N-Fmoc-dox

• 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-Fmoc-dox
• 英文别名: N-Fmoc-doxorubicin；(9H-Fluoren-9-yl)methyl ((2S,3S,4S,6R)-3-hydroxy-2-methyl-6-(((1S,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)carbamate；9H-fluoren-9-ylmethyl 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]carbamate
• 化学式: C₄₂H₃₉NO₁₃
• 分子量: 765.771
• InChiKey: RDYXRPGVNWOQLW-ZJZRNQTCSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5
• 重原子数：
  56
• 可旋转键数：
  9
• 环数：
  8.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  218
• 氢给体数：
  6
• 氢受体数：
  13

反应信息

• 作为反应物：
  描述：

  N-Fmoc-dox 在 哌啶 、 O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 、 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 3.17h， 生成 14-[(Tetradecanoyl)Succinyl]Doxorubicin
  参考文献：
  名称：

  Synthesis, Anticancer Activities, and Cellular Uptake Studies of Lipophilic Derivatives of Doxorubicin Succinate

  摘要：

  A number of lipophilic 14-substituted derivatives of doxorubicin were synthesized through conjugation of doxorubicin-14-hemisuccinate with different fatty amines or tetradecanol to enhance the lipophilicity, cellular uptake, and cellular retention for sustained anticancer activity. The conjugates inhibited the cell proliferation of human leukemia (CCRF-CEM, 69-76%), colon adenocarcinoma (HT-29, 60-77%), and breast adenocarcinoma (MDA-MB-361, 66-71%) cells at a concentration of 1 mu M after 96-120 h of incubation. The N-tetradecylamido derivative of doxorubicin 14-succinate (10) exhibited consistently comparable antiproliferative activity to doxorubicin in a time-dependent manner (IC50 = 77 nM in CCRF-CEM cells). Flow cytometry analysis showed a 3-fold more cellular uptake of 10 than doxorubicin in SK-OV-3 cells. Confocal microscopy revealed that the conjugate was distributed in cytoplasmic and perinuclear areas during the first 1 h of incubation and slowly relocalized in the nucleus after 24 h. The cellular hydrolysis study showed that 98% of compound 10 was hydrolyzed intracellularly within 48 h and released doxorubicin.

  DOI：

  10.1021/jm201653u
• 作为产物：
  描述：

  阿霉素 、 9-芴甲基-N-琥珀酰亚胺基碳酸酯 以 N,N-二甲基甲酰胺 为溶剂， 生成 N-Fmoc-dox
  参考文献：
  名称：

  靶向降低心脏毒性的药物-确定含有阿霉素，柔红霉素和甲氨蝶呤的GnRH基偶联物对人心肌细胞和内皮细胞的细胞毒性作用。

  摘要：

  背景：由化学治疗药物阿霉素和柔红霉素诱导的心肌病是其在癌症治疗中应用的主要限制因素。趋化药物靶向可能会增加药物的肿瘤选择性并降低其心脏毒性。据报道，促性腺激素释放激素（GnRH）受体在肿瘤细胞表面的表达增加。因此，前述化学治疗药物与基于GnRH的肽的附接可导致具有增加的治疗功效的化合物。本研究的目的是研究抗癌药物-GnRH-缀合物对两种必需的心血管细胞类型，例如心肌细胞和内皮细胞的细胞毒性作用。十六种先前开发的含有阿霉素的GnRH偶联物，本研究对柔红霉素和氨甲蝶呤进行了研究。使用xCELLigence SP系统测定了原代人心肌细胞（HCM）和人脐静脉内皮细胞（HUVEC）的细胞毒性，该系统可测量细胞粘附在孔底部金色电极阵列上引起的阻抗变化。计算阻抗-时间曲线的斜率，并且为了定量确定细胞毒性，分析与对照的差异。结果：在最高测试浓度下，阿霉素和柔红霉素对两种细胞均表现出细胞毒性作用。基于阿霉素

  DOI：

  10.3762/bjoc.14.136

文献信息

• Synthesis of cholesteryl doxorubicin and its anti-cancer activity
  作者：Jong-Soo Choi、Kyung-Oh Doh、Bieong-Kil Kim、Young-Bae Seu

