N-{(2S,3S,4S,6R)-3-Hydroxy-2-methyl-6-[(1S,3S)-3,5,12-trihydroxy-3-(2-hydroxy-acetyl)-10-methoxy-6,11-dioxo-1,2,3,4,6,11-hexahydro-naphthacen-1-yloxy]-tetrahydro-pyran-4-yl}-succinamic acid 2,5-dioxo-pyrrolidin-1-yl ester | 861668-33-9

• 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: N-{(2S,3S,4S,6R)-3-Hydroxy-2-methyl-6-[(1S,3S)-3,5,12-trihydroxy-3-(2-hydroxy-acetyl)-10-methoxy-6,11-dioxo-1,2,3,4,6,11-hexahydro-naphthacen-1-yloxy]-tetrahydro-pyran-4-yl}-succinamic acid 2,5-dioxo-pyrrolidin-1-yl ester
• CAS: 861668-33-9
• 化学式: C₃₅H₃₆N₂O₁₆
• 分子量: 740.675
• InChiKey: ZAQLYLJPIFGYDG-RCMKUBKMSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.45
• 重原子数：
  53.0
• 可旋转键数：
  10.0
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.46
• 拓扑面积：
  272.83
• 氢给体数：
  6.0
• 氢受体数：
  16.0

反应信息

• 作为产物：
  描述：

  阿霉素 在 吡啶 作用下， 生成 N-{(2S,3S,4S,6R)-3-Hydroxy-2-methyl-6-[(1S,3S)-3,5,12-trihydroxy-3-(2-hydroxy-acetyl)-10-methoxy-6,11-dioxo-1,2,3,4,6,11-hexahydro-naphthacen-1-yloxy]-tetrahydro-pyran-4-yl}-succinamic acid 2,5-dioxo-pyrrolidin-1-yl ester
  参考文献：
  名称：

  [EN] PROGRAMMABLE POLYMERIC DRUGS
  [FR] MÉDICAMENTS POLYMÈRES PROGRAMMABLES

  摘要：

  披露了作为生物活性化合物有用的化合物。这些化合物具有以下结构（I）：（I）或其立体异构体、互变异构体或盐，其中R1、R2、R3、L、L1、L2、L3、L4、M、m和n如本文所定义。还提供了与这些化合物的制备和使用相关的方法。

  公开号：

  WO2019099789A1

文献信息

• [EN] POLYMERS WITH RIGID SPACING GROUPS COMPRISING BIOLOGICALLY ACTIVE COMPOUNDS<br/>[FR] POLYMÈRES À GROUPES D'ESPACEMENT RIGIDES COMPRENANT DES COMPOSÉS BIOLOGIQUEMENT ACTIFS
  申请人：SONY CORP

  公开号：WO2019140301A1

  公开（公告）日：2019-07-18

  Compounds useful as biologically active compounds are disclosed. The compounds have the following structure (I): or a stereoisomer, tautomer or salt thereof, wherein A, R1, R2, R3, R4, R5, L, L1, L2, L3, L4, M, m and n are as defined herein. Methods associated with preparation and use of such compounds is also provided.

  揭示了作为生物活性化合物有用的化合物。这些化合物具有以下结构（I）：或其立体异构体、互变异构体或盐，其中A、R1、R2、R3、R4、R5、L、L1、L2、L3、L4、M、m和n如本文所定义。还提供了与这些化合物的制备和使用相关的方法。
• 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。
• WO2019140128A5
  申请人：——

  公开号：WO2019140128A5

  公开（公告）日：2022-01-13
• ——
  作者：Yi Luo、Nicole J. Bernshaw、Zheng‐Rong Lu、Jindrich Kopecek、Glenn D. Prestwich

  DOI：10.1023/a:1015170907274

  日期：——

  Purpose. Overexpression of hyaluronan (HA) receptors on cancer cells results in enhanced endocytotic uptake of the drug conjugate. An N-(2-hydroxypropyl)methacrylamide (HPMA)-HA polymeric drug delivery system was used for targeted delivery of doxorubicin to cancer cells.Methods. HA-doxorubicin (DOX) bioconjugates (HA-DOX), and HPMA copolymer-DOX conjugates containing HA as a side chain (HPMA-HA-DOX) were synthesized. The cytotoxicity of the polymer-drug conjugate was evaluated via in vitro cell culture. The internalization of the conjugate was visualized by fluorescence microscopy.Results. Cytotoxicity of HPMA-HA-DOX targeted bioconjugate was higher against human breast cancer (HBL-100), ovarian cancer (SKOV-3), and colon cancer (HCT-116) cells when compared to the non-targeted HPMA-DOX conjugate. Fluorescence confocal microscopy revealed that the targeted HPMA-HA-DOX conjugates were internalized more efficiently by cancer cells relative to the non-targeted HPMA-DOX conjugate. Both HPMA-DOX and HPMA-HA-DOX showed minimal cytotoxicity toward mouse fibroblast NIH 3T3 cells. The internalization of polymer conjugates was correlated with their cytotoxicity.Conclusions. Selective delivery of anti-cancer agents to cancer cells was achieved by biochemical targeting. The HA-modified HPMA copolymer showed improved toxicity due to receptor-mediated uptake of the macromolecular drug.