阿霉素 | 23214-92-8

• 物质功能分类: 原料药 - 抗肿瘤药 - 抗生素类抗肿瘤药
• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 蒽环类药物
• 中文名称: 阿霉素
• 中文别名: 10-((3-氨基-2,3,6-三去氧-alpha-L-来苏-己吡喃基)氧)-7,8,9,10-四氢-6,8,11-三羟基-8-羟乙酰基-1-甲氧基-5,12-萘二酮；多柔比星；羟基红比霉素；10-((3-氨基-2,3,6-三去氧-alpha-L-来苏-己吡喃基)氧)-7,8,9,10-四氢-6,8,11-三羟基-8-羟乙酰基-1-；羟基柔红霉素；亚法里亚霉素；14-羟正定霉素
• 英文名称: doxorubicin
• 英文别名: adriamycin；DOX；doxil；ADR；doxorubicine；doxorubicin hydrochloride；Adriacin；DOXO；ADM；DXR；(8S,10S)-10-(4-amino-5-hydroxy-6-methyltetrahydro-2H pyran-2-yloxy)-6,8,11-trihydroxy-8-(2-hydroxyacetyl )-1-methoxy-7,8,9,10-tetrahydrotetracene-5,12-dione；(7S,9S)-7-[(2R,4S,5S,6S)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-4-methoxy-8,10-dihydro-7H-tetracene-5,12-dione；hydroxyldaunorubicin；hydroxydaunorubicin；doxorubucin；(1S,3S)-3-glycoloyl-3,5,12-trihydroxy-10-methoxy-6,11-dioxo-1,2,3,4,6,11-hexahydro-1-tetracenyl 3-amino-2,3,6-trideoxy-α-L-lyxo-hexopyranoside；doxorobucin；NSC 123127；doxrubicin；caelyx；(1S,3S)-3,5,12-trihydroxy-3-(hydroxyacetyl)-10-methoxy-6,11-dioxo-1,2,3,4,6,11-hexahydrotetracen-1-yl 3-amino-2,3,6-trideoxy-α-L-lyxo-hexopyranoside；hydroxydaunomycin；DOX·HCl；doxorrubicin；adriamycine；negwer；rubex；DXN；DXO
• CAS: 23214-92-8
• 化学式: C₂₇H₂₉NO₁₁
• mdl: MFCD00869292
• 分子量: 543.527
• InChiKey: AOJJSUZBOXZQNB-TZSSRYMLSA-N

物化性质

• 熔点：
  205°C
• 沸点：
  617.77°C (rough estimate)
• 密度：
  1.3783 (rough estimate)
• 溶解度：
  DMSO 中≥27.2 mg/mL；不溶于乙醇；超声检测水中≥24.8 mg/mL
• 物理描述：
  Solid
• 颜色/状态：
  Red, crystalline solid
• 蒸汽压力：
  2.5X10-23 at 25 °C (est)
• 稳定性/保质期：
  Neutral aq soln are stable at room temp
• 旋光度：
  Specific optical rotation: +248 deg at 20 °C/D (0.1% in methanol)
• 分解：
  When heated to decomposition /temp unspecified/, adriamycin emits toxic fumes of ... /nitrogen oxides/ and hydrochloric acid.
• Caco2细胞的药物渗透性：
  -6.8
• 解离常数：
  pKa1 = 7.34 (phenol); pKa2 = 8.46 (amine); pKa3 = 9.46 (est)
• 碰撞截面：
  227 Ų [M+H]+ [CCS Type: TW, Method: calibrated with polyalanine and drug standards]

计算性质

• 辛醇/水分配系数(LogP)：
  1.3
• 重原子数：
  39
• 可旋转键数：
  5
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.444
• 拓扑面积：
  206
• 氢给体数：
  6
• 氢受体数：
  12