  DOI：10.1016/j.bmcl.2017.01.048

  日期：2017.2

  similar anti-cancer effect as dox, but lipo-dox C and lipo-dox D substituted at amino group did not. As a result, the amino group of dox seems an important site for its cancer cell inhibition. Lipophilic property of lipo-dox A and lipo-dox B induced more accumulation in cells compared to parent drug. Therefore, the newly synthesized lipo-dox A and lipo-dox B would be a good candidate for anti-cancer agent

  阿霉素（dox）已被用作抗癌剂，但存在诸如排泄迅速，保留时间短和心脏毒性之类的缺点。为了赋予dox亲脂性，使用胆固醇衍生物对其进行了修饰，这些胆固醇衍生物已被验证为脂质体基因传递的组成部分。本文介绍了dox衍生物（lipo-dox AD）的合成，其细胞毒性和细胞摄取。在A549，HeLa，MCF7和MDA MB 231细胞系中，被醇基取代的lipo-dox A和lipo-dox B与dox具有相似的抗癌作用，但是被氨基取代的lipo-dox C和lipo-dox D却表现出相似的抗癌作用。不是。结果，Dox的氨基似乎是其抑制癌细胞的重要部位。与母体药物相比，lipo-dox A和lipo-dox B的亲脂性在细胞中诱导了更多的积累。所以，
• 방사선 치료 증폭을 위한 사이토스테롤-독소루비신 유도체 및 이를 유효성분으로 포함하는 암 질환 예방 또는 치료용 조성물
  申请人：Kyungpook National University Industry-Academic Cooperation Foundation 경북대학교 산학협력단(220040016844) BRN ▼504-82-09678

  公开号：KR20200086541A

  公开（公告）日：2020-07-17

  본 발명은 방사선 치료 증폭을 위한 사이토스테롤-독소루비신 유도체 및 이를 유효성분으로 포함하는 암 질환 예방 또는 치료용 조성물에 관한 것으로, 본 발명에서는 β-사이토스테롤을 이용하여 독소루비신 유도체로서 Sito-dox A 및 Sito-dox B를 합성하였으며, 상기 Sito-dox A는 독소루비신 보다 우수한 항암 효과, 및 방사선 요법과의 병용 치료에서 시너지 효과를 나타내고, Sito-dox B는 세포 독성을 나타내지 않았으나, 방사선 요법과의 병용 치료에서 종양 붕괴 현상을 나타내는 것을 확인하였다. 즉, 본 발명의 β-사이토스테롤을 이용하여 합성된 독소루비신 유도체는 방사선 요법과 병용 치료 시, 항암 치료 효과를 증폭시킬 수 있고, 독소루비신의 체내 짧은 체류 시간과 빠른 용출의 단점을 극복할 수 있는 바, 보다 효과적인 암 질환 예방 또는 치료용 약학 조성물, 방사선 치료 민감제용 약학 조성물 등으로 유용하게 활용될 수 있다. 더불어, 사이토스테롤과 구조 및 물성이 유사한 콜릭산, 글리코콜릭산, 타우로콜릭산, 디옥시콜릭산, 케노데옥시콜릭산, 글리코케노디옥시콜릭산, 타우로케노데옥시콜릭산, 콜레스테롤 및 리토콜릭산 등의 지질로 치환된 독소루비신 유도체에서도 사이토스테롤로 치환된 독소루비신 유도체와 유사한 암 치료 효과를 보일 것으로 기대된다.

  This is the Chinese translation of the text you provided: 该发明涉及一种用于放射线治疗增强的鞘固醇-毒素鲁比汀衍生物及其作为有效成分包含在癌症预防或治疗组合物中，该发明利用β-鞘固醇合成了毒素鲁比汀衍生物Sito-dox A和Sito-dox B，其中Sito-dox A表现出比毒素鲁比汀更优越的抗癌效果，并在与放射线疗法联合治疗中显示出协同效应，Sito-dox B虽未表现出细胞毒性，但在与放射线疗法联合治疗中显示出肿瘤崩解现象。换言之，利用本发明的β-鞘固醇合成的毒素鲁比汀衍生物在放射线疗法与联合治疗时，可以增强抗癌治疗效果，并克服毒素鲁比汀在体内短暂停留时间和快速排出的缺点，因此可以更有效地用于癌症预防或治疗的药物组合物，放射线治疗敏感剂用药物组合物等。此外，预计在鞘固醇替代毒素鲁比汀衍生物中，如胆酸、甘露醇胆酸、牛磺酸胆酸、脱氧胆酸、肝胆酸、甘露糖肝胆酸、牛磺酸肝胆酸、胆固醇和脂肪酸等脂质中也替换为鞘固醇的毒素鲁比汀衍生物将表现出类似于鞘固醇替代毒素鲁比汀衍生物的抗癌治疗效果。
• 透明质酸-抗肿瘤药偶联物及复合纳米粒组合 物的制备和应用
  申请人：中国药科大学

