吉西他滨 | 95058-81-4

• 物质功能分类: 原料药 - 抗肿瘤药 - 抗代谢类抗肿瘤药
• 分子结构分类: 有机化合物 - 核苷、核苷酸和类似物 - 嘧啶核苷
• 中文名称: 吉西他滨
• 中文别名: 盐酸吉西他滨；4-氨基-1-(3,3-二氟-4-羟基-5-羟甲基四氢呋喃-2-基)-1H-嘧啶-2-酮；吉西他宾；吉西他滨碱；双氟脱氧胞苷；4-氨基-1-[3,3-二氟-4-羟基-5-(羟甲基)氧杂环戊-2-基]嘧啶-2-酮；吉西他滨碱基
• 英文名称: Gemcitabine
• 英文别名: gem；gemzar；gemcitabine hydrochloride；4-amino-1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidin-2(1H)-one；2′-deoxy-2′,2′-difluorocytidine；2′,2′-difluorodeoxycytidine；dFdC；4-amino-1-[(2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidin-2-one
• CAS: 95058-81-4
• 化学式: C₉H₁₁F₂N₃O₄
• mdl: MFCD00869720
• 分子量: 263.201
• InChiKey: SDUQYLNIPVEERB-QPPQHZFASA-N

物化性质

• 熔点：
  168,64 C
• 比旋光度：
  365 +425.36°; D +71.51°
• 沸点：
  482.7±55.0 °C(Predicted)
• 密度：
  1.84±0.1 g/cm3(Predicted)
• 溶解度：
  轻微溶于甲醇、加热微溶于水
• 物理描述：
  Solid
• 颜色/状态：
  Crystals from water, pH = 8.5
• 蒸汽压力：
  1.7X10-9 mm Hg at 25 °C (est)
• 旋光度：
  Specific optical rotation: +425.36 deg at 365 °C; + 71.51 deg at 25 °C/D (c = 0.96 in methanol)
• 解离常数：
  pKa1 = 5.27 (imine); pKa2 = 11.24 (alcohol) (est)

计算性质

• 辛醇/水分配系数(LogP)：
  -1.5
• 重原子数：
  18
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.555
• 拓扑面积：
  108
• 氢给体数：
  3
• 氢受体数：
  6

ADMET

代谢

吉西他滨（gemcitabine）在给药并被癌细胞摄取后，最初由脱氧胞苷激酶（dCK）磷酸化，以及在较小程度上，由线粒体外胸苷激酶2磷酸化，形成吉西他滨单磷酸（dFdCMP）。随后，dFdCMP通过核苷激酶的作用进一步磷酸化，生成活性代谢物，即吉西他滨二磷酸（dFdCDP）和吉西他滨三磷酸（dFdCTP）。吉西他滨还在细胞内和细胞外被胞苷脱氨酶去氨化为它的非活性代谢物2′,2′-二氟脱氧尿苷或2´-脱氧-2´,2´-二氟尿嘧啶（dFdU）。去氨化发生在血液、肝脏、肾脏和其他组织中，这一代谢途径是药物清除的主要方式。

Following administration and uptake into cancer cells, gemcitabine is initially phosphorylated by deoxycytidine kinase (dCK), and to a lower extent, the extra-mitochondrial thymidine kinase 2 to form gemcitabine monophosphate (dFdCMP). dFdCMP is subsequently phosphorylated by nucleoside kinases to form active metabolites, gemcitabine diphosphate (dFdCDP) and gemcitabine triphosphate (dFdCTP). Gemcitabine is also deaminated intracellularly and extracellularly by cytidine deaminase to its inactive metabolite 2′,2′-difluorodeoxyuridine or 2´-deoxy-2´,2´-difluorouridine (dFdU). Deamination occurs in the blood, liver, kidneys, and other tissues, and this metabolic pathway accounts for most of drug clearance.

来源:DrugBank

代谢

吉西他滨通过细胞内代谢，通过核苷激酶产生两种活性代谢物（吉西他滨二磷酸和吉西他滨三磷酸），并且还通过脱氨作用产生一种活性的尿嘧啶代谢物。

Gemcitabine undergoes intracellular metabolism, via nucleoside kinases, to produce two active metabolites (gemcitabine diphosphate and gemcitabine triphosphate) and also undergoes deamination to an active uracil metabolite.

来源:Hazardous Substances Data Bank (HSDB)

代谢

...静脉注射后，吉西他滨通过胞苷脱氨酶迅速转化为非活性的代谢物2'-脱氧-2',2'-二氟尿苷...

... After intravenous injection, gemcitabine is rapidly converted to the inactive metabolite 2'-deoxy-2',2'-difluorouridine by cytidine deaminase. ...