ADMET

代谢

多柔比星能够经历三种代谢途径：单电子还原、双电子还原和脱糖基化。然而，大约一半的剂量以不变的形式从体内消除。双电子还原产生多柔比星醇，这是一种二级醇。这一途径被认为是主要的代谢途径。单电子还原通过几种氧化还原酶来形成多柔比星半醌自由基，这些酶包括线粒体和细胞质NADPH脱氢酶、黄嘌呤氧化酶和一氧化氮合酶。脱糖基化是一种次要的代谢途径（大约1-2%的剂量经历这一途径）。产生的代谢物是通过还原或水解形成的脱氧糖苷元或羟基糖苷元。可能参与这一途径的酶包括黄嘌呤氧化酶、NADPH-细胞色素P450还原酶和细胞质NADPH脱氢酶。

Doxorubicin is capable of undergoing 3 metabolic routes: one-electron reduction, two-electron reduction, and deglycosidation. However, approximately half of the dose is eliminated from the body unchanged. Two electron reduction yields doxorubicinol, a secondary alcohol. This pathway is considered the primary metabolic pathway. The one electron reduction is facilitated by several oxidoreductases to form a doxirubicin-semiquinone radical. These enzymes include mitochondrial and cystolic NADPH dehydrogenates, xanthine oxidase, and nitric oxide synthases. Deglycosidation is a minor metabolic pathway (1-2% of the dose undergoes this pathway). The resultant metabolites are deoxyaglycone or hydroxyaglycone formed via reduction or hydrolysis respectively. Enzymes that may be involved with this pathway include xanthine oxidase, NADPH-cytochrome P450 reductase, and cytosolic NADPH dehydrogenase.

来源:DrugBank

代谢

非包封的阿霉素通过NADPH依赖的醇酮还原酶代谢为亲水性的13-羟基代谢物多柔比星酚，该代谢物具有抗肿瘤活性，是主要的代谢物；这些还原酶存在于几乎所有细胞中，尤其是在红细胞、肝脏和肾脏中。尽管尚未明确建立，但多柔比星酚似乎也是导致该药物心脏毒性的部分。在单次静脉注射10至50毫克/平方米剂量的多柔比星盐酸作为PEG稳定的脂质体注射剂后，多柔比星酚的血浆浓度不可检测或较低（即0.8-26.2 ng/mL）；尚需确定这样的脂质体包封的蒽环类抗生素是否比传统的（非包封）药物心脏毒性更小，目前也应当对脂质体制剂采取非包封药物通常的预防措施。在使用PEG稳定的脂质体注射剂时，多柔比星通常主要代谢物的显著降低或缺失的血浆浓度表明，要么药物在脂质体循环时并未显著释放，要么一些多柔比星可能被释放，但多柔比星酚的消除速率远远超过了释放速率；未用PEG稳定的脂质体中包封的多柔比星盐酸被代谢为多柔比星酚。

Nonencapsulated doxorubicin is metabolized by NADPH-dependent aldoketoreductases to the hydrophilic 13-hydroxyl metabolite doxorubicinol, which exhibits antineoplastic activity and is the major metabolite; these reductases are present in most if not all cells, but particularly in erythrocytes, liver, and kidney. Although not clearly established, doxorubicinol also appears to be the moiety responsible for the cardiotoxic effects of the drug. Undetectable or low plasma concentrations (ie, 0.8-26.2 ng/mL) of doxorubicinol have been reported following iv administration of a single 10- to 50-mg/sq m dose of doxorubicin hydrochloride as a PEG-stabilized liposomal injection; it remains to be established whether such liposomally encapsulated anthracyclines are less cardiotoxic than conventional (nonencapsulated) drug, and the usual precautions for unencapsulated drug currently also should be observed for the liposomal preparation. Substantially reduced or absent plasma concentrations of the usual major metabolite of doxorubicin observed with the PEG-stabilized liposomal injection suggests that either the drug is not released appreciably from the liposomes as they circulate or that some doxorubicin may be released but that the rate of doxorubicinol elimination greatly exceeds the release rate; doxorubicin hydrochloride encapsulated in liposomes that have not been PEG-stabilized is metabolized to doxorubicinol.

