丝裂霉素 C | 50-07-7

• 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 - 有机杂环化合物 - 吲哚及其衍生物
• 中文名称: 丝裂霉素 C
• 中文别名: 自力霉素；密吐霉素；自力霉素,嘧吡霉素；丝裂霉素C；嘧吡霉素
• 英文名称: mitomycin C
• 英文别名: mitomycin；MMC；mytomycin C；mytomycin；mytomicin C；NSC 26980；[(4S,6S,7R,8S)-11-amino-7-methoxy-12-methyl-10,13-dioxo-2,5-diazatetracyclo[7.4.0.02,7.04,6]trideca-1(9),11-dien-8-yl]methyl carbamate
• CAS: 50-07-7
• 化学式: C₁₅H₁₈N₄O₅
• mdl: MFCD00078109
• 分子量: 334.332
• InChiKey: NWIBSHFKIJFRCO-WUDYKRTCSA-N

物化性质

• 熔点：
  360 °C
• 沸点：
  471.14°C (rough estimate)
• 密度：
  1.2238 (rough estimate)
• 溶解度：
  在水中的溶解度4 mL/vial储备液应过滤灭菌并在2-8°C避光保存。透明至轻微混浊，蓝色至紫色
• 物理描述：
  Mitomycin c appears as blue-violet crystals. Used as an anti-tumor antibiotic complex. (EPA, 1998)
• 颜色/状态：
  BLUE-VIOLET CRYSTALS
• 稳定性/保质期：
  Commercially available mitomycin powder is stable for at least 4 years at room temperature.
• 碰撞截面：
  169.5 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)：
  -0.4
• 重原子数：
  24
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.533
• 拓扑面积：
  147
• 氢给体数：
  3
• 氢受体数：
  8

ADMET

代谢

主要在肝脏，也存在于其他各种组织中。

Primarily hepatic, some in various other tissues.

来源:DrugBank

代谢

建议的致癌物烷基化代谢物：丝裂霉素C：还原产物。/来自表格/

SUGGESTED ALKYLATING METABOLITES OF CARCINOGENS: MITOMYCIN C: REDUCTION PRODUCTS. /FROM TABLE/

来源:Hazardous Substances Data Bank (HSDB)

代谢

灭活是通过代谢发生的，但尚未确定代谢产物。它主要在肝脏中代谢，不到10%的活性药物通过尿液或胆汁排出。

Inactivation occurs by metabolism, but the products have not been identified. It is metabolized primarily in the liver, and less than 10% of the active drug is excreted in the urine or the bile.

来源:Hazardous Substances Data Bank (HSDB)

代谢

药物主要通过肝脏代谢消除，约20%的肝提取率，尿液中回收10-30%的完整药物。清除率为0.3-0.4升/小时/千克。

The drug is eliminated primarily by hepatic metabolism with about 20% hepatic extraction and 10-30% recovery of intact drug in the urine. Clearance is 0.3-0.4 l/hr/kg.

来源:Hazardous Substances Data Bank (HSDB)

代谢

丝裂霉素静脉注射后迅速从血液中消失。它广泛分布但似乎不穿过血脑屏障。丝裂霉素主要在肝脏代谢；多达10%的剂量以原形从尿液中排出。

Mitomycin disappears rapidly from the blood after intravenous injection. It is widely distributed but does not appear to cross the blood-brain barrier. Mitomycin is metabolized mainly in the liver; up to 10% of a dose is excreted unchanged in the urine.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

丝裂霉素在体内激活为双功能和三功能烷化剂。与DNA结合导致交联并抑制DNA合成和功能。丝裂霉素对细胞周期阶段非特异性。

Mitomycin is activated in vivo to a bifunctional and trifunctional alkylating agent. Binding to DNA leads to cross-linking and inhibition of DNA synthesis and function. Mitomycin is cell cycle phase-nonspecific.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 肝毒性