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 肝毒性

血清氨基转移酶水平升高发生在接受吉西他滨周期性治疗的30%到90%的患者中。这些升高通常是轻到中度的，无症状且自限性，经常在不中断治疗甚至不中断治疗的情况下解决。ALT或AST升高超过正常上限5倍的情况发生在1-4%的患者中，但很少导致症状或临床上明显的肝损伤。血清胆红素和碱性磷酸酶升高较少见，但也通常是短暂和轻微的。尽管广泛使用，吉西他滨只在极少数病例中被怀疑与急性肝损伤和黄疸有关，而且大多数已报告的病例都发生在有基础慢性肝病或广泛肝转移的患者中。吉西他滨的肝毒性临床特征尚未被很好地描述。大多数病例的特点是在有预先存在的慢性肝病（丙型肝炎、酒精性肝病）或显著的肝转移或局部侵犯的患者中，在接受几个周期的治疗后出现进行性胆汁淤积和肝衰竭。 与许多抗肿瘤药物和方案一样，吉西他滨治疗也与罕见病例中的乙型肝炎病毒再激活有关，这些患者血清中预先存在HBsAg。至少有一例在使用吉西他滨的患者中报告了窦状阻塞综合征（静脉阻塞性疾病），该患者有基础的慢性丙型肝炎，并且没有接受其他抗肿瘤药物。 可能性评分：C（可能是临床上明显肝损伤的罕见原因）。

Elevations in serum aminotransferase levels occur in 30% to 90% of patients receiving cyclic therapy with gemcitabine. The elevations are generally mild-to-moderate, asymptomatic and self-limited, frequently resolving without discontinuation or even interruption of therapy. ALT or AST elevations above 5 times the upper limit of the normal range occur in 1-4% of patients yet rarely lead to symptoms or clinically apparent liver injury. Serum bilirubin and alkaline phosphatase elevations are less common, but also typically transient and mild. Despite wide use, gemcitabine has only rarely been implicated in rare cases of acute liver injury with jaundice, and most published cases have been reported in patients with underlying chronic liver disease or extensive hepatic metastases. The clinical features of hepatotoxicity from gemcitabine have not been well described. Most cases were marked by a progressive cholestasis and hepatic failure developing after several cycles of therapy in patients with preexisting chronic liver disease (hepatitis C, alcoholic liver disease) or significant hepatic metastases or local invasion. As with many antineoplastic agents and regimens, therapy with gemcitabine has also been associated rare cases of with reactivation of hepatitis B in persons with preexisting HBsAg in serum. At least one case of sinusoidal obstruction syndrome (veno-occlusive disease) has been reported with use of gemcitabine in a patient with underlying chronic hepatitis C who received no other antineoplastic agent. Likelihood score: C (probable rare cause of clinically apparent liver injury).

来源:LiverTox

毒理性

• 药物性肝损伤

吉西他滨

Compound:gemcitabine

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

药物性肝损伤标注：最令人关注的药物性肝损伤

DILI Annotation:Most-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：8

Severity Grade:8

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

标签部分：警告和预防措施

Label Section:Warnings and precautions

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

• 吸收

吉西他滨的峰值血浆浓度在30分钟静脉输注后范围为10至40 mg/L，达到峰值的时间为15至30分钟。一项研究表明，吉西他滨的稳态浓度与剂量在53至1000 mg/m²的剂量范围内呈线性关系。吉西他滨三磷酸酯是吉西他滨的活性代谢物，可以在循环的外周血单核细胞中积累。在一项研究中，外周血单核细胞中吉西他滨三磷酸酯的Cmax在输注期结束后的30分钟内出现，并且随着吉西他滨剂量的增加而增加，剂量高达350 mg/m²。

Peak plasma concentrations of gemcitabine range from 10 to 40 mg/L following a 30-minute intravenous infusion, and are reached at 15 to 30 minutes. One study showed that steady-state concentrations of gemcitabine showed a linear relationship to dose over the dose range 53 to 1000 mg/m2. Gemcitabine triphosphate, the active metabolite of gemcitabine, can accumulate in circulating peripheral blood mononuclear cells. In one study, the Cmax of gemcitabine triphosphate in peripheral blood mononuclear cells occurred within 30 minutes of the end of the infusion period and increased increased proportionally with gemcitabine doses of up to 350 mg/m2.

来源:DrugBank

吸收、分配和排泄

• 消除途径

吉西他滨主要通过肾脏排泄。在单次给药1000 mg/m²，静脉滴注30分钟后的一周内，大约92-98%的剂量在尿液中回收，其中89%的回收剂量以二氟脱氧尿苷（dFdU）形式排出，不到10%以吉西他滨形式排出。吉西他滨的单磷酸、二磷酸或三磷酸代谢物在尿液中检测不到。在单次给药研究中，大约1%的给药剂量在粪便中回收。

Gemcitabine mainly undergoes renal excretion. Within a week following administration of a single dose of 1000 mg/m² infused over 30 minutes, about 92-98% of the dose was recovered in urine where 89% of the recovered dose was excreted as difluorodeoxyuridine (dFdU) and less than 10% as gemcitabine. Monophosphate, diphosphate, or triphosphate metabolites of gemcitabine are not detectable in urine. In a single-dose study, about 1% of the administered dose was recovered in the feces.

