乌头多柔比星 | 114390-31-7

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 蒽环类药物
• 中文名称: 乌头多柔比星
• 英文名称: cis-aconityl-doxorubicin
• 英文别名: Aconityldoxorubicin；(2Z)-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: 114390-31-7
• 化学式: C₃₃H₃₃NO₁₆
• 分子量: 699.622
• InChiKey: XULUYSQCLZAMJZ-DZMFYADZSA-N

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 盐酸 、 sodium hydroxide 作用下， 以 1,4-二氧六环 、 水 为溶剂， 反应 0.42h， 生成 乌头多柔比星
  参考文献：
  名称：

  In vitro and in vivo evaluation of stimuli-responsive vesicle from PEGylated hyperbranched PAMAM-doxorubicin conjugate for gastric cancer therapy

  摘要：

  Gastric Cancer is one of the major leading causes of death by cancer worldwide, but the chemotherapeutics, one of the preferred approaches, bring about extensive side effects when systemically injected. In our work, doxorubicin-loaded pH and redox responsive hyperbranched poly (amidoamine)(h-PAMAM)-based vesicle was prepared to enhance anti-tumor efficacy of chemotherapeutic compounds. The doxorubicin (DOX) molecules were attached to PEGylated h-PAMAM by acid sensitive cis-aconityl linkage to form pH sensitive conjugate (PPCD), which self-assembled in THF into micelles. The resulted micelles were then crosslinked by disulfide bonds and transferred from THF into water to form vesicles, which could be disassembled into small-sized conjugates under the redox condition. The drug release profiles showed that the PPCD vesicle presented stimuli-triggered drug release in acidic and reducing environment, and lower DOX leakage under neutral condition. The in vitro cell assay reflected the rapid DOX release and significant tumor-cytotoxic effect of the PPCD vesicle. The in vivo anticancer activity and systematic toxicity studies showed that the PPCD vesicles had lower tissue toxicity with good antitumor effect. In brief, h-PAMAM-based PPCD vesicle provides a safe and effective drug delivery system for the therapy of gastric cancer. (C) 2016 Elsevier B.V. All rights reserved.

  DOI：

  10.1016/j.ijpharm.2016.05.021

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。
• Engineering graphene oxide with ultrasmall SPIONs and smart drug release for cancer theranostics
  作者：Yu Luo、Yan Tang、Tianzhi Liu、Qian Chen、Xiaohan Zhou、Ning Wang、Ming Ma、Yingsheng Cheng、Hangrong Chen

  DOI：10.1039/c8cc09185d

  日期：——

  An intelligent nanoplatform is constructed by conjugating cis-aconitic anhydride-modified doxorubicin to weakly crystallized, ultrasmall SPION loaded graphene oxide (GO) nanosheets. More importantly, the composites present ultrasensitive breakage hydrolysis induced by pH alteration, achieving on-demand, gradual drug release in the tumor microenvironment.

  通过将顺式乌头酸酐修饰的多柔比星与弱结晶的超小 SPION 负载氧化石墨烯（GO）纳米片共轭，构建了一种智能纳米平台。更重要的是，这种复合材料在 pH 值改变的诱导下发生超灵敏的断裂水解，从而在肿瘤微环境中实现按需逐步释放药物。
• Poly(amidoamine) Dendrimer–Doxorubicin Conjugates: <i>In Vitro</i> Characteristics and Pseudosolution Formulation in Pressurized Metered-Dose Inhalers
  作者：Qian Zhong、Sandro R. P. da Rocha

  DOI：10.1021/acs.molpharmaceut.5b00876

  日期：2016.3.7

  Lung cancers are the leading cause of cancer death for both men and women. A series of PEGylated poly(amidoamine) dendrimer-based doxorubicin (DOX) nanocarriers (G3NH(2)-mPEG-nDOX) were synthesized and their chemistry tailored for the development of novel pseudosolution formulations in propellant-based metered dose inhalers (pMDIs) with enhanced aerosol characteristics. A pH-labile bond was used to conjugate DOX to dendrimer for controlled intracellular release. We employed a two-step PEGylation strategy to cover a range of DOX loading and PEGylation density. We investigated the impact of pH, PEGylation density, and DOX payload on the release of DOX from the conjugate. We also determined the cellular internalization of the conjugate, the intracellular release kinetics of DOX from the conjugate, and their ability to kill human alveolar carcinoma cells (A549). The acid-labile conjugates sustained the release of DOX in acidic medium, and also intracellularly, as determined by nuclear colocalization studies with confocal microscopy. Meanwhile, DOX was retained in the conjugate at extracellular physiological conditions, indicating their potential to achieve spatial and temporal controlled release profiles. We also observed that the kinetics of cellular entry of the conjugates with DOX increased significantly compared to free DOX. Due to controlled release, the G3NH2-mPEG-nDOX conjugates showed time dependent cell kill, but their cell kill ability was comparable to free DOX, which suggests their potential in vivo as compared to free DOX. The conjugates were formulated in pMDIs as pseudosolution formulations, with the help of a minimum amount of cosolvent (ethanol; <0.4%; v/v). The physical stability and aerosol characteristics of the conjugates were controlled by the PEGylation density of the carriers: the higher the PEG density, the better the dispersibility and the better the deep lung deposition of the conjugates (fine particle fraction up to ca. 80%).
• pH-sensitive polymeric micelles formed by doxorubicin conjugated prodrugs for co-delivery of doxorubicin and paclitaxel
  作者：Yakun Ma、Xiaohui Fan、Lingbing Li

  DOI：10.1016/j.carbpol.2015.10.050

  日期：2016.2

  A doxorubicin conjugated prodrug incorporated acid-sensitive linkage between drug and Pluronic F127-chitosan (F127-CS) polymer was successfully synthesized. Subsequently a pH-sensitive polymeric micelle system was designed based on the conjugated prodrugs (F127-CS-DOX) to co-deliver doxorubicin and paclitaxel. Paclitaxel (PTX) was physically entrapped in the hydrophobic inner core of the micelles simultaneously. The structures of conjugates were analyzed by means of H-1 NMR and UV-vis spectrum. Size distribution and morphology of the micelles were observed by dynamic light scattering (DLS) and transmission electron microscopy (TEM). The results indicated that obtained micelles had good dispersity and the diameter was between 56.3 and 403.4 nm. The loading of PTX into the micelle increased with higher DOX content. DOX and PTX release from polymeric micelles followed an acid-triggered manner. Furthermore, in vivo pharmacokinetic study also showed that the area under the plasma concentration time curve (AUC(0 infinity)) values of PTX and DOX for PTX-loaded F127-CS-DOX micelles in rats were 3.97 and 4.38-fold higher than those for PTX plus DOX solution. These results suggested the PTX-loaded F127-CS-DOX micelles would be a promising carrier for co-delivering DOX and PTX. (C) 2015 Elsevier Ltd. All rights reserved.