来源:Hazardous Substances Data Bank (HSDB)

代谢

其他代谢物在治疗上是不活跃的，包括水溶性差的苷元、多柔比星酮（阿霉素酮）和7-脱氧多柔比星酮（17-脱氧阿霉素酮）以及它们的结合物。苷元是通过微粒体内的NADPH依赖性、细胞色素还原酶介导的氨基糖部分裂解形成的。多柔比星还原为7-脱氧苷元的过程对药物的细胞毒性效果很重要，因为它会产生导致广泛细胞损伤和死亡的羟基自由基。在非包裹型多柔比星中，给药后5分钟内，超过20%的总药物以代谢物的形式存在于血浆中，30分钟内达到70%，4小时内达到75%，24小时内达到90%。

Other metabolites, which are therapeutically inactive, include the poorly water-soluble aglycones, doxorubicinone (adriamycinone) and 7-deoxydoxorubicinone (17-deoxyadriamycinone), and conjugates. The aglycones are formed in microsomes by NADPH-dependent, cytochrome reductase-mediated cleavage of the amino sugar moiety. The enzymatic reduction of doxorubicin to 7-deoxyaglycones is important to the cytotoxic effect of the drug since it results in hydroxyl radicals that cause extensive cell damage and death. With nonencapsulated doxorubicin, more than 20% of the total drug in plasma is present as metabolites as soon as 5 minutes after a dose, 70% in 30 minutes, 75% in 4 hours, and 90% in 24 hours.

来源:Hazardous Substances Data Bank (HSDB)

代谢

至少已确定有6种代谢物，其中主要的是阿霉素醇。这种产物是由白细胞和红细胞中发现的酶以及可能存在于恶性组织中的酶，将C13上的酮基还原而来。

... At least 6 metabolites have been identified, the principal one being adriamycinol. This product results from redn of the keto group on C13 by an enzyme found in leukocytes and erythrocytes, and presumably in malignant tissues.

来源:Hazardous Substances Data Bank (HSDB)

代谢

多柔比星被转化为多柔比星醇、糖苷元和其他衍生物。

Doxorubicin is converted to doxorubicinol, to aglycones, and to other derivatives

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

多柔比星具有抗有丝分裂和细胞毒性活性，通过多种提出的机制发挥作用：多柔比星通过与碱基对之间的嵌入形成与DNA的复合物，并且通过稳定DNA-拓扑异构酶II复合物来抑制拓扑异构酶II的活性，阻止拓扑异构酶II催化的连接-再连接反应中的再连接部分。

Doxorubicin has antimitotic and cytotoxic activity through a number of proposed mechanisms of action: Doxorubicin forms complexes with DNA by intercalation between base pairs, and it inhibits topoisomerase II activity by stabilizing the DNA-topoisomerase II complex, preventing the religation portion of the ligation-religation reaction that topoisomerase II catalyzes.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 药物性肝损伤

化合物：多柔比星

Compound:doxorubicin

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

严重程度等级：3

Severity Grade:3

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

“标签部分：不良反应”

Label Section:Adverse reactions

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

• 消除途径

在5天内，40%的剂量出现在胆汁中。在同一时间段内，5-12%的药物及其代谢物出现在尿液中。在尿液中回收的剂量中，不到3%是多柔比星醇。

40% of the dose appears in bile in 5 days. 5-12% of the drug and its metabolites appears in urine during the same time period. <3% of the dose recovered in urine was doxorubicinol.