来源:DrugBank

吸收、分配和排泄

• 分布容积

在各种实体瘤患者中，分布容积随着输注时间的增加而增加。输注时间少于70分钟的吉西他滨分布容积为50 L/m²。对于长时间输注，分布容积增加到370 L/m²。吉西他滨三磷酸酯，是吉西他滨的活性代谢物，在体外和体内实体瘤细胞中积累并保留。在短时间输注（少于70分钟）后，它不会广泛分布到组织中。目前尚不清楚吉西他滨是否能够穿过血脑屏障，但吉西他滨会广泛分布到组织中，包括腹水。在大鼠中，药物给药后5至15分钟内，胎盘和乳腺转运迅速发生。

In patients with various solid tumours, the volume of distribution increased with infusion length. The volume of distribution of gemcitabine was 50 L/m² following infusions lasting less than 70 minutes. For long infusions, the volume of distribution rose to 370 L/m². Gemcitabine triphosphate, the active metabolite of gemcitabine, accumulates and retains in solid tumour cells _in vitro_ and _in vivo_. It is not extensively distributed to tissues after short infusions that last less than 70 minutes. It is not known whether gemcitabine crosses the blood-brain barrier, but gemcitabine is widely distributed into tissues, including ascitic fluid. In rats, placental and lacteal transfer occurred rapidly at five to 15 minutes following drug administration.

来源:DrugBank

吸收、分配和排泄

• 清除

静脉输注持续时间少于70分钟的情况下，男性的清除率范围是41到92 L/h/m²，女性的清除率范围是31到69 L/h/m²。清除率随年龄增长而降低。女性的清除率比男性患者低大约30%。

Following intravenous infusions lasting less than 70 minutes, clearance ranged from 41 to 92 L/h/m² in males and ranged from 31 to 69 L/h/m² in females. Clearance decreases with age. Females have about 30% lower clearance than male patients.

来源:DrugBank

吸收、分配和排泄

吉西他滨的药代动力学呈线性，可用双室模型描述。结合单次和多次给药的研究的群体药代动力学分析显示，吉西他滨的分布容积受到输注持续时间和性别的显著影响。清除率受到年龄和性别的影响。基于患者特征或输注持续时间，清除率或分布容积的差异导致半衰期和血浆浓度的变化。

Gemcitabine pharmacokinetics are linear and are described by a 2-compartment model. Population pharmacokinetic analyses of combined single and multiple dose studies showed that the volume of distribution of gemcitabine was significantly influenced by duration of infusion and gender. Clearance was affected by age and gender. Differences in either clearance or volume of distribution based on patient characteristics or the duration of infusion result in changes in half-life and plasma concentrations.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险品标志：
  Xn,Xi
• 安全说明：
  S25,S26,S36/37,S53
• 危险类别码：
  R36/38,R63,R21,R62,R46
• 海关编码：
  29349990
• 危险性防范说明：
  P261,P280,P305+P351+P338
• 危险性描述：
  H302+H312+H332,H315,H319,H335
• 储存条件：
  温度低于0°C时，请避免加热。

SDS

Material Safety Data Sheet

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Section 1. Identification of the substance
Product Name: Gemcitabine
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: Gemcitabine
CAS number: 95058-81-4

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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, under −20◦C.
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: C9H11F2N3O4
Molecular weight: 263.2

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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, hydrogen fluoride.

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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

概述

吉西他滨是一种嘧啶核苷酸类似物，属于抗代谢类抗癌药。它主要作用于DNA合成期（S期），在一定条件下可阻止G1期向S期进展。吉西他滨具有抗癌谱广、作用机制独特、毒性反应低、与其他化疗药物无交叉耐药且毒性反应无叠加等特点。如今，该药物已在90多个国家获得批准使用，并成为治疗非小细胞肺癌的一线药物和治疗胰腺癌的“金标准”。