使用丝裂霉素联合其他药物进行化疗与一部分患者血清酶水平升高有关，具体取决于使用的剂量和其他药物。在丝裂霉素治疗期间ALT升高通常是无需治疗且短暂的，可能会在无需调整剂量的情况下解决。在许多情况下，由于接触其他可能具有肝毒性的药物，很难将肝功能测试异常归因于丝裂霉素。高剂量的丝裂霉素与窦道阻塞综合征的案例有关，典型表现为输注后10到30天内出现右上象限疼痛，随后是体重增加、腹水和肝功能测试异常。由于肝衰竭导致的死亡案例已经发生，但大多数患者在发病后1到3个月内恢复。窦道阻塞综合征的发生频率限制了在癌症化疗和为骨髓移植做准备的骨髓清除中使用丝裂霉素的剂量。目前还没有确切的急性、临床上明显的与丝裂霉素治疗相关的特异质性肝损伤和黄疸的实例。

Chemotherapy with mitomycin in combination with other agents is associated with serum enzyme elevations in a proportion of patients, depending upon the dose and other agents used. ALT elevations during mitomycin therapy are usually asymptomatic and transient and may resolve without dose modification. In many instances, it is difficult to attribute the liver test abnormalities to mitomycin, because of the exposure to other potentially hepatotoxic agents. High doses of mitomycin have been linked to cases of sinusoidal obstruction syndrome, typically presenting with right upper quadrant pain 10 to 30 days after the infusion, followed by weight gain, ascites and liver test abnormalities. Fatalities due to hepatic failure have occurred, but most patients recover within 1 to 3 months of onset. The frequency of sinusoidal obstruction syndrome limits the dosage of mitomycin that can be used in cancer chemotherapy and in myeloablation in preparation for bone marrow transplantation. There have been no convincing instances of acute, clinically apparent idiosyncratic liver injury with jaundice associated with mitomycin therapy.

来源:LiverTox

毒理性

• 药物性肝损伤

化合物：丝裂霉素

Compound:mitomycin

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

标签部分：没有匹配项

Label Section:No match

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

• 吸收

不稳定。

Erratic.

来源:DrugBank

吸收、分配和排泄

• 消除途径

大约10%的丝裂霉素剂量以原形从尿液中排出。

Approximately 10% of a dose of mitomycin is excreted unchanged in the urine.

来源:DrugBank

吸收、分配和排泄

在给予2毫克/千克体重的Wistar大鼠静脉注射后...24小时内尿液中回收了18%未改变的药物...在8毫克/千克剂量下...尿液中回收了35%，但在粪便或组织中未检测到。

FOLLOWING IV INJECTION OF 2 MG/KG BODY WT ... WISTAR RATS, 18% WAS RECOVERED UNCHANGED IN URINE WITHIN 24 HR AT ... 8 MG/KG ... 35% WAS RECOVERED IN URINE, BUT NONE IN FECES OR TISSUES.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

在小鼠静脉注射8毫克/千克体重30分钟后，血液中仍有微量药物残留。在豚鼠中，药物在肾脏中浓缩，而不是在肝脏、脾脏或大脑中，并通过尿液排出。

THIRTY MIN AFTER IV INJECTION OF 8 MG/KG BODY WT TO MICE TRACES REMAINED IN BLOOD. IN GUINEA PIGS DRUG WAS CONCN IN KIDNEYS & NOT IN LIVER, SPLEEN OR BRAIN & WAS EXCRETED IN URINE.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

米托蒽醌从胃肠道的吸收不一致，因此通过静脉给药。注射后，它迅速从血液中消失。在20 mg/m²剂量下，血浆中的峰浓度为0.4微克/毫升……该药物在体内广泛分布，但在大脑中检测不到。

Mitomycin is absorbed inconsistently from the gastrointestinal tract, and it is therefore administered intravenously. It disappears rapidly from the blood after injection. Peak concentrations in plasma are 0.4 ug/ml after doses of 20 mg/m sq ... The drug is widely distributed throughout the body but is not detected in the brain.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• TSCA：
  Yes
• 危险等级：
  6.1(a)
• 危险品标志：
  T
• 安全说明：
  S28,S28A,S36/37,S45
• 危险类别码：
  R40,R25
• WGK Germany：
  3
• 海关编码：
  29419090
• 危险品运输编号：
  UN 3462 6.1/PG 2
• 危险类别：
  6.1(a)
• RTECS号：
  CN0700000
• 包装等级：
  II
• 储存条件：
  请将本品密封、阴凉处保存，并避免光照。

