米托蒽醌 | 65271-80-9

• 物质功能分类: 原料药 - 抗肿瘤药 - 抗肿瘤辅助用药
• 分子结构分类: 有机化合物 - 苯类化合物 - 蒽
• 中文名称: 米托蒽醌
• 中文别名: 米拖蒽醌；1,4-二羟基-5,8-双[[2-[(2-羟乙基)氨基]乙基]氨基]-9,10-蒽醌
• 英文名称: novantrone
• 英文别名: Mitoxantron；Mitoxantrone；1,4-dihydroxy-5,8-bis[2-(2-hydroxyethylamino)ethylamino]anthracene-9,10-dione
• CAS: 65271-80-9
• 化学式: C₂₂H₂₈N₄O₆
• 分子量: 444.488
• InChiKey: KKZJGLLVHKMTCM-UHFFFAOYSA-N

物化性质

• 熔点：
  170-1740C
• 沸点：
  554.47°C (rough estimate)
• 密度：
  1.3049 (rough estimate)
• 溶解度：
  DMSO（少量）、甲醇（少量）、水（少量）
• 物理描述：
  Liquid
• 颜色/状态：
  Blue-black solid from water ethanol
• 稳定性/保质期：
  Mitoxantrone HCl is not photolabile. Exposure of the product to direct sunlight for one month caused no change in its appearance or potency. Mitoxantrone HCl 0.2 mg/ml in sodium chloride 0.9% in polypropylene syringes is reported to be stable for 28 days at 4 & 20 °C & for 24 hr at 37 °C. Mitoxantrone HCl 2 mg/ml in glass vials & drawn into 12 ml plastic syringes exhibited no visual changes & little or no loss by HPLC when stored for 42 days at 4 & 23 °C. ... Mitoxantrone HCl 0.2 mg/ml in sterile water for injection was stable in Parker Micropump PVC reservoirs for 14 days at 4 & 37 °C, exhibiting no loss by HPLC. Mitoxantrone HCl was cultured with human lymphoblasts to determine whether its cytotoxic activity was retained. The soln retained cytotoxicity for 24 hr at 4 °C & room temp. The pH range of max stability is 2-4.5. Mitoxantrone HCl was unstable when the pH was increased to 7.4.
• 分解：
  When heated to decomposition it emits toxic fumes of /nitrogen oxides & hydrochloric acid/.

计算性质

• 辛醇/水分配系数(LogP)：
  1
• 重原子数：
  32
• 可旋转键数：
  12
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  163
• 氢给体数：
  8
• 氢受体数：
  10

ADMET

代谢

肝脏的

Hepatic

来源:DrugBank

代谢

肝脏 半衰期：75小时

Hepatic Half Life: 75 hours

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 毒性总结

米托蒽醌是一种能够通过氢键插入脱氧核糖核酸（DNA）的DNA反应性剂，它会导致交联和链断裂。米托蒽醌还能干扰核糖核酸（RNA），并且是一种强效的拓扑异构酶II抑制剂，该酶负责解开和修复受损的DNA。米托蒽醌对培养中的人体细胞，无论增殖还是非增殖，都具有细胞毒作用，这表明它对细胞周期阶段没有特异性。

Mitoxantrone, a DNA-reactive agent that intercalates into deoxyribonucleic acid (DNA) through hydrogen bonding, causes crosslinks and strand breaks. Mitoxantrone also interferes with ribonucleic acid (RNA) and is a potent inhibitor of topoisomerase II, an enzyme responsible for uncoiling and repairing damaged DNA. It has a cytocidal effect on both proliferating and nonproliferating cultured human cells, suggesting lack of cell cycle phase specificity.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 肝毒性

米托蒽醌单药化疗与高达40%的患者血清酶水平升高有关，但这些升高通常为轻到中度严重程度，短暂且不伴有症状或黄疸。据报道，包含米托蒽醌的联合化疗方案中，肝脏酶水平升高的比例更高。在高剂量下，米托蒽醌与高黄疸率有关，但胆红素水平的升高程度轻微，短暂且未与显著的血清酶升高或肝炎证据相关。在接受米托蒽醌治疗的患者中，罕见急性肝损伤的案例，包括一例药物皮疹伴嗜酸性粒细胞增多和系统性症状（DRESS）。发病潜伏期为8周，血清酶升高的模式先是胆汁淤积性，后为混合型。免疫过敏特征显著，并且似乎对皮质类固醇治疗有反应。患者还在使用其他药物，与米托蒽醌的关联并不确定（案例1）。因此，米托蒽醌可能引起特异质性和临床上明显的肝损伤，但这种情况非常罕见。