  公开号：CN103751795B

  公开（公告）日：2017-02-08

  本发明涉及具有抗肿瘤主动靶向作用的生物降解性透明质酸‑抗肿瘤药物偶联物及复合物纳米粒的制备方法及应用。其特征包括：(1)抗肿瘤药物与连接臂偶联，靶向配基透明质酸或其铵盐与抗肿瘤药物‑连接臂偶联的合成方法；(2)透明质酸‑抗肿瘤药物偶联物与两亲性聚酯嵌段共聚物复合纳米粒的组装新技术。其组合物载药量大大提高，药效提高，体内达到长循环作用，具有肿瘤主动靶向性，降低药物毒副作用。该大分子偶联物及复合物纳米粒组合物可用于注射、口服或黏膜给药；本发明的制备方法工艺成熟、产率较高，适于工业化生产。
• Smart nanocarrier from norbornene based triblock copolymers for the sustained release of multi-cancer drugs
  作者：Vijayakameswara Rao N、Himadri Dinda、Parvathy Venu、Jayasri Das Sarma、Raja Shunmugam

  DOI：10.1039/c4ra07549h

  日期：——

  A stimuli responsive, multi-anticancer drug derived nanocarrier has been synthesized by conjugating doxorubicin, chlorambucil, folate to the backbone of a norbornene polymer. Monomers namely NOR–DOX (mono 1), NOR–CHO (mono 2), and norbornene grafted poly(ethyleneglycol)–folate NOR–PEG–FOL (mono 3), are connected to the norbornene backbone by ester linkers to demonstrate the pH responsive capabilities. The complete chemical and biological properties of the nanocarriers, intended for combination cancer chemotherapy, are discussed. This nanocarrier, DOX–CHO–FOL is designed in such a way that doxorubicin, and chlorambucil, are both conjugated to the same polymer. The presence of the PEG–FOL functionality makes the system water-soluble as well as site-specific. The nanocarrier capabilities are tested by dynamic light scattering, scanning electron and transmission electron microscopies. The drug release profile shows the importance of having the ester linker which helps the drug at the mild acidic conditions resembling the pH of the cancerous cells. Confocal microscope studies confirm the cell internalization of the nanocarrier. MTT assay against 4T cells suggests the importance of the nanocarrier in the anticancer efficacy.

  合成了一种刺激响应型的多抗癌药物衍生纳米载体，通过将多柔比星、氯阿霉素和叶酸共轭到诺尔本烯聚合物的骨架上。单体包括NOR–DOX（单体1）、NOR–CHO（单体2）和诺尔本烯接枝聚乙二醇–叶酸（NOR–PEG–FOL，单体3），通过酯键将其连接到诺尔本烯骨架上，以展示其pH响应能力。文中讨论了这种针对组合癌症化疗的纳米载体的完整化学和生物特性。这个纳米载体DOX–CHO–FOL的设计方式使得多柔比星和氯阿霉素都共轭到同一聚合物上。PEG–FOL功能的存在使得该系统既水溶性又具有靶向特性。通过动态光散射、扫描电子显微镜和透射电子显微镜测试纳米载体的能力。药物释放曲线显示了酯键的重要性，该键在模拟癌细胞pH的弱酸性条件下有助于药物释放。共聚焦显微镜研究确认了纳米载体的细胞内化。针对4T细胞的MTT实验表明纳米载体在抗癌疗效中的重要性。
• 阿霉素-胆酸缀合物,其合成,活性和应用
  申请人：首都医科大学

  公开号：CN107686498B

  公开（公告）日：2020-11-27

  本发明公开了下式的阿霉素-胆酸缀合物(简称BCBAOLys)，公开了它的制备方法，公开了它的抗肿瘤活性，公开了它的抗炎活性。本发明的特征在于，在抗肿瘤治疗中BCBAOLys完全消除了阿霉素的肝、肾和心脏毒性。本发明的特征还在于，在抗炎治疗中BCBAOLys的活性比胆酸强10倍。因而本发明公开了BCBAOLys在制备抗肿瘤药物和抗炎药物中的应用。