trans-aconityl-doxorubicin | 1039230-32-4

• 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: trans-aconityl-doxorubicin
• 英文别名: (2E)-2-[2-[[(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]amino]-2-oxoethylidene]butanedioic acid
• CAS: 1039230-32-4
• 化学式: C₃₃H₃₃NO₁₆
• 分子量: 699.622
• InChiKey: XULUYSQCLZAMJZ-IAHUKSHJSA-N

物化性质

• 沸点：
  1062.7±65.0 °C(Predicted)
• 密度：
  1.68±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0.8
• 重原子数：
  50
• 可旋转键数：
  10
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.39
• 拓扑面积：
  284
• 氢给体数：
  8
• 氢受体数：
  16

反应信息

• 作为产物：
  描述：

  顺-乌头酸酐 、 阿霉素 在 sodium hydroxide 作用下， 以 1,4-二氧六环 、 水 为溶剂， 反应 0.17h， 生成 乌头多柔比星 、 trans-aconityl-doxorubicin
  参考文献：
  名称：

  PEGylated PAMAM Dendrimer-Doxorubicin Conjugates: In Vitro Evaluation and In Vivo Tumor Accumulation

  摘要：

  研究PEG化程度和药物共轭方式对PEG化聚氨基胺（PAMAM）树枝状聚合物药物递送系统体内外行为的影响。多柔比星（Doxorubicin，DOX）通过对酸敏感的顺式乌头酰连接和对酸不敏感的琥珀酸连接与不同的 PEG 化 PAMAM 树枝状聚合物共轭，分别生成 PPCD 和 PPSD 共轭产物。体外评估包括 pH 依赖性 DOX 释放、细胞毒性、细胞摄取、细胞内化机制和细胞内定位。此外，还通过体内荧光成像观察了肿瘤的蓄积情况。PPCD 共轭物的 DOX 释放遵循酸触发方式，并随着 PEG 化程度的增加而增加。PPCD 结合物对卵巢癌（SKOV-3）细胞的体外细胞毒性随着 PEG 化程度的增加而增加，而细胞吸收则随着 PEG 化程度的增加而减少。PPSD 共轭物在任何测试的 pH 条件下释放的药物都微乎其微，细胞毒性较低。共轭物通过凝集素介导的吸附性内吞作用被 SKOV-3 细胞内化，并被输送到酸性溶酶体，在那里 DOX 从 PPCD 共轭物中释放出来并扩散到细胞核中。PEG化程度最高的PPCD共轭物在接种SKOV-3细胞的小鼠体内显示出最高的肿瘤蓄积性。这些结果表明，PEG化程度最高的PPCD共轭物有望成为实体瘤治疗的候选药物。

  DOI：

  10.1007/s11095-009-9992-1

文献信息

• Synthesis of Poly(vinyl alcohol)-Doxorubicin Conjugates Containing cis-Aconityl Acid-Cleavable Bond and Its Isomer Dependent Doxorubicin Release
  作者：Atsufumi Kakinoki、Yoshiharu Kaneo、Yuka Ikeda、Tetsuro Tanaka、Kahee Fujita

  DOI：10.1248/bpb.31.103

  日期：——

  Aconityl-doxorubicin (ADOX) was synthesized by the modified method of Shen and Ryser. Two isomers of cis-ADOX (cis-configuration) and trans-ADOX (trans-configuration) were generated in the reaction of DOX and cis-aconitic anhydride. These products were separated completely by using HPLC and analyzed by TOF-MS spectroscopy and 1H- and 13C-NMR experiments. The yields of cis-ADOX and trans-ADOX were 36.3 and 44.8%, respectively. The free γ-carboxylic group of ADOX molecule was coupled to poly(vinyl alcohol) (PVA) via ethylenediamine spacer, resulting the macromolecular conjugates of PVA–cis-ADOX and PVA–trans-ADOX, respectively. The DOX content of the conjugates estimated by the hydrolysis method detected the aglycone of DOX which can be estimated as the PVA-bound DOX selectively was 4.4 w/w% which was similar to 4.6 w/w% by the ordinary UV method. Both PVA–cis-ADOX and PVA–trans-ADOX were very stable at neutral pH, but the release of DOX was increased markedly under acidic conditions. Half-life of the release of DOX from PVA–cis-ADOX at pH 5.0 was 3 h which was 4.7-fold shorter than that from PVA–trans-ADOX (14 h). The cytotoxicities of PVA–cis-ADOX and PVA–trans-ADOX were evaluated by using J774.1 cells employing a [3H]uridine incorporation assay as a measure of RNA synthesis. A significant difference in antitumor activity between PVA–cis-ADOX and PVA–trans-ADOX was observed where the former was much active than the later. It was suggested that the conjugate enters the cells and reaches the lysosomal/endosomal compartment, and that the aconityl spacer releases DOX from the conjugate in the acidic compartment of lysosomes/endosomes due to the participation of a free carboxylic group.