Chemotherapy with mitoxantrone alone is associated with serum enzyme elevations in up to 40% of patients, but these elevations are generally mild-to-moderate in severity, transient and not accompanied by symptoms or jaundice. Higher rates of liver enzyme elevations have been reported with combination chemotherapeutic regimens that include mitoxantrone. In high doses, mitoxantrone has been associated with a high rate of jaundice, but the degree of hyperbilirubinemia has been mild, transient and not associated with significant serum enzyme elevations or evidence of hepatitis. Rare instances of acute liver injury have been reported in patients taking mitoxantrone, including a single case of drug-rash with eosinophilia and systemic symptoms (DRESS). The latency to onset was 8 weeks and the pattern of serum enzyme elevations was cholestatic and later mixed. Immunoallergic features were prominent and appeared to respond to corticosteroid therapy. Other drugs were being taken and the association with mitoxantrone was not definite (Case 1). Thus, idiosyncratic and clinically apparent liver injury from mitoxantrone may occur but is quite rare.

来源:LiverTox

毒理性

• 药物性肝损伤

化合物：米托蒽醌

Compound:mitoxantrone

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

DILI 注解：较少的药物性肝损伤关注

DILI Annotation:Less-DILI-Concern

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

严重性等级：3

Severity Grade:3

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

• 吸收

口服给药后吸收不良

Poorly absorbed following oral administration

来源:DrugBank

吸收、分配和排泄

• 分布容积

1000升/平方米

1000 L/m2

来源:DrugBank

吸收、分配和排泄

• 清除

21.3 L/hr/m2 [接受15-90 mg/m2静脉给药的老年乳腺癌患者] 28.3 L/hr/m2 [接受15-90 mg/m2静脉给药的非老年鼻咽癌患者] 16.2 L/hr/m2 [接受15-90 mg/m2静脉给药的非老年恶性淋巴瘤患者]

21.3 L/hr/m2 [Elderly patients with breast cancer receiving IV administration of 15-90 mg/m2] 28.3 L/hr/m2 [Non-elderly patients with nasopharyngeal carcinoma receiving IV administration of 15-90 mg/m2] 16.2 L/hr/m2 [Non-elderly patients with malignant lymphoma receiving IV administration of 15-90 mg/m2]

来源:DrugBank

安全信息

• 危险品标志：
  T+,T
• 安全说明：
  S22,S36/37/39,S45,S53
• 危险类别码：
  R46
• WGK Germany：
  3
• 危险品运输编号：
  HAZARD
• RTECS号：
  CB5748500
• 包装等级：
  III
• 危险类别：
  9
• 危险性防范说明：
  P201,P273,P308+P313
• 危险性描述：
  H350,H410
• 储存条件：
  -20°C 冰箱

制备方法与用途

生物活性

Mitoxantrone 是拓扑异构酶II (topoisomerase II) 的抑制剂；也可抑制蛋白激酶C (PKC)，其 IC50 值为 8.5 μM。

靶点

PKC	8.5 μM (IC50)
Topoisomerase II

体外研究

Mitoxantrone 能以竞争性方式抑制 PKC，与组蛋白 H1 的 IC50 值为 6.3 μM，并以非竞争性方式抑制磷脂酰丝氨酸和 ATP。在 B-CLL 细胞中以 0.5 μg/mL 浓度处理 48 小时可导致细胞存活率下降。Mitoxantrone 可引起 DNA 碎裂及多聚（ADP-核糖）聚合酶 (PARP) 的蛋白水解性切割，这表明 Mitoxantrone 的细胞毒性作用是通过诱导凋亡实现的。其对人乳腺癌细胞系 MDA-MB-231 和 MCF-7 的 IC50 值分别为 18 nM 和 196 nM。

体内研究

通过腹腔注射 (IP) 给予 Mitoxantrone 在最佳剂量（1.6 mg/kg/天；作为游离碱）下能显著提高携带 L1210 白血病的小鼠的存活率。在皮下移植 Lewis 肺癌的小鼠中，Mitoxantrone 和 ADM 通过静脉注射 (IV) 同样表现出有效的抗肿瘤活性，分别产生 60% 和 45% 的生存期延长 (ILS)。

化学性质

蓝黑色结晶。熔点为 203-205℃。微溶于水，略溶于乙醇，不溶于氯仿和丙酮。无臭味，易吸潮。

用途

Mitoxantrone 是一种蒽环类抗癌药物，其抗癌活性与阿霉素相似或略高，明显高于环磷酰胺、阿糖胞苷、甲氨喋呤、氟脲嘧啶、长春新碱等常用抗癌药。临床主要用于治疗乳腺癌。