来源:DrugBank

吸收、分配和排泄

• 分布容积

分布半衰期是5分钟，这表明多柔比星能迅速被组织摄取。稳态分布体积为809至1214 L/m²。

The distributive half-life is 5 minutes, which suggests that doxorubicin is rapidly taken up by tissue. Steady state volume of distribution = 809 to 1214 L/m2

来源:DrugBank

吸收、分配和排泄

• 清除

324-809 mL/min/m2 [通过代谢和胆汁排泄] 1088 mL/min/m2 [男性] 433 mL/min/m2 [女性] 1540 mL/min/m2 [大于2岁的儿童接受10至75 mg/m2剂量的给药] 813 mL/min/m2 [小于2岁的婴儿接受10至75 mg/m2剂量的给药]

324-809 mL/min/m2 [by metabolism and biliary excretion] 1088 mL/min/m2 [Men] 433 mL/min/m2 [Women] 1540 mL/min/m2 [children greater than 2 years of age receiving administration of 10 to 75 mg/m2 doses] 813 mL/min/m2 [infants younger than 2 years of age receiving administration of 10 to 75 mg/m2 doses]

来源:DrugBank

吸收、分配和排泄

盐酸阿霉素非包封形式在胃酸中不稳定，动物研究表明该药物从胃肠道吸收很少，甚至几乎没有。该药物对组织极为刺激，因此必须静脉给药。在AIDS相关卡波西肉瘤患者中，单次静脉输注10或20毫克/平方米剂量的脂质体阿霉素后，平均血浆阿霉素（大部分与脂质体结合）浓度分别为4.33或10.1微克/毫升，输注时间为15分钟，4.12或8.34微克/毫升，输注时间为30分钟。在AIDS相关卡波西肉瘤的成人中，静脉输注15分钟40毫克/平方米剂量的脂质体阿霉素后，平均血浆峰浓度为20.1微克/毫升。

Nonencapsulated doxorubicin hydrochloride is not stable in gastric acid, and animal studies indicate that the drug undergoes little, if any, absorption from the GI tract. The drug is extremely irritating to tissues and, therefore, must be administered iv. Following iv infusion of a single 10- or 20-mg/sq m dose of liposomal doxorubicin hydrochloride in patients with AIDS-related Kaposi's sarcoma, average peak plasma doxorubicin (mostly bound to liposomes) concentrations are 4.33 or 10.1 ug/mL, respectively, following a 15-minute infusion and 4.12 or 8.34 ug/mL, respectively, following a 30-minute infusion. Following iv infusion over 15 minutes of a 40-mg/sq m dose of liposomal doxorubicin hydrochloride in adults with AIDS-related Kaposi's, peak plasma concentrations averaged 20.1 ug/mL.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

非包封（常规）盐酸阿霉素表现出线性药代动力学；聚乙二醇稳定的脂质体盐酸阿霉素在10-20 mg/平方米的剂量范围内也表现出剂量正比的线性药代动力学。据报道，在50 mg/平方米的剂量下，脂质体包封的阿霉素的药代动力学是非线性的。在50 mg/平方米的剂量下，预计消除半衰期会更长，清除率低于20 mg/平方米剂量时观察到的清除率，血浆浓度-时间曲线下的面积会有大于比例的增加。将盐酸阿霉素包封在聚乙二醇稳定的（隐形）脂质体中，与传统的静脉注射制剂（即，非包封药物）相比，显著改变了药物的药代动力学，导致药物分布到外周室减少，分布到卡波西肉瘤病变增加，血浆清除率降低。

Nonencapsulated (conventional) doxorubicin hydrochloride exhibits linear pharmacokinetics; PEG-stabilized liposomal doxorubicin hydrochloride also exhibits dose-proportional, linear pharmacokinetics over a dosage range of 10-20 mg/sq m. The pharmacokinetics of liposomally encapsulated doxorubicin at a dose of 50 mg/sq m have been reported to be nonlinear. At a dose of 50 mg/sq m, a longer elimination half-life and lower clearance compared to those observed with a 20 mg/sq m dose are expected, with greater-than-proportional increases in area under the plasma concentration-time curve. Encapsulation of doxorubicin hydrochloride in PEG-stabilized (Stealth) liposomes substantially alters the pharmacokinetics of the drug relative to conventional iv formulations (ie, nonencapsulated drug), with resultant decreased distribution into the peripheral compartment, increased distribution into Kaposi's lesions, and decreased plasma clearance.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 储存条件：
  库房应保持通风、低温和干燥，并与其他食品原料分开存放。

SDS

Material Safety Data Sheet

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Section 1. Identification of the substance
Product Name: Adriamycin
Synonyms:

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Section 2. Hazards identification
Harmful by inhalation, in contact with skin, and if swallowed.

