streptozocin | 66395-18-4

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: streptozocin
• 英文别名: streptozotocin；STZ；alkylating agent；N-(methylnitrosocarbamoyl)-α-D-glucosamine；1-methyl-1-nitroso-3-[(2S,3R,4R,5S,6R)-2,4,5-trihydroxy-6-(hydroxymethyl)oxan-3-yl]urea
• CAS: 66395-18-4
• 化学式: C₈H₁₅N₃O₇
• mdl: MFCD00006607
• 分子量: 265.223
• InChiKey: ZSJLQEPLLKMAKR-GKHCUFPYSA-N

物化性质

• 密度：
  1.86±0.1 g/cm3(Predicted)
• 物理描述：
  D-glucose, 2-deoxy-2-[[(methylnitrosoamino)-carbonyl]amino]- is an off-white powder. Melting point 115°C. Used as an anti-cancer drug. Carcinogenic.
• 颜色/状态：
  POINTED PLATELETS OR PRISMS FROM 95% ETHANOL
• 熔点：
  115 °C
• 溶解度：
  Soluble (NTP, 1992)
• 稳定性/保质期：
  DECOMPOSES TO DIAZOMETHANE IN ALKALINE SOLN @ 0 °C.
• 旋光度：
  SPECIFIC OPTICAL ROTATION: +39 DEG @ 25 °C/D (AQ SOLN); MAX ABSORPTION (ALCOHOL): 228 NM (E= 6360).
• 解离常数：
  pKa= 1.35

计算性质

• 辛醇/水分配系数(LogP)：
  -1.4
• 重原子数：
  18
• 可旋转键数：
  2
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.875
• 拓扑面积：
  152
• 氢给体数：
  5
• 氢受体数：
  8

ADMET

代谢

主要是肝脏的

Primarily hepatic

来源:DrugBank

代谢

使用(14)C标记在不同位置的研究表明，链脲佐菌素在大鼠体内迅速代谢...结果产生了来自甲基脲基侧链的代谢物。/SRP:重氮甲烷/

STUDIES WITH STREPTOZOTOCIN LABELLED WITH (14)C IN DIFFERENT POSITIONS INDICATE THAT ITS RAPID METABOLISM IN RAT ... RESULTS IN METABOLITE DERIVED FROM METHYL BEARING NITROSOUREIDO SIDECHAIN. /SRP: DIAZOMETHANE/

来源:Hazardous Substances Data Bank (HSDB)

代谢

在老鼠尿液中检测到五种尿液代谢物；其中两种是对抗生素的α和β-异构体。

/IN MICE URINE/ FIVE URINARY METABOLITES WERE DETECTED; 2 OF THEM WERE THE ALPHA AND BETA-ANOMERS OF THE ANTIBIOTIC.

来源:Hazardous Substances Data Bank (HSDB)

代谢

链脲佐菌素及其代谢物有一个短暂的分布期（t1/2 6分钟），随后可能有两个消除期，代表活性代谢物（t1/2 beta 3.5小时，t1/2 gamma 40小时）。

Streptozocin and metabolites have a short distribution phase (t1/2 6 min) followed by possibly two elimination phases representing active metabolites (t1/2 beta 3.5 hr, t1/2 gamma 40 hr).

来源:Hazardous Substances Data Bank (HSDB)

代谢

链脲佐菌素口服不活性。静脉给药后，它迅速从血浆中被清除，三小时后无法检测到。代谢物在血浆中可以检测到长达24小时。药物在某些组织中浓缩；肝脏和肾脏含有最高水平，胰腺也浓缩链脲佐菌素。原药和代谢物通过肾脏迅速消除；60%至70%的剂量在四小时内通过尿液回收。只有10%至20%的排泄剂量是原药。

Streptozocin is not orally active. After intravenous administration, it is rapidly cleared from plasma and is undetectable after three hours. Metabolites are detected in plasma for up to 24 hours. The drug concentrates in certain tissues; the liver and kidneys contain the highest levels, and pancreas also concentrates streptozocin. Parent drug and metabolites are eliminated rapidly by the kidney; 60% to 70% of a dose is recovered in urine within four hours. Only 10% to 20% of an excreted dose is parent drug.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

链脲佐菌素是一种天然存在的化学物质，对胰腺产生胰岛素的β细胞尤其有毒。在大量使用时，它用于医学研究，以产生1型糖尿病的动物模型，以及通过多次低剂量使用产生2型糖尿病。链脲佐菌素与葡萄糖足够相似，可以通过葡萄糖转运蛋白GLUT2被转运进入细胞，但不会被其他葡萄糖转运蛋白识别。这解释了它对β细胞的相对毒性，因为这些细胞相对含有较高水平的GLUT2。链脲佐菌素是一种葡萄糖胺-亚硝基脲（即烷化）化合物。与其他亚硝基脲类中的烷化剂一样，它通过造成DNA损伤对细胞有毒，尽管可能还有其他机制参与。