反应信息

• 作为反应物：
  描述：

  米托蒽醌 在 盐酸 作用下， 以 水 为溶剂， 反应 0.5h， 以6.4 g的产率得到novantrone
  参考文献：
  名称：

  抗肿瘤的新化合物及其用途

  摘要：

  本发明的盐酸米托蒽醌ν型、ω型化合物，更易于制备，更利于降低能耗，具有较少的吸湿性、更好的存储稳定性等，适用于制备恶性淋巴瘤、乳腺癌、急性白血病、肺癌、黑色素瘤、软组织肉瘤、多发性骨髓瘤、复发性视神经脊髓炎、多发性硬化症等的治疗或预防的药物中的应用。

  公开号：

  CN110551038B
• 作为产物：
  描述：

  2,3-二氢-1,4,5,8-四羟基-9,10-蒽醌 在 四甲基乙二胺 、 四氯苯醌 作用下， 以 乙二醇甲醚 为溶剂， 生成 米托蒽醌
  参考文献：
  名称：

  Antitumor agents. 1. 1,4-Bis[(aminoalkyl)amino]-9,10-anthracenediones

  摘要：

  The condensation of alkylenediamines with quinizarin or with 2,3-dihydro-1,4,5,8-tetrahydroxy-9,10-anthracenedione, followed by oxidation, gave 1,4-bis[aminoalkyl)amino]-9,10-anthracenediones. Some of these compounds and their 2,3-dihydro derivatives were markedly active against both leukemias and solid tumors in mice. Activity was maximal with 5,8-dihydroxylation and 1,4-bis[(2-aminoethyl)amino] substitution, in which the terminal nitrogen atoms were either unsubstituted (compound 50) or carried 2-hydroxyethyl groups (compound 40), indicating the importance of hydrophilicity. Against B-16 melanoma, 50 gave greater than 433% increase in median life span (ILS) with 7/10 80-day survivors. Against P-388 leukemia, 40 gave greater than 500% ILS with 4/5.60-day survivors; its efficacy and therapeutic index equaled or surpassed those of adriamycin, cyclophosphamide, daunorubicin, methotrexate, or 5-fluorouracil. Against L-1210 leukemia, B-16 melanoma, and colon tumor 26, 40 was generally as effective or more effective than adriamycin and is now undergoing preclinical toxicological evaluation.

  DOI：

  10.1021/jm00195a002
• 作为试剂：
  描述：

  novantrone 、 三乙胺 在 氩 、 乙腈 、 米托蒽醌 、 solution 、 sodium hydroxide 、 水 作用下， 以 乙腈 为溶剂， 反应 214.0h， 生成 米托蒽醌
  参考文献：
  名称：

  Lactones of carboxylic acid polysaccharides and methods for forming conjugates thereof

  摘要：

  提供了多种多糖羧酸的新型内酯及其制备各种共轭物的方法，以及新型共轭物。共轭物包括金属配位顺铂（和卡铂）共轭物，以及椭圆丙素、氨基戊酸酯、米托蒽醌、米托瓜Zone、顺式3-己烯-1-醇和其他亲核生物有效剂的共轭物。还提供了通过偶联剂偶联生物有效剂（如维生素E、DTPA、紫杉醇和紫杉醇酯）的共轭物。

  公开号：

  US20060235211A1

文献信息

• [EN] ACC INHIBITORS AND USES THEREOF<br/>[FR] INHIBITEURS DE L'ACC ET UTILISATIONS ASSOCIÉES
  申请人：GILEAD APOLLO LLC

  公开号：WO2017075056A1

  公开（公告）日：2017-05-04

  The present invention provides compounds I and II useful as inhibitors of Acetyl CoA Carboxylase (ACC), compositions thereof, and methods of using the same.

  本发明提供了化合物I和II，这些化合物可用作乙酰辅酶A羧化酶（ACC）的抑制剂，以及它们的组合物和使用方法。
• THIOXANTHONE RING SYSTEM DERIVATIVES
  申请人：HUANG Hsu-Shan

  公开号：US20120088810A1

  公开（公告）日：2012-04-12

  A thioxanthone ring system derivative compound is provided. The thioxanthone ring system derivative compound is represented by a formula (I): wherein X is a substituent being one selected from a group consisting of halogens, wherein R 1 is a substituent being one selected from a group consisting of sulfur and sulfur dioxide, wherein R 2 is a substituent being one selected from a group consisting of C 1 ˜C 10 alkyl group, C 3 ˜C 10 branched alkyl group, C 3 ˜C 10 cyclic alkyl group, phenyl group, phenyl alkyl group, and wherein hydrogen of phenyl group can be partially substituted by halogens, alkoxyl group, C 1 ˜C 10 alkyl group, nitro group or amine group.

