streptozotocin | 72521-89-2

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: streptozotocin
• 英文别名: streptozocin；STZ；1-methyl-1-nitroso-3-[(3R,4R,5S,6R)-2,4,5-trihydroxy-6-(hydroxymethyl)oxan-3-yl]urea
• CAS: 72521-89-2
• 化学式: C₈H₁₅N₃O₇
• 分子量: 265.223
• InChiKey: ZSJLQEPLLKMAKR-YDEIVXIUSA-N

物化性质

• 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：
  239 °F (Decomposes) (NTP, 1992)
• 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：
  0.88
• 拓扑面积：
  152
• 氢给体数：
  5
• 氢受体数：
  8

ADMET

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...产生源自甲基脒基硝基脲侧链的代谢物。/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排出；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

• 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、短暂的，并且不伴有症状或黄疸。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掩盖了肝脏损伤。已有两例报告称，接受链脲佐菌素治疗的病人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，同时给予了氟尿嘧啶，病人在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，尚未有单独发表的个案报告称链脲佐菌素引起了自限性的临床明显肝损伤，但由于胰腺胰岛细胞癌和神经内分泌肿瘤较为罕见，链脲佐菌素的使用也受到了限制。

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

• 致癌性证据

美国环保局健康与环境评估办公室的人类健康评估小组已经对链脲佐菌素进行了致癌性评估。根据他们的分析，链脲佐菌素的证据权重被归类为B2组，这一分类是基于在动物中的充分证据。在人类中尚无数据。作为一个B2组化学物质，链脲佐菌素被认为对人类可能是致癌的。

The Human Health Assessment Group in EPA's Office of Health and Environmental Assessment has evaluated streptozotocin for carcinogenicity. According to their analysis, the weight-of-evidence for streptozotocin is group B2, which is based on sufficient evidence in animals. No data are available in humans. As a group B2 chemical, streptozotocin is considered probably carcinogenic to humans.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 致癌性证据

没有关于人类的数据。动物中有充分的致癌性证据。总体评估：2B组：该物质可能对人类有致癌性。

No data are available in humans. Sufficient evidence of carcinogenicity in animals. OVERALL EVALUATION: Group 2B: The agent is possibly carcinogenic to humans.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 致癌性证据

链脲佐菌素：合理预期为人类致癌物。

Streptozotocin: reasonably anticipated to be a human carcinogen.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 致癌物分类

国际癌症研究机构致癌剂：链脲佐菌素

IARC Carcinogenic Agent:Streptozotocin

来源:International Agency for Research on Cancer (IARC)

吸收、分配和排泄

在这些物种中（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集中；例如，在狗中...在肝脏中保留了许多小时之后...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

静脉注射的(14)C-标记链脲佐菌素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)

吸收、分配和排泄

链脲佐菌素（NSC-85998）在处理的小鼠尿液中迅速排出；4小时尿液中注射剂量的72%。检测到五种尿代谢物...。

STREPTOZOTOCIN (NSC-85998) WAS RAPIDLY EXCRETED IN URINE OF TREATED MICE; 72% OF AN INJECTED DOSE IN THE 4-HR URINE. FIVE URINARY METABOLITES WERE DETECTED ... .

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

静脉或腹腔内给药后，链脲佐菌素及其代谢物在动物体内迅速分布，主要分布到肝脏、肾脏、肠道和胰腺，较低浓度分布到骨骼肌、脾脏、肺、心脏和胸腺。药物或其代谢物在肝脏、肾脏、肠道和胰腺中的浓度始终高于血浆。链脲佐菌素在动物或人类中似乎不能穿过血脑屏障；然而，在人类中，链脲佐菌素的代谢物容易分布到脑脊液（CSF）中。在猴子中，该药物容易穿过胎盘。

Following intraperitoneal or IV administration of streptozocin in animals, the drug and its metabolites are rapidly distributed mainly into the liver, kidneys, intestine, and pancreas, with lower concentrations being distributed into skeletal muscle, spleen, lungs, heart, and thymus. Concentrations of the drug or its metabolites in the liver, kidneys, intestine, and pancreas are consistently higher than those in plasma. Streptozocin does not appear to cross the blood-brain barrier in animals or humans; however, in humans, metabolites of streptozocin readily distribute into CSF. ... The drug readily crosses the placenta in monkeys.

