N-Fmoc doxorubicin hemisuccinate

• 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 doxorubicin hemisuccinate
• 英文别名: 4-[2-[(2S,4S)-4-[(2R,4S,5S,6S)-4-(9H-fluoren-9-ylmethoxycarbonylamino)-5-hydroxy-6-methyloxan-2-yl]oxy-2,5,12-trihydroxy-7-methoxy-6,11-dioxo-3,4-dihydro-1H-tetracen-2-yl]-2-oxoethoxy]-4-oxobutanoic acid
• 化学式: C₄₆H₄₃NO₁₆
• 分子量: 865.845
• InChiKey: FNWFYCKYRAUORQ-YAHDECPSSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.5
• 重原子数：
  63
• 可旋转键数：
  14
• 环数：
  8.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  262
• 氢给体数：
  6
• 氢受体数：
  16

反应信息

• 作为反应物：
  描述：

  N-Fmoc doxorubicin hemisuccinate 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 在 N,N-二异丙基乙胺 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 生成 N-Fmoc doxorubicin hemisuccinate
  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

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。
• Synthesis and cytotoxicity evaluation of doxorubicin-polyethyleneimine conjugate as a potential carrier for dual delivery of drug and gene
  作者：Shohreh Alipour、Hadis Chahabdar Shirazi、Maryam Kazemi、Ali Dehshahri、Fatemeh Ahmadi

  DOI：10.1016/j.jddst.2021.102994

  日期：2022.2

  polyethyleneimine as a gene carrier and the chemotherapeutic agent, doxorubicin was synthesized and evaluated. The conjugation of doxorubicin to polyethyleneimine was performed using N-(9-fluroenylmethoxycarbonyl)-DOX-14-O-sccinate, an ester derivative of doxorubicin. Drug release of conjugate was slower than doxorubicin solution of the marketed formulation. Capability of this carrier for delivery of a reporter

  阿霉素是一种广谱化疗药物，主要用于治疗白血病和实体瘤。其治疗效果受到其剂量依赖性心脏毒性和多药耐药性 (MDR) 的限制。克服 MDR 的有希望的策略之一是将药物与可以沉默肿瘤细胞上 P-糖蛋白过度表达的基因共同递送。在这项研究中，合成并评估了使用聚乙烯亚胺作为基因载体和化学治疗剂阿霉素的药物-聚合物偶联物。使用 N-（9-氟烯基甲氧基羰基）-DOX-14-O-sccinate（一种多柔比星的酯衍生物）进行阿霉素与聚乙烯亚胺的缀合。缀合物的药物释放比市售制剂的多柔比星溶液慢。还通过测定缓冲能力、凝胶阻滞和 DNase 保护试验来检查和确认该载体递送报告基因的能力。偶联物对 HepG2 细胞的细胞毒性研究表明，与游离多柔比星相比，在较低浓度下具有更高的毒性。这种较低的浓度提供了使用低剂量药物和降低不良反应发生率的可能性。由于 PEI 被称为基因递送的黄金标准，通过药物和沉默 P-糖蛋白的基因
• Design, synthesis and evaluation of N-acetyl glucosamine (NAG)–PEG–doxorubicin targeted conjugates for anticancer delivery
  作者：Smita K. Pawar、Archana J. Badhwar、Firuza Kharas、Jayant J. Khandare、Pradeep R. Vavia

  DOI：10.1016/j.ijpharm.2012.05.078

  日期：2012.10

  Efficacy of anticancer drug is limited by the severe adverse effects induced by drug; therefore the crux is in designing delivery systems targeted only to cancer cells. Toward this objectives, we propose, synthesis of poly(ethylene glycol) (PEG)-doxorubicin (DOX) prodrug conjugates consisting N-acetyl glucosamine (NAG) as a targeting moiety. Multicomponent system proposed here is characterized by H-1 NMR, UV spectroscopy, and HPLC. The multicomponent system is evaluated for in vitro cellular kinetics and anticancer activity using MCF-7 and MDA-MB-231 cells. Molecular modeling study demonstrated sterically stabilized conformations of polymeric conjugates. Interestingly, PEG-DOX conjugate with NAG ligand showed significantly higher cytotoxicity compared to drug conjugate with DOX. In addition, the polymer drug conjugate with NAG and DOX showed enhanced internalization and retention effect in cancer cells, compared to free DOX. Thus, with enhanced internalization and targeting ability of PEG conjugate of NAG-DOX has implication in targeted anticancer therapy. (c) 2012 Elsevier B.V. All rights reserved.
• Synthesis of Doxorubicin Conjugates Through 14-Hydroxy Group to Melanotransferrin P97
  作者：Qingqi Chen、Damian A. Sowa、Reinhard Gabathuler

  DOI：10.1081/scc-120021828

  日期：2003.1.8

  Using Fmoc to protect the amino group, Fmoc-doxorubicin is conjugated through the 14-hydroxy group to the amino group of melanotransferrin p97 by spacer arms such as succinate and glutarate. The Fmoc group is then removed under basic conditions, which affords doxorubicin-p97 conjugates. The resulting bioconjugates are potential agents for treating brain tumors.