  提供了一种噻二酮环系统衍生物化合物。该噻二酮环系统衍生物化合物由以下式（I）表示： 其中X是从卤素组成的一组取代基之一，其中R1是从硫和二氧化硫组成的一组取代基之一，其中R2是从C1~C10烷基，C3~C10支链烷基，C3~C10环烷基，苯基，苯基烷基中选取的一组取代基，其中苯基的氢可以部分被卤素、烷氧基、C1~C10烷基、硝基或胺基取代。
• [EN] COMPOUNDS AND COMPOSITIONS COMPRISING CDK INHIBITORS AND METHODS FOR THE TREATMENT OF CANCER<br/>[FR] COMPOSÉS ET COMPOSITIONS COMPRENANT DES INHIBITEURS DES CDK ET MÉTHODES DE TRAITEMENT DU CANCER
  申请人：UNIV GEORGIA STATE RES FOUND

  公开号：WO2010129858A1

  公开（公告）日：2010-11-11

  Disclosed herein are compounds suitable for use as antitumor agents, methods for treating cancer wherein the disclosed compounds are used in making a medicament for the treatment of cancer, methods for treating a tumor comprising, administering to a subject a composition comprising one or more of the disclosed cytotoxic agents, and methods for preparing the disclosed antitumor agents.

  本文披露了适用作抗肿瘤药剂的化合物，用于治疗癌症的方法，其中所披露的化合物用于制备治疗癌症的药物，治疗肿瘤的方法包括向受试者施用包含一种或多种所披露的细胞毒性药剂的组合物，以及制备所披露的抗肿瘤药剂的方法。
• Cobalamin conjugates for anti-tumor therapy
  申请人：Weinshenker M. Ned

  公开号：US20050054607A1

  公开（公告）日：2005-03-10

  The present invention provides a cobalamin-drug conjugate suitable for the treatment of tumor related diseases. Cobalamin is indirectly covalently bound to an anti-tumor drug via a cleavable linker and one or more optional spacers. Cobalamin is covalently bound to a first spacer or the cleavable linker via the 5′-OH of the cobalamin ribose ring. The drug is bound to a second spacer of the cleavable linker via an existing or added functional group on the drug. After administration, the conjugate forms a complex with transcobalamin (any of its isoforms). The complex then binds to a receptor on a cell membrane and is taken up into the cell. Once in the cell, an intracellular enzyme cleaves the conjugate thereby releasing the drug. Depending upon the structure of the conjugate, a particular class or type of intracellular enzyme affects the cleavage. Due to the high demand for cobalamin in growing cells, tumor cells typically take up a higher percentage of the conjugate than do normal non-growing cells. The conjugate of the invention advantageously provides a reduced systemic toxicity and enhanced efficacy as compared to a corresponding free drug.

  本发明提供了一种适用于治疗肿瘤相关疾病的钴胺素-药物结合物。钴胺素通过可切割的连接剂间接共价结合到抗肿瘤药物上，还可以通过一个或多个可选的间隔物。钴胺素通过其核糖环的5'-OH与第一间隔物或可切割连接剂共价结合。药物通过其现有或添加的功能基团与可切割连接剂的第二间隔物结合。在给药后，结合物与转钴胺素（其任何同工异构体）形成复合物。然后，该复合物结合到细胞膜上的受体并被细胞摄取。一旦进入细胞，细胞内酶将切割结合物，从而释放药物。根据结合物的结构，特定类别或类型的细胞内酶影响切割。由于生长细胞对钴胺素的需求量较高，肿瘤细胞通常摄取结合物的比例高于正常非生长细胞。本发明的结合物与相应的游离药物相比，具有较低的全身毒性和增强的疗效。
• [EN] SUBSTITUTED N-HETEROCYCLIC CARBOXAMIDES AS ACID CERAMIDASE INHIBITORS AND THEIR USE AS MEDICAMENTS<br/>[FR] CARBOXAMIDES N-HÉTÉROCYCLIQUES SUBSTITUÉS UTILISÉS EN TANT QU'INHIBITEURS DE LA CÉRAMIDASE ACIDE ET LEUR UTILISATION EN TANT QUE MÉDICAMENTS
  申请人：BIAL BIOTECH INVEST INC

  公开号：WO2021055627A1

  公开（公告）日：2021-03-25

  The invention provides substituted N-heterocyclic carboxamides and related compounds, compositions containing such compounds, medical kits, and methods for using such compounds and compositions to treat a medical disorder, e.g., cancer, lysosomal storage disorder, neurodegenerative disorder, inflammatory disorder, in a patient.

  这项发明提供了替代的N-杂环羧酰胺和相关化合物，含有这些化合物的组合物，医疗工具包，以及使用这些化合物和组合物治疗患者的医疗疾病（例如癌症、溶酶体贮积症、神经退行性疾病、炎症性疾病）的方法。