Streptozotocin is a naturally occurring chemical that is particularly toxic to the insulin-producing beta cells of the pancreas. It is used in medical research to produce an animal model for Type 1 diabetes in large dose as well as Type 2 diabetes with multiple low doses. Streptozotocin is similar enough to glucose to be transported into the cell by the glucose transport protein GLUT2, but is not recognized by the other glucose transporters. This explains its relative toxicity to beta cells, since these cells have relatively high levels of GLUT2. Streptozotocin is a glucosamine-nitrosourea (i.e. alkylating) compound. As with other alkylating agents in the nitrosourea class, it is toxic to cells by causing damage to the DNA, though other mechanisms may also contribute.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 肝毒性

血清转氨酶升高发生在多达三分之二的使用链脲佐菌素治疗的病人中，但异常通常是轻微的、暂时的，并且不伴随症状或黄疸。每日剂量和高剂量的链脲佐菌素更常见肝毒性，但高剂量时，肾脏和血液毒性通常比肝脏损伤更为突出。已有两例报告称，在接受链脲佐菌素治疗的患者中出现了快速进展且致命的急性肝衰竭。在一个案例中，没有给予其他化疗，在另一个案例中，患者同时接受了氟尿嘧啶治疗，并在5天治疗结束时出现了发热、无尿、急性肝炎[ALT 1280，胆红素 11.9，凝血酶原指数 10%，嗜酸性粒细胞 2600/μL]。相比之下，尚未有公开报道的个案因链脲佐菌素引起的自限性临床明显肝损伤，但由于胰腺胰岛细胞癌和神经内分泌肿瘤较为罕见，链脲佐菌素的使用有限。

Serum aminotransferase elevations occur in up to two-thirds of patients treated with streptozocin, but the abnormalities are generally mild, transient and not associated with symptoms or jaundice. Hepatotoxicity is more common with daily dosing and high doses of streptozocin, but with higher doses renal and hematologic toxicities usually overshadow hepatic injury. There have been two reports of rapidly progressive and fatal acute liver failure in patients treated with streptozocin. In one instance, no other chemotherapy was given, in another fluorouracil was coadministered and the patient presented with fever, anuria, acute hepatitis [ALT 1280, bilirubin 11.9, prothrombin index 10%, eosinophils 2600/ µL] at the end of a 5 day course of treatment. In contrast, there have been no individual published case reports of self-limited clinically apparent liver injury attributed to streptozocin, but it has had limited use, as pancreatic islet cell carcinoma and neuroendocrine tumors are rare.

来源:LiverTox

毒理性

• 药物性肝损伤

链脲佐菌素

Compound:streptozocin

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

DILI 注解：模糊的 DILI 关注

DILI Annotation:Ambiguous 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

吸收、分配和排泄

• 吸收

口腔吸收差（17-25%）

Poor oral absorption (17-25%)

来源:DrugBank

吸收、分配和排泄

• 消除途径

多达20%的药物（或含N-亚硝脲基团的代谢物）通过肾脏被代谢和/或排泄。

As much as 20% of the drug (or metabolites containing an N-nitrosourea group) is metabolized and/or excreted by the kidney.

来源:DrugBank

吸收、分配和排泄

在所有这些物种中（小鼠、大鼠、猫、猴子和狗），通过静脉注射给予链脲佐菌素（STZ）...在肝脏和肾脏中显著浓缩；例如，在狗中...在肝脏中保留了许多小时后...在血液中不再能检测到。

IN ALL THESE SPECIES /MICE, RATS, CATS, MONKEYS & DOGS/ STR /STREPTOZOTOCIN/ GIVEN PARENTERALLY ... MARKEDLY CONCENTRATED IN LIVER & KIDNEY; FOR EXAMPLE, IN DOGS ... RETAINED IN LIVER FOR MANY HR AFTER ... NO LONGER ... DETECTED IN BLOOD .

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

链脲佐菌素...在小鼠中从胃肠道很好地被吸收，但在猴子中吸收较差，在狗中几乎不被吸收。

STREPTOZOTOCIN ... WELL ABSORBED FROM GI TRACT IN MICE, BUT ABSORPTION WAS POOR IN MONKEYS & NEGLIGIBLE IN DOGS.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

(14)C标记的链脲佐菌素通过静脉注射给药后，在大鼠血液中迅速清除，10分钟后剩余量不到1%。

(14)C-LABELLED STREPTOZOTOCIN GIVEN BY IV INJECTION WAS RAPIDLY CLEARED FROM BLOOD OF RATS, SO THAT LESS THAN 1% REMAINED AFTER 10 MINUTES.

