2'-CBZ-glycyltaxol | 117527-55-6

• 英文名称: 2'-CBZ-glycyltaxol
• CAS: 117527-55-6
• 化学式: C₅₇H₆₀N₂O₁₇
• 分子量: 1045.11
• InChiKey: CQJWKLKBFDEDHA-LVHUYIHISA-N

物化性质

• 沸点：
  1072.0±65.0 °C(Predicted)
• 密度：
  1.39±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  5.21
• 重原子数：
  76.0
• 可旋转键数：
  15.0
• 环数：
  8.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  265.69
• 氢给体数：
  4.0
• 氢受体数：
  17.0

反应信息

• 作为反应物：
  描述：

  2'-CBZ-glycyltaxol 在 palladium on activated charcoal 氢气 作用下， 生成 2'-gly-paclitaxel
  参考文献：
  名称：

  Paclitaxel Delivery Systems: The Use of Amino Acid Linkers in the Conjugation of Paclitaxel with Carboxymethyldextran to Create Prodrugs

  摘要：

  紫杉醇通过其羟基与羧甲基二葡聚糖（CMDex，150 kDa）的氨基酸连接体结合；连接体通过酯键引入紫杉醇的 2′-或 7-羟基。这些共轭物（CMDex-2′-紫杉醇和 CMDex-7-紫杉醇）设计为水溶性，紫杉醇含量在 6-8%（重量/重量）之间，每个糖残基的 CM 基团亚取代度（DS）为 0.6。紫杉醇从共轭物中的释放受引入氨基酸连接体的紫杉醇羟基（2′- 或 7-）和用作连接体的氨基酸的影响。在 37 ℃ 培养 72 小时的小鼠血浆中，使用 2′-gly 的 CMDex 紫杉醇共轭物释放的紫杉醇最多，其次依次是 2′-ala、2′-leu、2′-ile 和 7-gly。将对 Taxol® 有抗药性的结肠癌 26 放入小鼠体内，通过静脉注射共轭物进行肿瘤分布研究，以及间歇性静脉注射共轭物进行肿瘤生长消退研究。在这两项研究中，CMDex-2′-gly-紫杉醇的紫杉醇释放量最高，其次是 CMDex-2′-ala-紫杉醇、CMDex-2′-leu-紫杉醇和紫杉醇。紫杉醇的释放量与观察到的疗效直接相关。CMDex-2′-ile-紫杉醇和CMDex-7-gly-紫杉醇没有显示出任何抗肿瘤活性。这些结果清楚地表明，带有适当氨基酸连接体的 CMDex 紫杉醇对结肠 26 具有显著的抗肿瘤活性，而且这些抗肿瘤作用似乎与肿瘤中释放的紫杉醇量有关。

  DOI：

  10.1248/bpb.25.632
• 作为产物：
  描述：

  紫杉醇 在 N-苄氧羰基甘氨酸 、 N,N'-羰基二咪唑 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 19.0h， 以43.7%的产率得到2'-CBZ-glycyltaxol
  参考文献：
  名称：

  Synthesis of congeners and prodrugs. 3. Water-soluble prodrugs of taxol with potent antitumor activity

  摘要：

  Taxol has shown good in vivo antitumor activity in a number of test systems. The formulation of taxol for antitumor testing has been difficult. Esterification at either C-2' or C-7 resulted in loss of in vitro tubulin assembly activity but not cytotoxicity. These observations suggested that esters at C-2' and/or C-7, which would tend to promote water solubility, might serve as useful prodrugs of taxol. The reaction of taxol with either succinic anhydride or glutaric anhydride in pyridine solution at room temperature gave the crystalline mono 2'-adducts 1b and 1f, respectively. Salts of these acids (1b, 1f, 1i) were formed by the addition of 1 equiv of the corresponding base, followed by evaporation and/or freeze-drying of the solvent(s). The salts had improved antitumor activity as compared to the free acids. The triethanolamine and N-methylglucamine salts showed greatly improved aqueous solubility and were more active than the sodium salts. The glutarate series was preferred because of the higher activity and the higher yields obtained. 2'-Glutaryltaxol (1f) was coupled with 3-(dimethylamino)-1-propylamine, using CDI, to form in excellent yield the amino amide 1o. The hydrochloride salt (1p) showed good solubility and was extremely potent and active. At 10 mg/kg, in the B16 screen, 1p gave a T/C of 352 with 5 out of 10 cures. In the MX-1 breast xenograft assay, this prodrug gave values of -100 at doses of 40 and 20 mg/kg, with all live animals being tumor free.

  DOI：

  10.1021/jm00124a011

文献信息

• [EN] POLYACETAL DRUG CONJUGATES AS RELEASE SYSTEM<br/>[FR] SYSTEME DE LIBERATION DE MEDICAMENT EN DEUX PHASE
  申请人：GEN HOSPITAL CORP

  公开号：WO2005023294A3

  公开（公告）日：2005-06-09