来源:Hazardous Substances Data Bank (HSDB)

反应信息

• 作为反应物：
  描述：

  streptozotocin 在 氨基磺酸 作用下， 生成 (3aS)-5c-((R)-1,2-dihydroxy-ethyl)-6c-hydroxy-3-methyl-(3ar,6ac)-hexahydro-furo[2,3-d]imidazol-2-one
  参考文献：
  名称：

  Streptozocin: structure and chemistry

  摘要：

  DOI：

  10.1021/jo01315a003
• 作为产物：
  描述：

  2-deoxy-2-amino glucose 在 盐酸 、 sodium hydroxide 、 sodium nitrite 作用下， 以 乙醚 、 乙醇 、 氯仿 、 水 为溶剂， 反应 4.5h， 生成 streptozotocin
  参考文献：
  名称：

  在寻找新的抗癌药。XXIII：探索含有N-亚硝基氯乙基氨基，N-亚硝基甲基和N-亚硝基氨基甲苯基成分的碳水化合物的抗癌药物的预测设计。

  摘要：

  自旋标记的葡萄糖亚硝基脲13-16，链脲佐菌素（18），氯唑菌素（31），半乳糖基24和甘露糖基28的链脲佐菌素类似物及其四-O-乙酰基衍生物25和29，MCNU（Cymerin，34）和葡萄糖胺（21）已合成并在体内评估了其对鼠淋巴细胞性白血病P388的抗癌活性。化合物13-16、18、24、28、31和34的活性增长寿命（％ILS）在33％至603％之间，而21、25和29种化合物则无活性（％ILS = 9至10）。在30天后，所有用活性最高的化合物（13、14和34）以20 mg / kg治疗的CD2F1雄性小鼠均存活，而所有经临床链脲佐菌素（18）和经临床测试的氯佐霉素（31）治疗的小鼠均被淘汰。化合物13-16、18、31，进一步评估了34和34的抗淋巴白血病L1210的抗肿瘤活性。与CCNU（1）和自旋标记SLCNU（3）相比，化合物13和34在第60天的％ILS值分别为557

  DOI：

  10.1002/jps.2600800717

文献信息

• Selective Modification of Streptozotocin at the C3 Position to Improve Its Bioactivity as Antibiotic and Reduce Its Cytotoxicity towards Insulin-Producing β Cells
  作者：Ji Zhang、Liubov Yakovlieva、Bart J. de Haan、Paul de Vos、Adriaan J. Minnaard、Martin D. Witte、Marthe T. C. Walvoort

  DOI：10.3390/antibiotics9040182

  日期：——

  resistance of bacteria to current antibiotics, novel compounds are urgently needed to treat bacterial infections. Streptozotocin (STZ) is a natural product that has broad-spectrum antibiotic activity, albeit with limited use because of its toxicity to pancreatic β cells. In an attempt to derivatize STZ through structural modification at the C3 position, we performed the synthesis of three novel STZ analogues

  随着细菌对当前抗生素的抗性增加，迫切需要新型化合物来治疗细菌感染。链脲佐菌素（STZ）是一种具有广谱抗生素活性的天然产物，尽管由于其对胰腺β细胞的毒性而用途有限。为了尝试通过C3位置的结构修饰衍生STZ，我们通过利用我们最近开发的区域选择性氧化方案进行了三种新颖的STZ类似物的合成。Keto-STZ（2）对细菌的生长具有最高的抑制作用（最小抑制浓度（MIC）和活力测定），但也是最具细胞毒性的化合物。用GlcNAc对细菌进行预敏化可以提高抗菌效果，但并不能完全杀死细菌。有趣的是
• [EN] BETA-GLUGURONIDASE CLEAVABLE PRODRUGS OF O6-ALKYLGUANINE-DNA ALKYLTRANSFERASE INACTIVATORS<br/>[FR] PROMEDICAMENTS A BASE D'AGENTS D'INACTIVATION DE L'O6-ALKYLGUANINE-ADN ALKYLTRANSFERASE, CLIVABLES PAR LA BETA-GLUCURONIDASE
  申请人：US GOV HEALTH & HUMAN SERV