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Section 3. Composition/information on ingredients.
Ingredient name: Adriamycin
CAS number: 23214-92-8

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Section 4. First aid measures
Skin contact: Immediately wash skin with copious amounts of water for at least 15 minutes while removing
contaminated clothing and shoes. If irritation persists, seek medical attention.
Eye contact: Immediately wash skin with copious amounts of water for at least 15 minutes. Assure adequate
flushing of the eyes by separating the eyelids with fingers. If irritation persists, seek medical
attention.
Inhalation: Remove to fresh air. In severe cases or if symptoms persist, seek medical attention.
Ingestion: Wash out mouth with copious amounts of water for at least 15 minutes. Seek medical attention.

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Section 5. Fire fighting measures
In the event of a fire involving this material, alone or in combination with other materials, use dry
powder or carbon dioxide extinguishers. Protective clothing and self-contained breathing apparatus
should be worn.

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Section 6. Accidental release measures
Personal precautions: Wear suitable personal protective equipment which performs satisfactorily and meets local/state/national
standards.
Respiratory precaution: Wear approved mask/respirator
Hand precaution: Wear suitable gloves/gauntlets
Skin protection: Wear suitable protective clothing
Eye protection: Wear suitable eye protection
Methods for cleaning up: Mix with sand or similar inert absorbent material, sweep up and keep in a tightly closed container
for disposal. See section 12.
Environmental precautions: Do not allow material to enter drains or water courses.

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Section 7. Handling and storage
Handling: This product should be handled only by, or under the close supervision of, those properly qualified
in the handling and use of potentially hazardous chemicals, who should take into account the fire,
health and chemical hazard data given on this sheet.
Store in closed vessels, refrigerated.
Storage:

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Section 8. Exposure Controls / Personal protection
Engineering Controls: Use only in a chemical fume hood.
Personal protective equipment: Wear laboratory clothing, chemical-resistant gloves and safety goggles.
General hydiene measures: Wash thoroughly after handling. Wash contaminated clothing before reuse.

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Section 9. Physical and chemical properties
Appearance: Not specified
Boiling point: No data
No data
Melting point:
Flash point: No data
Density: No data
Molecular formula: C27H29NO11
Molecular weight: 543.5

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Section 10. Stability and reactivity
Conditions to avoid: Heat, flames and sparks.
Materials to avoid: Oxidizing agents.
Possible hazardous combustion products: Carbon monoxide, nitrogen oxides.

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Section 11. Toxicological information
No data.

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Section 12. Ecological information
No data.

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Section 13. Disposal consideration
Arrange disposal as special waste, by licensed disposal company, in consultation with local waste
disposal authority, in accordance with national and regional regulations.

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Section 14. Transportation information
Non-harzardous for air and ground transportation.

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Section 15. Regulatory information
No chemicals in this material are subject to the reporting requirements of SARA Title III, Section
302, or have known CAS numbers that exceed the threshold reporting levels established by SARA
Title III, Section 313.

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SECTION 16 - ADDITIONAL INFORMATION
N/A

制备方法与用途

抗肿瘤抗生素——阿霉素 概述

阿霉素，又称14-羟正定霉素、14-羟柔红霉素、多柔比星、阿得里亚霉素、亚德里亚霉素或羟基红比霉素，是一种由波赛链霉菌青灰亚种（Streptomyces peucetius subsp caesius）产生的蒽环类抗肿瘤抗生素。其为细胞周期非特异性药物，对S及M期细胞较为敏感。阿霉素是橘红色针状结晶，熔点在204～205℃之间，易溶于水和乙醇甲醇等溶剂。虽然水溶液相对稳定，但在酸性或碱性环境中不稳定。其盐酸盐为橙黄色，在中性和碱性条件下呈橙红色和紫蓝色。