  Aconityl-doxorubicin（ADOX）是通过Shen和Ryser的改良方法合成的。在DOX和顺-鬼针草酸无水物的反应中生成了两种同分异构体：顺-ADOX（顺式构型）和反-ADOX（反式构型）。这些产物通过高效液相色谱（HPLC）完全分离，并通过TOF-MS光谱和1H-及13C-NMR实验进行分析。顺-ADOX和反-ADOX的产率分别为36.3%和44.8%。ADOX分子的游离γ-羧基通过乙二胺间隔物与聚乙烯醇（PVA）偶联，从而形成了PVA–顺-ADOX和PVA–反-ADOX的高分子共轭物。通过水解法测定的共轭物中的DOX含量检测到的DOX的非糖苷成分，估算出连接的PVA-bound DOX的含量为4.4 w/w%，与普通UV法测得的4.6 w/w%相似。PVA–顺-ADOX和PVA–反-ADOX在中性pH下非常稳定，但在酸性条件下DOX的释放显著增加。在pH 5.0时，PVA–顺-ADOX释放DOX的半衰期为3小时，比PVA–反-ADOX的14小时短4.7倍。通过使用J774.1细胞，利用[3H]尿苷掺入实验作为RNA合成的测量方法评估了PVA–顺-ADOX和PVA–反-ADOX的细胞毒性。观察到PVA–顺-ADOX和PVA–反-ADOX之间的抗肿瘤活性有显著差异，前者的活性远高于后者。研究表明，该共轭物能够进入细胞并到达溶酶体/内质小体，而鬼针草酸间隔物则通过游离羧基的参与在溶酶体/内质小体的酸性环境中释放DOX。
• PEGylated PAMAM Dendrimer-Doxorubicin Conjugates: In Vitro Evaluation and In Vivo Tumor Accumulation
  作者：Saijie Zhu、Minghuang Hong、Lihong Zhang、Guotao Tang、Yanyan Jiang、Yuanying Pei

  DOI：10.1007/s11095-009-9992-1

  日期：2010.1

  To investigate the effects of PEGylation degree and drug conjugation style on the in vitro and in vivo behavior of PEGylated polyamidoamine (PAMAM) dendrimers-based drug delivery system. Doxorubicin (DOX) was conjugated to differently PEGylated PAMAM dendrimers by acid-sensitive cis-aconityl linkage and acid-insensitive succinic linkage to produce the products of PPCD and PPSD conjugates, respectively. In vitro evaluations including pH-dependent DOX release, cytotoxicity, cellular uptake, cell internalization mechanism, and intracellular localization were performed. Tumor accumulation was also visualized by in vivo fluorescence imaging. DOX release from PPCD conjugates followed an acid-triggered manner and increased with increasing PEGylation degree. In vitro cytotoxicity of PPCD conjugates against ovarian cancer (SKOV-3) cells increased, while cellular uptake decreased with increasing PEGylation degree. PPSD conjugates released negligible drug at any tested pH condition and were less cytotoxic. The conjugates were internalized by SKOV-3 cells via clathrin-mediated and adsorptive endocytosis, and were delivered to acidic lysosomes where DOX was released from PPCD conjugates and diffused into the nuclei. PPCD conjugates with highest PEGylation degree showed the highest tumor accumulation in mice inoculated with SKOV-3 cells. The obtained results suggested that PPCD conjugates with highest PEGylation degree would be a potential candidate for solid tumor treatment.

  研究PEG化程度和药物共轭方式对PEG化聚氨基胺（PAMAM）树枝状聚合物药物递送系统体内外行为的影响。多柔比星（Doxorubicin，DOX）通过对酸敏感的顺式乌头酰连接和对酸不敏感的琥珀酸连接与不同的 PEG 化 PAMAM 树枝状聚合物共轭，分别生成 PPCD 和 PPSD 共轭产物。体外评估包括 pH 依赖性 DOX 释放、细胞毒性、细胞摄取、细胞内化机制和细胞内定位。此外，还通过体内荧光成像观察了肿瘤的蓄积情况。PPCD 共轭物的 DOX 释放遵循酸触发方式，并随着 PEG 化程度的增加而增加。PPCD 结合物对卵巢癌（SKOV-3）细胞的体外细胞毒性随着 PEG 化程度的增加而增加，而细胞吸收则随着 PEG 化程度的增加而减少。PPSD 共轭物在任何测试的 pH 条件下释放的药物都微乎其微，细胞毒性较低。共轭物通过凝集素介导的吸附性内吞作用被 SKOV-3 细胞内化，并被输送到酸性溶酶体，在那里 DOX 从 PPCD 共轭物中释放出来并扩散到细胞核中。PEG化程度最高的PPCD共轭物在接种SKOV-3细胞的小鼠体内显示出最高的肿瘤蓄积性。这些结果表明，PEG化程度最高的PPCD共轭物有望成为实体瘤治疗的候选药物。