  公开号：WO2006029065A1

  公开（公告）日：2006-03-16

  Disclosed are prodrugs of inactivators of 06-alkylguanine-DNA alkyltransferase (AGT). The prodrugs are cleavable by the (3-glucuronidase enzyme, which is either administered to the patient or produced by necrotic tumor cells. The prodrugs are represented by the formula A-B-C, wherein A is a glucuronosyl residue linked through its 1-oxygen to the phenyl ring of B; B is a benzyloxycarbonyl group, optionally ring­ substituted with one or more electron withdrawing groups; and C is an inactivator of AGT, e.g., a substituted or unsubstituted 06-benzylguanine or 06-benzyl-2'-deoxyguanosine. Also disclosed are pharmaceutical compositions comprising a prodrug and a pharmaceutically acceptable carrier, and a method of use of the prodrugs in enhancing the chemotherapeutic treatment of tumor cells in a mammal, e.g., a human, with an antineoplastic alkylating agent that causes cytotoxic lesions at the 06-position of guanine.

  本发明公开了06-烷基鸟嘌呤-DNA烷基转移酶（AGT）失活剂的前药。这些前药可以被（3-葡萄糖醛酸酶酶）水解，该酶可以被注射到患者体内或由坏死肿瘤细胞产生。前药由公式A-B-C表示，其中A是通过其1-氧原子与B的苯环连接的葡萄糖醛酸残基；B是苄氧羰基基团，可以选择性地被一个或多个电子提取基团取代；而C是AGT的失活剂，例如取代或未取代的06-苄基鸟嘌呤或06-苄基-2'-脱氧鸟苷。本发明还公开了包含前药和药学上可接受的载体的制药组合物，以及在增强哺乳动物（例如人类）中肿瘤细胞的化疗治疗中使用前药的方法，该方法使用一种抗肿瘤烷基化剂，在鸟嘌呤的06位引起细胞毒性损伤。
• [EN] 2-AMINO-O4-SUBSTITUTED PTERIDINES AND THEIR USE AS INACTIVATORS OF O6-ALKYLGUANINE-DNA ALKYLTRANSFERASE<br/>[FR] PTERIDINES A SUBSTITUTION 2-AMINO-O4-ET LEUR UTILISATION COMME INACTIVEURS DE LA O6-ALKYLGUANINE-ADN ALKYLTRANSFERASE
  申请人：US GOV HEALTH & HUMAN SERV

  公开号：WO2005068465A1

  公开（公告）日：2005-07-28

  Disclosed are pteridine derivatives of formula (I): (I), wherein, for example, R1 and R2 are hydrogen, C1-C6 alkyl, carboxyl, formyl, C1-C6 hydroxyalkyl, C1-C6 carboxyalkyl, C1-C6 formyl alkyl, C1-C6 alkoxy, acyloxy, acyloxyalkyl wherein the alkyl is C1-C6, halogen, or hydroxy, or a group of formula II: (II); and R3 is (a) phenyl or (b) a cyclic group having at least one 5 or 6-membered heterocyclic ring, optionally with a carbocyclic or heterocyclic ring fused thereto, wherein each heterocyclic ring has at least one hetero atom chosen from O, N, or S; or (c) a phenyl group or a cyclic group, the cyclic group optionally with a carbocyclic or heterocyclic ring fused thereto, which is substituted with 1 to 5 substituents. Disclosed also are pharmaceutical compositions, a method of enhancing the chemotherapeutic effectiveness of cancer treatment agents, a method of deactivating the O6-alkylguanine-DNA alkyltransferase enzyme, and a method of inhibiting the reaction of O6-alkylguanine-DNA alkyltransferase enzyme with an alkylated DNA.

