚胺而生成的。
• Cancer-targeting Antibody–Drug Conjugates: Site-specific Conjugation of Doxorubicin to Anti-EGFR 528 Fab' through a Polyethylene Glycol Linker
  作者：Lisa P. T. Hong、Judith A. Scoble、Larissa Doughty、Gregory Coia、Charlotte C. Williams

  DOI：10.1071/ch11071

  日期：——

  Antibody–drug conjugates have been prepared to examine the effect that attaching small-molecule drugs to an antibody fragment has on antibody activity. The anticancer drug doxorubicin was covalently attached through a polyethylene glycol linker to a cancer-targeting, anti-epidermal growth factor receptor antibody fragment (Fab′). The reactivity of maleimide was compared with a substituted maleimide derivative (citraconimide) in conjugation reactions with cysteine residues on a Fab′. Introduction of polyethylene glycol increased aqueous solubility of the cytotoxic drug, which led to an improvement in overall yield of the conjugation reaction with the antibody fragment. Antibody–drug conjugates prepared retained activity of the parent antibody, as determined by antigen binding experiments measured by surface plasmon resonance.

  我们制备了抗体-药物共轭物，以研究将小分子药物连接到抗体片段对抗体活性的影响。抗癌药物多柔比星通过聚乙二醇连接体共价连接到癌症靶向抗表皮生长因子受体抗体片段（Fab′）上。在与 Fab′ 上的半胱氨酸残基发生共轭反应时，比较了马来酰亚胺与取代的马来酰亚胺衍生物（柠康酰亚胺）的反应性。聚乙二醇的加入增加了细胞毒性药物的水溶性，从而提高了与抗体片段共轭反应的总产率。通过表面等离子共振测量的抗原结合实验确定，制备的抗体-药物共轭物保留了母体抗体的活性。
• WO2007/90094
  申请人：——

  公开号：——

  公开（公告）日：——
• Development of elastin-like polypeptide for thermally targeted delivery of doxorubicin
  作者：Gene L. Bidwell、Izabela Fokt、Waldemar Priebe、Drazen Raucher

  DOI：10.1016/j.bcp.2006.10.028

  日期：2007.3

  The chemotherapeutic drug doxorubicin (Dox) is widely used as an antitumor agent in hematological malignancies and solid tumors. However, one of the limitations of its clinical use is that systemic administration of an effective dose of Dox results in nonselective cardiac toxicity and myelosuppression. In order to minimize this nonspecific toxicity, Elastin-like polypeptide (ELP) was examined for its ability to serve as a macromolecular carrier for thermally targeted delivery of Dox. The ELP-based doxorubicin delivery vehicle (Tat-ELP-GFLG-Dox) consists of: (1) a peptide derived from the HIV-1 Tat protein to facilitate its cellular uptake, (2) ELP to allow thermal targeting, and (3) the lysosomally degradable glycylphenylalanylleucylglycine (GFLG) spacer and a cysteine residue conjugated to a thiol reactive doxorubicin derivative. Cytotoxicity of Tat-ELP-GFLG-Dox in MES-SA uterine sarcoma cells was enhanced 20-fold when aggregation of ELP was induced with hyperthermia. The ELP delivered doxorubicin displayed a cytoplasmic distribution and induced temperature dependent caspase activation. (c) 2006 Elsevier Inc. All rights reserved.