SDS

Name:	Mitomycin C (Contains 2mg Mitomycin C and 48mg Sodium Chloride) Material Safety Data Sheet
Synonym:	Ametycine
CAS:	50-07-7

Section 1 - Chemical Product MSDS Name:Mitomycin C (Contains 2mg Mitomycin C and 48mg Sodium Chloride) Material Safety Data Sheet
Synonym:Ametycine

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Section 2 - COMPOSITION, INFORMATION ON INGREDIENTS

CAS#	Chemical Name	content	EINECS#
50-07-7	Mitomycin C	4	200-008-6

Hazard Symbols: T
Risk Phrases: 25 33

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Section 3 - HAZARDS IDENTIFICATION
EMERGENCY OVERVIEW
Toxic if swallowed. Danger of cumulative effects.
Potential Health Effects
Eye:
May cause eye irritation.
Skin:
May cause skin irritation.
Ingestion:
Harmful if swallowed. May cause liver damage. May cause digestive tract disturbances. May cause bone marrow depression.
Inhalation:
May cause respiratory tract irritation. May cause effects similar to those described for ingestion. May cause pulmonary fibrosis and permanent damage.
Chronic:
May cause cancer according to animal studies. Chronic exposure may cause liver damage. Adverse reproductive effects have been reported in animals. Potential cancer hazard.

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Section 4 - FIRST AID MEASURES
Eyes: Flush eyes with plenty of water for at least 15 minutes, occasionally lifting the upper and lower eyelids. Get medical aid.
Skin:
Get medical aid. Flush skin with plenty of water for at least 15 minutes while removing contaminated clothing and shoes. Wash clothing before reuse.
Ingestion:
Do not induce vomiting. If victim is conscious and alert, give 2-4 cupfuls of milk or water. Never give anything by mouth to an unconscious person. Get medical aid.
Inhalation:
Remove from exposure and move to fresh air immediately. If not breathing, give artificial respiration. If breathing is difficult, give oxygen. Get medical aid. Do NOT use mouth-to-mouth resuscitation.
Notes to Physician:

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Section 5 - FIRE FIGHTING MEASURES
General Information:
As in any fire, wear a self-contained breathing apparatus in pressure-demand, MSHA/NIOSH (approved or equivalent), and full protective gear. During a fire, irritating and highly toxic gases may be generated by thermal decomposition or combustion.
Non-combustible, substance itself does not burn but may decompose upon heating to produce irritating, corrosive and/or toxic fumes.
Extinguishing Media:
In case of fire, use water, dry chemical, chemical foam, or alcohol-resistant foam. Substance is noncombustible; use agent most appropriate to extinguish surrounding fire.

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Section 6 - ACCIDENTAL RELEASE MEASURES
General Information: Use proper personal protective equipment as indicated in Section 8.
Spills/Leaks:
Clean up spills immediately, observing precautions in the Protective Equipment section. Sweep up, then place into a suitable container for disposal. Avoid generating dusty conditions. Provide ventilation.

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Section 7 - HANDLING and STORAGE
Handling:
Wash thoroughly after handling. Remove contaminated clothing and wash before reuse. Use only in a well-ventilated area. Minimize dust generation and accumulation. Do not get in eyes, on skin, or on clothing. Keep container tightly closed. Do not ingest or inhale.
Storage:
Do not store in direct sunlight. Keep container closed when not in use. Store in a cool, dry, well-ventilated area away from incompatible substances. Hormones and antibiotics room. Store below 40C.

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Section 8 - EXPOSURE CONTROLS, PERSONAL PROTECTION
Engineering Controls:
Facilities storing or utilizing this material should be equipped with an eyewash facility and a safety shower. Use adequate general or local exhaust ventilation to keep airborne concentrations below the permissible exposure limits.
Exposure Limits CAS# 50-07-7: CAS# 7647-14-5: Russia: 5 mg/m3 TWA Personal Protective Equipment Eyes: Wear safety glasses and chemical goggles if splashing is possible.
Skin:
Wear appropriate protective gloves and clothing to prevent skin exposure.
Clothing:
Wear appropriate protective clothing to minimize contact with skin.
Respirators:
A respiratory protection program that meets OSHA's 29 CFR 1910.134 and ANSI Z88.2 requirements or European Standard EN 149 must be followed whenever workplace conditions warrant respirator use.

