(9Z,12Z,15Z)-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]octadeca-9,12,15-trienamide | 1116566-29-0

• 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: (9Z,12Z,15Z)-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]octadeca-9,12,15-trienamide
• CAS: 1116566-29-0
• 化学式: C₄₅H₅₇NO₁₂
• 分子量: 803.947
• InChiKey: XBKPGLRBLZRDOV-CYJAXVJWSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.6
• 重原子数：
  58
• 可旋转键数：
  19
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.51
• 拓扑面积：
  209
• 氢给体数：
  6
• 氢受体数：
  12

反应信息

• 作为反应物：
  描述：

  (9Z,12Z,15Z)-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]octadeca-9,12,15-trienamide 在 水 作用下， 以 aq. phosphate buffer 为溶剂， 生成 阿霉素
  参考文献：
  名称：

  Synthesis of Doxorubicin α-Linolenic Acid Conjugate and Evaluation of Its Antitumor Activity

  摘要：

  Doxorubicin (DOX) is a broad-spectrum antitumor drug used in the clinic. However, it can cause serious heart toxicity. To increase the therapeutic index of DOX and to attenuate its toxicity toward normal tissues, we conjugated DOX with either alpha-linolenic acid (LNA) or palmitic acid (PA) by a hydrazone or an amide bond to produce DOX-hyd-LNA, DOX-ami-LNA, DOX-hyd-PA, and DOX-ami-PA. The cytotoxicity of DOX-hyd-LNA on HepG2, MCF-7, and MDA-231 cells was higher compared to that of DOX, DOX-ami-LNA, DOX-hyd-PA, and DOX-ami-PA. The cytotoxicity of DOX-hyd-LNA on HUVECs was lower than that of DOX. DOX-hyd-LNA released significantly more DOX in pH 5.0 medium than it did in pH 7.4 medium. DOX-hyd-LNA induced more apoptosis in MCF-7 and HepG2 cells than DOX or DOX-ami-LNA. Significantly more DOX was released from DOX-hyd-LNA in both MCF-7 and HepG2 cells compared with DOX-ami-LNA. Compared to free DOX, a biodistribution study showed that DOX-hyd-LNA greatly increased the content of DOX in tumor tissue and decreased the content of DOX in heart tissue after it was intravenously administered. DOX-hyd-LNA improved the survival rate, prolonged the life span, and slowed the growth of the tumor in tumor-bearing nude mice. These results indicate that DOX-hyd-LNA improved the therapeutic index of DOX. Therefore, DOX-hyd-LNA is a potential compound for use as a cancer-targeting therapy.

  DOI：

  10.1021/mp4004139
• 作为产物：
  描述：

  Γ-十八碳三烯酸 、 盐酸多柔比星 在 N,N'-二环己基碳二亚胺 、 4-二甲氨基吡啶 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 20.25h， 以68%的产率得到(9Z,12Z,15Z)-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]octadeca-9,12,15-trienamide
  参考文献：
  名称：

  阿霉素和不饱和脂肪酸（LNA和DHA）缀合物的合成及其抗癌作用

  摘要：

  阿霉素（DOX）是一种领先的细胞抑制药物，在使用中具有许多不良作用。我们仍在寻找可以使我们保持对肿瘤细胞的治疗效果并减少对正常细胞毒性的方法。在我们的工作中，我们得到的DOX的酰胺衍生物通过与α亚麻酸（LNA）和二十二碳六（DHA）酸（氨基的反应2，3通过酰胺键和酯键（），以及双取代的衍生物4，5）。化合物的结构通过质子核磁共振（1H NMR），碳13核磁共振（13C NMR）和高分辨率质谱（HRMS）分析确定。对于所有化合物，使用3-（4,5-二甲基噻唑基-2）-2,5-二苯基四唑溴化物（MTT）分析法测定对人癌细胞系（SW480，SW620和PC3）和中国仓鼠肺成纤维细胞的细胞毒性作用（V79）用作对照。通过计算抑制浓度IC 50确定细胞毒性活性。另外，对于测试化合物的针对肿瘤细胞的细胞毒性能力表示为选择性因子（选择性指数，SI）。对所有化合物进行乳酸脱氢酶（LDH）测定，以评估细胞损

  DOI：

  10.1007/s00044-019-02443-0

文献信息

• Conjugation with α-linolenic acid improves cancer cell uptake and cytotoxicity of doxorubicin
  作者：Meng-lei Huan、Si-yuan Zhou、Zeng-hui Teng、Bang-le Zhang、Xin-you Liu、Jie-pin Wang、Qi-bing Mei