  本发明涉及式(I)的黄嘌呤衍生物：(I)，其中，例如，R1和R2是氢、C1-C6烷基、羧基、甲酰基、C1-C6羟基烷基、C1-C6羧基烷基、C1-C6甲酰基烷基、C1-C6烷氧基、酰氧基、酰氧基烷基，其中烷基为C1-C6，卤素或羟基，或式II的基团：(II)；以及R3是(a)苯基或(b)至少具有一个5或6元杂环环的环状基团，可选地与碳环或杂环环融合在一起，其中每个杂环环至少有一个从O、N或S中选择的杂原子；或(c)苯基或环状基团，环状基团可选地与碳环或杂环环融合在一起，其被1到5个取代基取代。本发明还涉及制药组合物、增强癌症治疗药物的化疗效果的方法、失活O6-烷基鸟嘌呤-DNA烷基转移酶酶的方法以及抑制O6-烷基鸟嘌呤-DNA烷基转移酶与烷基化DNA反应的方法。
• INACTIVATORS OF O6-ALKYLGUANINE-DNA ALKYLTRANSFERASE
  申请人：Moschel Robert C.

  公开号：US20100204172A1

  公开（公告）日：2010-08-12

  Disclosed are compounds that are AGT inactivators that include a folate residue, e.g., a compound of formula (I), wherein X 1 , X 2 , R 1 , and R 2 are as described herein. Also disclosed is a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable carrier. Also disclosed are methods of enhancing the chemotherapeutic treatment of tumor cells and inactivating AGT in a tumor cell. The methods comprise, inter alia, administering a compound or pharmaceutically acceptable salt of formula (I).

  本发明涉及一种包括叶酸残基的AGT失活剂化合物，例如式(I)的化合物，其中X1、X2、R1和R2如本文所述。本发明还涉及一种包括本发明化合物和药学上可接受的载体的制药组合物。本发明还涉及增强肿瘤细胞化疗治疗和失活肿瘤细胞中AGT的方法。该方法包括，除其他外，给予式(I)的化合物或药学上可接受的盐。
• Substituted O6-benzyl-8-aza-guanines
  申请人：The Government of the United States of America, Department of Health and Human Services

  公开号：US20020013299A1

  公开（公告）日：2002-01-31

  The present invention provides AGT inactivating compounds such as substituted O 6 -benzylguanines of the formula 1 7- or 9-substituted 8-aza-O 6 -benzylguanines, 7,8-disubstituted O 6 -benzylguanines, 7,9-disubstituted O 6 -benzylguanines, 4(6)-substituted 2-amino-5-nitro-6 (4) -benzyloxypyrimidines, and 4 (6) -substituted 2-amino-5-nitroso-6(4)-benzyloxypyrimidines, as well as pharmaceutical compositions comprising such compounds along with a pharmaceutically acceptable carrier. The present invention further provides a method of enhancing the chemotherapeutic treatment of tumor cells in a mammal with an antineoplastic alkylating agent, which causes cytotoxic lesions at the O 6 -position of guanine, by administering to a mammal an effective amount of one of the aforesaid compounds, 2,4-diamino-6-benzyloxy-s-triazine, 5-substituted 2,4-diamino-6-benzyloxypyrimidines, or 8-aza-O 6 -benzylguanine, and administering to the mammal an effective amount of an antineoplastic alkylating agent which causes cytotoxic lesions at the Deposition of guanine.

  本发明提供了AGT失活化合物，例如公式17-或9-取代的8-aza-O6-苄基鸟嘌呤、7,8-二取代的O6-苄基鸟嘌呤、7,9-二取代的O6-苄基鸟嘌呤、4（6）-取代的2-氨基-5-硝基-6（4）-苄氧嘧啶和4（6）-取代的2-氨基-5-亚硝基-6（4）-苄氧嘧啶，以及包含这些化合物和药用载体的制药组合物。本发明还提供了一种增强抗肿瘤烷化剂治疗哺乳动物肿瘤细胞的方法，该方法通过向哺乳动物投与上述化合物、2,4-二氨基-6-苄氧基-s-三嗪、5-取代的2,4-二氨基-6-苄氧基嘧啶或8-aza-O6-苄基鸟嘌呤的有效量，并向哺乳动物投与一种在鸟嘌呤O6位引起细胞毒性损伤的抗肿瘤烷化剂的有效量。