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Section 9 - PHYSICAL AND CHEMICAL PROPERTIES

Physical State: Crystalline powder
Color: blue-violet
Odor: None reported.
pH: Not available.
Vapor Pressure: Not available.
Viscosity: Not available.
Boiling Point: Not available.
Freezing/Melting Point: > 360 deg C
Autoignition Temperature: Not applicable.
Flash Point: Not applicable.
Explosion Limits, lower: Not available.
Explosion Limits, upper: Not available.
Decomposition Temperature:
Solubility in water: soluble
Specific Gravity/Density:
Molecular Formula: C15H18N4O5
Molecular Weight: 334.32

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Section 10 - STABILITY AND REACTIVITY
Chemical Stability:
Stable under normal temperatures and pressures.
Conditions to Avoid:
Incompatible materials, light, dust generation, excess heat, temperatures above 40C.
Incompatibilities with Other Materials:
Strong oxidizing agents - strong acids - strong bases.
Hazardous Decomposition Products:
Nitrogen oxides, carbon monoxide, carbon dioxide, nitrogen.
Hazardous Polymerization: Has not been reported.

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Section 11 - TOXICOLOGICAL INFORMATION
RTECS#:
CAS# 50-07-7: CN0700000 CAS# 7647-14-5: VZ4725000 LD50/LC50:
CAS# 50-07-7: Oral, mouse: LD50 = 23 mg/kg; Oral, rat: LD50 = 30 mg/kg.
CAS# 7647-14-5: Draize test, rabbit, eye: 100 mg Mild; Draize test, rabbit, eye: 100 mg/24H Moderate; Draize test, rabbit, eye: 10 mg Moderate; Draize test, rabbit, skin: 50 mg/24H Mild; Draize test, rabbit, skin: 500 mg/24H Mild; Inhalation, rat: LC50 = >42 gm/m3/1H; Oral, mouse: LD50 = 4 gm/kg; Oral, rat: LD50 = 3000 mg/kg; Skin, rabbit: LD50 = >10 gm/kg.
Carcinogenicity:
Mitomycin C - California: carcinogen, initial date 4/1/88 IARC: Group 2B carcinogen Sodium chloride - Not listed by ACGIH, IARC, or NTP.
Other:
See actual entry in RTECS for complete information.

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Section 12 - ECOLOGICAL INFORMATION

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Section 13 - DISPOSAL CONSIDERATIONS
Dispose of in a manner consistent with federal, state, and local regulations.

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Section 14 - TRANSPORT INFORMATION

IATA
Shipping Name: TOXIC SOLID, ORGANIC, N.O.S.*
Hazard Class: 6.1
UN Number: 2811
Packing Group: II
IMO
Shipping Name: TOXIC SOLID, ORGANIC, N.O.S.
Hazard Class: 6.1
UN Number: 2811
Packing Group: II
RID/ADR
Shipping Name: TOXIC SOLID, ORGANIC, N.O.S.
Hazard Class: 6.1
UN Number: 2811
Packing group: II
USA RQ: CAS# 50-07-7: 10 lb final RQ; 4.54 kg final RQ

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Section 15 - REGULATORY INFORMATION

European/International Regulations
European Labeling in Accordance with EC Directives
Hazard Symbols: T
Risk Phrases:
R 25 Toxic if swallowed.
R 33 Danger of cumulative effects.
Safety Phrases:
S 45 In case of accident or if you feel unwell, seek
medical advice immediately (show the label where
possible).
WGK (Water Danger/Protection)
CAS# 50-07-7: 3
CAS# 7647-14-5: 0
Canada
CAS# 50-07-7 is listed on Canada's NDSL List.
CAS# 7647-14-5 is listed on Canada's DSL List.
CAS# 50-07-7 is not listed on Canada's Ingredient Disclosure List.
CAS# 7647-14-5 is not listed on Canada's Ingredient Disclosure List.
US FEDERAL
TSCA
CAS# 50-07-7 is listed on the TSCA inventory.
CAS# 7647-14-5 is listed on the TSCA inventory.