  DOI：10.1016/j.bmcl.2009.03.016

  日期：2009.5

  The synthetic DOX-LNA conjugate was characterized by proton nuclear magnetic resonance and mass spectrometry. In addition, the purity of the conjugate was analyzed by reverse-phase high-performance liquid chromatography. The cellular uptake, intracellular distribution, and cytotoxicity of DOX-LNA were assessed by flow cytometry, fluorescence microscopy, liquid chromatography/electrospray ionization tandem mass spectrometry, and the tetrazolium dye assay using the in vitro cell models. The DOX-LNA conjugate showed substantially higher tumor-specific cytotoxicity compared with DOX. Crown Copyright (C) 2009 Published by Elsevier Ltd. All rights reserved.
• Synthesis of Doxorubicin α-Linolenic Acid Conjugate and Evaluation of Its Antitumor Activity
  作者：Chun-hui Liang、Wei-liang Ye、Chun-lai Zhu、Ren Na、Ying Cheng、Han Cui、Dao-zhou Liu、Zhi-fu Yang、Si-yuan Zhou

  DOI：10.1021/mp4004139

  日期：2014.5.5

  Doxorubicin (DOX) is a broad-spectrum antitumor drug used in the clinic. However, it can cause serious heart toxicity. To increase the therapeutic index of DOX and to attenuate its toxicity toward normal tissues, we conjugated DOX with either alpha-linolenic acid (LNA) or palmitic acid (PA) by a hydrazone or an amide bond to produce DOX-hyd-LNA, DOX-ami-LNA, DOX-hyd-PA, and DOX-ami-PA. The cytotoxicity of DOX-hyd-LNA on HepG2, MCF-7, and MDA-231 cells was higher compared to that of DOX, DOX-ami-LNA, DOX-hyd-PA, and DOX-ami-PA. The cytotoxicity of DOX-hyd-LNA on HUVECs was lower than that of DOX. DOX-hyd-LNA released significantly more DOX in pH 5.0 medium than it did in pH 7.4 medium. DOX-hyd-LNA induced more apoptosis in MCF-7 and HepG2 cells than DOX or DOX-ami-LNA. Significantly more DOX was released from DOX-hyd-LNA in both MCF-7 and HepG2 cells compared with DOX-ami-LNA. Compared to free DOX, a biodistribution study showed that DOX-hyd-LNA greatly increased the content of DOX in tumor tissue and decreased the content of DOX in heart tissue after it was intravenously administered. DOX-hyd-LNA improved the survival rate, prolonged the life span, and slowed the growth of the tumor in tumor-bearing nude mice. These results indicate that DOX-hyd-LNA improved the therapeutic index of DOX. Therefore, DOX-hyd-LNA is a potential compound for use as a cancer-targeting therapy.
• Synthesis and anticancer effects of conjugates of doxorubicin and unsaturated fatty acids (LNA and DHA)
  作者：Magdalena Mielczarek-Puta、Marta Struga、Piotr Roszkowski

  DOI：10.1007/s00044-019-02443-0

  日期：2019.12

  the therapeutic effect against the tumor cells and reduce the toxicity to the normal cells. In our work, we obtained amide derivatives of DOX by reaction of the amino group with α-linolenic (LNA) and docosahexaenoic (DHA) acids (2, 3), as well as double-substituted derivatives via amide and ester linkages (4, 5). The structures of the compounds were confirmed by Proton Nuclear Magnetic Resonance (1H

  阿霉素（DOX）是一种领先的细胞抑制药物，在使用中具有许多不良作用。我们仍在寻找可以使我们保持对肿瘤细胞的治疗效果并减少对正常细胞毒性的方法。在我们的工作中，我们得到的DOX的酰胺衍生物通过与α亚麻酸（LNA）和二十二碳六（DHA）酸（氨基的反应2，3通过酰胺键和酯键（），以及双取代的衍生物4，5）。化合物的结构通过质子核磁共振（1H NMR），碳13核磁共振（13C NMR）和高分辨率质谱（HRMS）分析确定。对于所有化合物，使用3-（4,5-二甲基噻唑基-2）-2,5-二苯基四唑溴化物（MTT）分析法测定对人癌细胞系（SW480，SW620和PC3）和中国仓鼠肺成纤维细胞的细胞毒性作用（V79）用作对照。通过计算抑制浓度IC 50确定细胞毒性活性。另外，对于测试化合物的针对肿瘤细胞的细胞毒性能力表示为选择性因子（选择性指数，SI）。对所有化合物进行乳酸脱氢酶（LDH）测定，以评估细胞损