生物化学与药理作用 作用机制

阿霉素通过在DNA相邻碱基对之间插入醌-氢醌结构产生活性自由基，导致DNA双股螺旋解旋及断裂，干扰转录过程并阻止mRNA合成。此外，它还能引起细胞膜破裂，发挥细胞毒性作用。总体而言，阿霉素是一种细胞周期非特异性药物，对各期细胞均有影响，尤其在S期和M期更为敏感。

临床应用

阿霉素广泛应用于多种恶性肿瘤的治疗，包括急性或慢性淋巴细胞白血病、霍奇金与非霍奇金淋巴瘤、恶性淋巴瘤等。此外，它也被用于治疗尤文瘤、骨肉瘤、软组织瘤、肺癌、绒毛膜上皮癌、乳腺癌和膀胱癌等。

不良反应与副作用 心脏毒性

阿霉素过量使用可能导致心电图异常、心律不齐甚至充血性心力衰竭。晚期慢性心肌病变，可能引发不可逆的心肌损伤，严重时可导致死亡。

骨髓抑制

该药物还可能导致白细胞减少、血小板减少及贫血等骨髓抑制症状。

药物相互作用

阿霉素与柔红霉素、长春新碱和放线菌素D有交叉耐药性；同时，它与环磷酰胺、氟尿嘧啶、甲氨蝶呤、氯烯咪胺、顺铂以及亚硝基脲类药物有协同作用。此外，在使用期间应避免活病毒疫苗接种，并且与硫唑嘌呤或巯嘌呤合用可能会增加肝毒性。

物理化学性质 急性毒性

阿霉素的腹腔注射LD50值分别为大鼠16毫克/公斤、小鼠1.07毫克/公斤。

可燃性危险特性

阿霉素可燃，燃烧时释放有毒氮氧化物和氯化氢烟雾。库房应保持通风干燥，并与食品原料分开存放。

安全储存

建议在低温干燥的环境下保存药物，并使用干粉、泡沫、砂土、二氧化碳或雾状水作为灭火剂。

类别

有毒物品

毒性分级

高毒

通过以上信息，可以全面了解阿霉素的作用机制、临床应用及其潜在风险和相互作用。在实际操作中需谨慎遵循医嘱，并确保安全储存与处置。

反应信息

• 作为反应物：
  描述：

  阿霉素 在 咪唑 、 甲醇 、 sodium tetrahydroborate 、 乙醇 、 四丁基氟化铵 、 水 、 二甲基亚砜 、 三氟乙酸酐 、 sodium hydroxide 作用下， 以 甲醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 24.0h， 生成 盐酸表柔比星
  参考文献：
  名称：

  Method for Preparing Epirubicin and Intermediate Thereof

  摘要：

  本发明提供了一种制备依托泊甙的方法及适用于该方法的中间体。制备方法可能包括：将叔丁基二甲基硅氯与N-三氟乙酰阿霉素反应，得到第一化合物N-三氟乙酰-14-O-叔丁基二甲基硅基阿霉素；将第一化合物氧化，得到第二化合物4'-酮基-N-三氟乙酰-14-O-叔丁基二甲基硅基阿霉素；将第二化合物还原，得到第三化合物N-三氟乙酰-14-O-叔丁基二甲基硅基依托泊甙；并对第三化合物进行去保护和水解反应，得到依托泊甙。本发明方法成本低，反应步骤少，产率高，产品纯度高，并且避免了传统方法中溴化反应引起的严重污染。

  公开号：

  US20160137683A1
• 作为产物：
  描述：

  道诺霉素 在 cytochrome P₄₅₀ monoxygenase DoxA 作用下， 生成 阿霉素
  参考文献：
  名称：

  Understanding of real alternative redox partner of Streptomyces peucetius DoxA: Prediction and validation using in silico and in vitro analyses