在国内临床上应用的主要有国产吉西他滨（商品名泽菲，江苏豪森药业股份有限公司）和进口吉西他滨（商品名健择，法国礼来制药厂）。

作用原理

吉西他滨进入人体后由脱氧胞嘧啶激酶活化起作用，形成吉西他滨磷酸盐（dFdCMP）、吉西他滨二磷酸盐（dFdCDP）和吉西他滨三磷酸盐（dFdCTP），其中dFdCDP和dFdCTP为活性物质。这些物质可以抑制DNA合成——通过抑制核糖核酸还原酶，使三磷酸脱氧核苷产生量减少（尤其是脱氧三磷酸胞苷 dCTP 减少），最终导致细胞凋亡；此外，dFdCTP 与 dCTP 竞争掺入 DNA 链中（自身增强作用）使 DNA 链延长，DNA 聚合酶不能去除掺入的 dFdCTP，从而使延伸的 DNA 链无法修复，从而抑制 DNA 合成，最终导致细胞凋亡。

适应症

1999年CFDA批准吉西他滨用于治疗局部晚期或转移性非小细胞肺癌（NSCLC）、局部晚期或转移性胰腺癌；2010年CFDA又批准吉西他滨与紫杉醇联合，可用于治疗经辅助/新辅助化疗后复发、不能切除的、局部复发或转移性乳腺癌。

吉西他滨相关基因

• RRM1：核糖核苷酸还原酶 M1（RRM1）是 DNA 合成通路中的限速酶，其表达可抑制肿瘤细胞增殖并引起细胞凋亡。
• CDA：胞嘧啶核苷脱氨酶（CDA）是嘧啶解救途径中的一种酶，它的多态性会影响吉西他滨的药代动力学。

抗肿瘤药物

吉西他滨是一种新型二氟核苷类抗代谢药物，可以与顺铂联合使用治疗非小细胞肺癌，也可以用于治疗晚期或转移性胰腺癌。同时，吉西他滨也是一种骨髓抑制剂，在用药期间（特别是每次静脉输液给药之前）需进行血细胞计数的检查。

不良反应和处置

吉西他滨具有骨髓抑制作用，应用该药物后可出现贫血、白细胞计数降低和血小板减少。通常情况下，血小板计数在用药第8日后开始下降，在第15日降至最低点，之后逐步回升至下一周期开始前（第22天），多数患者的血小板计数已恢复正常。

对于老年或血象较差的患者，化疗期间可口服鲨肝醇+利可君预防。当出现严重骨髓抑制时，可用重组人粒细胞刺激因子注射液（如瑞白等）提升白细胞，以及重组人促血小板生成素或重组人白介素-11提升血小板。部分患者血液中存在抗血小板抗体或吉西他滨诱导的免疫反应，升血小板药物或输注血小板无效时，可使用糖皮质激素治疗（如泼尼松 30mg 每天一次，连续四天）。

药物过量

对吉西他滨过量尚无解毒剂。隔周单次静脉滴注给药5700mg/m2，输注时间需超过30分钟。如临床怀疑有过量情况，应监测血液学指标并进行适当的支持治疗。

• 用途：用于晚期和转移性胰腺癌。
• 用途：适用于治疗中、晚期非小细胞肺癌。

反应信息

• 作为反应物：
  描述：

  吉西他滨 在 盐酸 作用下， 以 水 为溶剂， 生成 盐酸吉西他滨
  参考文献：
  名称：

  吉西他滨脂氨基酸缀合物的合成及其对人间变性甲状腺癌的体外细胞毒活性

  摘要：

  本文描述了抗肿瘤药吉西他滨（GEM）的亲脂性衍生物，它有可能改善基于脂质的胶体载体（如脂质体或脂质纳米颗粒）中的载药量。通过碳二亚胺辅助或乙基氯甲酸酯辅助的偶联反应，将GEM游离碱与带有不同长度烷基侧链的脂氨基酸共轭，得到N 4酰基GEM衍生物。这些化合物保留了母体药物对两株人间变性甲状腺癌细胞的相同的体外细胞生长抑制活性。稳定性研究表明，观察到的活性主要归因于完整的衍生物，而不是由于释放的GEM。因此，可以在进一步的步骤中提出这些两亲衍生物，以用于封装在脂质体或脂质纳米载体中，以实现GEM的药代动力学和治疗活性的改善作为最终目标。Drug Dev Res2010。©2010 Wiley-Liss，Inc.。

  DOI：

  10.1002/ddr.20374
• 作为产物：
  描述：

  盐酸吉西他滨 在 potassium carbonate 作用下， 以 乙醇 、 二氯甲烷 为溶剂， 生成 吉西他滨
  参考文献：
  名称：

  [EN] PHARMACEUTICAL COMPOSITION COMPRISING GEMCITABINE AND CYCLODEXTRINES
  [FR] PREPARATIONS PHARMACEUTIQUES COMPRENANT DE LA GEMCITABINE ET DE LA CYCLODEXTRINE

  摘要：

  本发明提供一种包含吉西他滨和环糊精的药物组合物。该药物配方适用于液体静脉给药。

  公开号：

  WO2005014010A1

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。
• [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。
• [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。