来源:Hazardous Substances Data Bank (HSDB)

反应信息

• 作为反应物：
  描述：

  streptozocin 、 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran 以8%的产率得到2-(2-(3-Chloro-1-(thiophen-2-yl)propoxy)phenyl)-N,N,3,4-tetramethyl-2H-pyrazolo[3,4-d]pyridazin-7-amine
  参考文献：
  名称：

  ORTHO SUBSTITUTED PHENYLPYRAZOLO- AND PHENYLPYRROLO-PYRIDAZINE DERIVATIVES HAVING MULTIMODAL ACTIVITY AGAINST PAIN

  摘要：

  本发明涉及具有双重药理活性的邻位取代苯基吡唑基和吡咯基吡啶嗪衍生物，其对电压门控钙通道的α2δ亚单位，特别是α2δ-1亚单位，和μ-阿片受体具有双重药理活性，以及这些化合物的制备过程，包含它们的药物组合物，以及它们在治疗中的使用，特别是用于疼痛治疗。

  公开号：

  US20190284195A1

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] INHIBITORS OF BRUTON'S TYROSINE KINASE<br/>[FR] INHIBITEURS DE TYROSINE KINASE DE BRUTON
  申请人：BIOCAD JOINT STOCK CO

  公开号：WO2018092047A1

  公开（公告）日：2018-05-24

  The present invention relates to a new compound of formula I: or pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: V1 is C or N, V2 is C(R2) or N, whereby if V1 is C then V2 is N, if V1 is C then V2 is C(R2), or if V1 is N then V2 is C(R2); each n, k is independently 0, 1; each R2, R11 is independently H, D, Hal, CN, NR'R", C(O)NR'R", C1-C6 alkoxy; R3 is H, D, hydroxy, C(O)C1-C6 alkyl, C(O)C2-C6 alkenyl, C(O)C2-C6 alkynyl, C1-C6 alkyl; R4 is H, Hal, CN, CONR'R", hydroxy, C1-C6 alkyl, C1-C6 alkoxy; L is CH2, NH, O or chemical bond; R1 is selected from the group of the fragments, comprising: Fragment 1, Fragment 2, Fragment 3 each A1, A2, A3, A4 is independently CH, N, CHal; each A5, A6, A7, A8, A9 is independently C, CH or N; R5 is H, CN, Hal, CONR'R", C1-C6 alkyl, non-substituted or substituted by one or more halogens; each R' and R" is independently selected from the group, comprising H, C1-C6 alkyl, C1-C6 cycloalkyl, aryl; R6 is selected from the group: [formula II] each R7, R8, R9, R10 is independently vinyl, methylacetylenyl; Hal is CI, Br, I, F, which have properties of inhibitor of Bruton's tyrosine kinase (Btk), to pharmaceutical compositions containing such compounds, and their use as pharmaceuticals for treatment of diseases and disorder.

  本发明涉及一种新的化合物，其化学式为I：或其药学上可接受的盐、溶剂化合物或立体异构体，其中：V1为C或N，V2为C(R2)或N，如果V1为C，则V2为N，如果V1为C，则V2为C(R2)，或者如果V1为N，则V2为C(R2)；每个n，k独立地为0或1；每个R2，R11独立地为H，D，Hal，CN，NR'R"，C(O)NR'R"，C1-C6烷氧基；R3为H，D，羟基，C(O)C1-C6烷基，C(O)C2-C6烯基，C(O)C2-C6炔基，C1-C6烷基；R4为H，Hal，CN，CONR'R"，羟基，C1-C6烷基，C1-C6烷氧基；L为CH2，NH，O或化学键；R1从包括的片段组中选择：片段1，片段2，片段3，每个A1，A2，A3，A4独立地为CH，N，CHal；每个A5，A6，A7，A8，A9独立地为C，CH或N；R5为H，CN，Hal，CONR'R"，C1-C6烷基，未取代或被一个或多个卤素取代；每个R'和R"独立地从包括H，C1-C6烷基，C1-C6环烷基，芳基的组中选择；R6从组中选择：[化学式II]每个R7，R8，R9，R10独立地为乙烯基，甲基乙炔基；Hal为CI，Br，I，F，具有布鲁顿酪氨酸激酶（Btk）抑制剂的性质，以及含有这种化合物的药物组合物，以及它们作为治疗疾病和紊乱的药物的用途。
• [EN] DIHYDROPYRROLONAPHTYRIDINONE COMPOUNDS AS INHIBITORS OF JAK<br/>[FR] COMPOSÉS DE DIHYDROPYRROLONAPHTYRIDINONE COMME INHIBITEURS DE JAK
  申请人：TAKEDA PHARMACEUTICAL

  公开号：WO2010144486A1

  公开（公告）日：2010-12-16

  Disclosed are JAK inhibitors of formula (I) where G1, R1, R2, R3, R4, R5, R6, and R7 are defined in the specification. Also disclosed are pharmaceutical compositions, kits and articles of manufacture which contain the compounds, methods and materials for making the compounds, and methods of using the compounds to treat diseases, disorders, and conditions involving the immune system and inflammation, including rheumatoid arthritis, hematological malignancies, epithelial cancers (i.e., carcinomas), and other diseases, disorders or conditions associated with JAK.

  揭示了式(I)的JAK抑制剂，其中G1、R1、R2、R3、R4、R5、R6和R7在规范中定义。还披露了含有这些化合物的药物组合物、试剂盒和制造物品，制备这些化合物的方法和材料，以及使用这些化合物治疗涉及免疫系统和炎症的疾病、紊乱和症状的方法，包括类风湿关节炎、血液恶性肿瘤、上皮癌（即癌症）和其他与JAK相关的疾病、紊乱或症状。