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SECTION 16 - ADDITIONAL INFORMATION
N/A

制备方法与用途

简介

丝裂霉素C是从链霉菌中提取的一种广谱抗肿瘤抗生素，具有遗传毒性和抗肿瘤性，是普遍认可的DNA损伤抑制剂。它对多种癌症有抗癌作用，在激活后可起到DNA烷化剂的作用，通过使细胞的DNA解聚、选择性抑制DNA、RNA和蛋白质的合成来抑制肿瘤细胞分裂。

应用

丝裂霉素C是一种非特异性细胞周期药物，抗肿瘤谱广且作用迅速，但治疗指数不高，毒性较大。临床主要用于消化道癌症如胃癌、肠癌、肝癌及胰腺癌等，疗效较好。对肺癌、乳腺癌、宫颈癌和绒毛膜上皮癌等也有一定效果。还可用于恶性淋巴瘤和癌性胸腹腔积液。此外，丝裂霉素C也是一种化学诱变剂，能够导致DNA突变；藏红花提取物可以显著抑制顺铂、环磷酰胺、丝裂霉素C及氨基甲酸乙酯等抗癌药产生的生殖毒性，且其抑制作用与剂量无关。因此，未来藏红花与其他抗癌药联合使用有望减少这些药物的毒副作用。

化学性质

丝裂霉素C为蓝紫色有光泽结晶或结晶性粉末，固体稳定但在酸性和碱性溶液中易失活。熔点高于360℃；在甲醇中的最大吸收波长分别为216nm、360nm和560nm，在水溶液中的最大吸收波长约为365nm±2nm。该品溶于水、甲醇、丙酮及乙酸乙酯等有机溶剂，微溶于苯、乙醚和四氯化碳，不溶于石油醚。其剧毒，大鼠口服LD₅₀为14mg/kg。研究表明本品对实验动物有潜在致癌作用。

用途

丝裂霉素C用作细胞分裂抑制剂、核酸抑制剂及噬菌体诱导剂；临床主要用于抗肿瘤治疗。它对抗瘤谱较广，尤其在胃癌和乳腺癌中效果显著。此外，对肺癌、肝癌、恶性淋巴瘤、何杰金氏病、网状细胞肉瘤、子宫癌、白血病、肠道癌和胰腺癌等也有一定疗效，但缓解期相对较短。与尿激酶合用可提高疗效；其作用迅速，但由于治疗指数低且毒性较大，需谨慎使用。

生产方法

丝裂霉素C通过发酵方法生产，自放线菌（Strepto-myces caespitosus）培养液中可提取出丝裂霉素A、B、C。我国从自行分离的放线菌H2760菌株中提取，并称为自力霉素，与国外报道的丝裂霉素C相同。

类别

有毒物品
毒性分级：剧毒
急性毒性：口服-大鼠LD50: 30毫克/公斤；口服-小鼠LD50: 23毫克/公斤
可燃性危险特性：可燃，燃烧产生有毒氮氧化物烟雾
储运特性：库房通风低温干燥
灭火剂：干粉、泡沫、砂土、二氧化碳及雾状水

反应信息

• 作为反应物：
  描述：

  丝裂霉素 C 在 sodium methylate 作用下， 以 甲醇 、 苯 为溶剂， 以80%的产率得到10-去氨基甲酰丝裂霉素 C
  参考文献：
  名称：

  Synthesis of N-Substituted 10-Des(carbamoyloxy)-10-azidomitomycins

  摘要：

  已开发出一种合成N-取代的10-脱(氨甲酰氧基)-10-叠氮基丝裂霉素5的通用方法。这些化合物预期能迅速转化为相应的C-10异硫氰酸酯衍生物，使丝裂霉素能够与生物分子耦合。关键的合成中间体是10-脱(氨甲酰氧基)-10-叠氮基丝裂霉素C（12）。化合物12是通过丝裂霉素C（1）的去氨甲酰化，随后用芴甲氧羰基氯进行氮丙啶保护，以及用甲磺酰氯激活C-10位点制备的。通过用吗啉脱除芴甲氧羰基单元并处理叠氮化钠得到12。