  摘要：

  Streptomyces peucetius ATCC27952 contains the cytochrome P450 monoxygenase DoxA that is responsible for the hydroxylation of daunorubicin into doxorubicin. Although S. peucetius ATCC27952 contains several potential redox partners, the most suitable endogenous electron-transport system is still unclear; therefore, we conducted a study of potential redox partners using Accelrys Discovery Studio 3.5. Recombinant DoxA along with its redox partners from S. peucetius FDX1, FDR2, and FDX3, and the putidaredoxin and putidaredoxin reductase from Pseudomonas putida that are essential equivalents of the class I type of bacterial electron-transport system were over-expressed and purified. The successful development of an efficient redox system was achieved by an in vitro enzymatic catalysis reaction with DoxA. The optimal pH for the activation of the heme was 7.6 and the optimal temperature was 30 degrees C. Our findings suggest a two-fold increase of DoxA activity via the NADH -> FDR2 -> FDX1 -> DoxA pathway for the hydroxylation of the daunorubicin, and indicate that the usage of a native redox partner may increase daunorubicin-derived doxorubicin production due to the inclusion of DoxA. (C) 2015 Elsevier Inc. All rights reserved.

  DOI：

  10.1016/j.abb.2015.08.019
• 作为试剂：
  描述：

  4,5-dimethoxy-2-nitrobenzyl-p-nitrophenyl carbonate 、 doxazolidine 在 阿霉素 、 1-羟基苯并三唑 作用下， 以 二甲基亚砜 为溶剂， 以62%的产率得到
  参考文献：
  名称：

  [EN] ANTHRACYCLINE PRODRUGS AND METHODS OF MAKING AND USING THE SAME
  [FR] PROMÉDICAMENTS D'ANTHRACYNE ET PROCÉDÉS DE PRODUCTION ET D'UTILISATION DE CES DERNIERS

  摘要：

  用于预防和治疗癌症的具有治疗效果的前药化合物，以及含有这些化合物的药物组合物，以及制备和使用这些化合物的方法。

  公开号：

  WO2016176332A1

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。
• Heterocyclic derivatives for the treatment of cancer and other proliferative diseases
  申请人：——

  公开号：US20020143182A1

  公开（公告）日：2002-10-03

  The invention relates to certain heterocyclic compounds useful for the treatment of cancer and other diseases, having the Formula (I): 1 wherein: (a) m is an integer 0 or 1; (b) R 12 is an alkyl, a substituted alkyl, a cycloalkyl, a substituted cycloalkyl, a heterocyclic, a substituted heterocyclic, a heteroaryl, a substituted heteroaryl, an aryl or a substituted aryl residue; (c) Ar 3 is an aryl, a substituted aryl, a heteroaryl or a substituted heteroaryl residue; (d) Ar 4 is an aryl, a substituted aryl, a heteroaryl or a substituted heteroaryl residue; (e) R 5 is hydrogen, hydroxy, alkyl or substituted alkyl; (f) - - - - - represents a bond present or absent; and (g) W, X, Y and Z are independently or together C(O)—, C(S), S, O, or NH; or a pharmaceutically acceptable salt thereof.

  该发明涉及某些对治疗癌症和其他疾病有用的杂环化合物，其具有以下式（I）： 1 其中： (a) m是整数0或1； (b) R12是烷基，取代烷基，环烷基，取代环烷基，杂环基，取代杂环基，杂芳基，取代杂芳基，芳基或取代芳基残基； (c) Ar3是芳基，取代芳基，杂芳基或取代杂芳基残基； (d) Ar4是芳基，取代芳基，杂芳基或取代杂芳基残基； (e) R5是氢，羟基，烷基或取代烷基； (f) - - - - - 代表存在或不存在的键；以及 (g) W、X、Y和Z独立或一起是C(O)、C(S)、S、O或NH；或其药学上可接受的盐。
• [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。