  DOI：

  10.1055/s-1997-1297
• 作为产物：
  描述：

  2-((2-(piperidin-1-yl)ethyl)disulfanyl)ethyl(1aS,8S,8aR,8bS)-6-amino-8-((carbamoyloxy)methyl)-8a-methoxy-5-methyl-4,7-dioxo-1a,4,7,8,8a,8b-hexahydroazirino [2’,3’:3,4]pyrrolo[1,2-a]indole-1(2H)-carboxylate 在 L-半胱氨酸盐酸盐无水物 作用下， 以 乙醇 、 水 为溶剂， 反应 2.0h， 以92%的产率得到丝裂霉素 C
  参考文献：
  名称：

  [EN] MITOMYCIN C PRODRUG LIPOSOME FORMULATIONS AND USES THEREOF
  [FR] FORMULATIONS DE LIPOSOME DE PROMÉDICAMENT DE MITOMYCINE C ET LEURS UTILISATIONS

  摘要：

  本发明提供了用于治疗癌症的MMC前药化合物和脂质体MMC前药及其组合物。该组合物包括含有磷脂酰胆碱脂质、固醇、PEG-脂质和MMC前药的脂质体。本发明还提供了用于治疗癌症的脂质体组合物，包括向需要的患者施用脂质体，其中脂质体包括：磷脂酰胆碱脂质；固醇；PEG-脂质和MMC前药或其药用可接受的盐。

  公开号：

  WO2018089481A1
• 作为试剂：
  描述：

  1-羟基苯并三唑 、 Carbonic acid 4-((S)-2-{(S)-2-[6-(2,5-dioxo-2,5-dihydro-pyrrol-1-yl)-hexanoylamino]-3-phenyl-propionylamino}-6-{[(4-methoxy-phenyl)-diphenyl-methyl]-amino}-hexanoylamino)-benzyl ester 4-nitro-phenyl ester 在 4 A molecular sieve 、 丝裂霉素 C 、 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 18.0h， 以33%的产率得到[4-[[(2S)-2-[[(2S)-2-[6-(2,5-dioxopyrrol-1-yl)hexanoylamino]-3-phenylpropanoyl]amino]-6-[[(4-methoxyphenyl)-diphenylmethyl]amino]hexanoyl]amino]phenyl]methyl 11-amino-8-(carbamoyloxymethyl)-7-methoxy-12-methyl-10,13-dioxo-2,5-diazatetracyclo[7.4.0.02,7.04,6]trideca-1(9),11-diene-5-carboxylate
  参考文献：
  名称：

  Efficient mitomycin C coupling with stable p-nitrophenyl-benzyl carbonates using n-hydroxybenzotriazole as a catalytic additive

  摘要：

  Mitomycin C benzyl carbamates were prepared in high yield from stable p-nitrophenyl carbonates in the presence of catalytic amounts of 1-hydroxybenzotriazole/diisopropylethylamine in DMF. (C) 1997 Elsevier Science Ltd.

  DOI：

  10.1016/s0040-4039(97)01159-3

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。
• 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。
• [EN] 2-QUINOLONE DERIVED INHIBITORS OF BCL6<br/>[FR] INHIBITEURS DE BCL6 DÉRIVÉS DE 2-QUINOLONE
  申请人：CANCER RESEARCH TECH LTD

  公开号：WO2018215798A1

  公开（公告）日：2018-11-29

  The present invention relates to compounds of formula I that function as inhibitors of BCL6(B- cell lymphoma 6) activity: Formula I wherein X1, X2, X3, R1, R2, R3, R4 and R5 are each as defined herein. The present invention also relates to processes for the preparation of these compounds, to pharmaceutical compositions comprising them, and to their use in the treatment of proliferative disorders, such as cancer,as well as other diseases or conditions in which BCL6 activity is implicated.

  本发明涉及作为BCL6（B细胞淋巴瘤6）活性抑制剂的I式化合物：式中X1、X2、X3、R1、R2、R3、R4和R5分别如本文所定义。本发明还涉及制备这些化合物的方法，包括含有它们的药物组合物，以及它们在治疗增生性疾病（如癌症）以及其他BCL6活性所涉及的疾病或病况中的用途。