1-methyl-1-nitroso-3-[(2S,4S,5S)-2,4,5-trihydroxy-6-(hydroxymethyl)oxan-3-yl]urea | 66395-18-4

• 物质功能分类: 原料药 - 抗生素类药物 - 其它抗生素类药
• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 1-methyl-1-nitroso-3-[(2S,4S,5S)-2,4,5-trihydroxy-6-(hydroxymethyl)oxan-3-yl]urea
• CAS: 66395-18-4；18883-66-4
• 化学式: C₈H₁₅N₃O₇
• 分子量: 265.22
• InChiKey: ZSJLQEPLLKMAKR-FEQHFJGESA-N

物化性质

• 熔点：
  121 °C (dec.) (lit.)
• 比旋光度：
  D25 +39°
• 沸点：
  408.44°C (rough estimate)
• 密度：
  1.4410 (rough estimate)
• 溶解度：
  可溶于DMSO（高达25mg/ml）或水（高达25mg/ml）
• 颜色/状态：
  POINTED PLATELETS OR PRISMS FROM 95% ETHANOL
• 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

使用放射性碳-14标记链脲佐菌素的研究表明，在大鼠体内，链脲佐菌素会迅速代谢...产生源自甲基脲基侧链的代谢物。/备选方案：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

• 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超过肝脏损伤。已有两例报告在使用链脲佐菌素治疗的病人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，氟尿嘧啶同时给药，病人在5天治疗结束时时出现了发热、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将链脲佐菌素归因于自限性临床明显的肝损伤，但由于胰腺胰岛细胞癌和神经内分泌肿瘤较为罕见，链脲佐菌素的使用受限。

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

• 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为B2组，这是基于动物实验中的充分证据。在人类中没有可用的数据。作为B2组化学物质，链脲佐菌素被认为可能对人类具有致癌性。

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。有充分的证据表明对动物具有致癌性。总体评估：2B组：该物质可能对人类具有致癌性。

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)

吸收、分配和排泄

链脲佐菌素（NSC-85998）在处理过的小鼠尿液中迅速排出；4小时尿液中的注射剂量有72%。检测到五种尿液代谢物...。

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

在动物中进行链脲佐菌素（streptozocin）的腹腔内或静脉注射后，药物及其代谢物会迅速分布，主要进入肝脏、肾脏、肠道和胰腺，较低浓度的分布到骨骼肌、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通常高于血浆中的浓度。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，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)

安全信息

• 危险等级：
  6.1(b)

制备方法与用途

理化性质

理化性质：淡黄色结晶性粉末，易溶于水，但其水溶液在室温下极不稳定，可在半小时后分解为气体而挥发掉，故需现用现配。溶于较低度醇和酮，不溶于极性的有机溶剂。

发现历史

链脲菌素是一种由链球菌产生的天然化合物，属于亚硝脲类抗生素，对哺乳动物胰脏中产生胰岛素的胰岛B细胞具有特异毒性。它与脂溶性的亚硝脲不同，在氯乙基处是一个甲基，在分子的另一端是一个氨基糖。链脲佐菌素可自行分解活泼的甲基正碳离子，与DNA呈链间交叉连结，从而使DNA烷化，但其烷化作用比其他亚硝脲类药物弱。其代谢产物甲基亚硝脲的烷化作用较STZ强3~4倍。STZ在体内可形成异氰酸盐，从而与核酸蛋白结合，抑制DNA多聚酶活力，使受损的DNA难于修复。1950年代末被发现之初被认为是一种抗生素，来自卡拉马祖的Upjohn制药公司（现在辉瑞的一个子公司）的科学家在一个土壤中不产色链霉菌的菌株里发现了STZ。在1960年代中期，人们发现链脲佐菌素对于产生胰岛素的胰岛B细胞具有特异毒性。这一点的发现使得STZ后来被用于建立糖尿病的动物模型以及治疗胰岛B细胞瘤。19世纪60到70年代，美国国家癌症研究中心开始研究链脲佐菌素在化疗中的应用。Upjohn公司在1976年11月向FDA申请批准其对于胰岛癌的治疗，并于1982年7月获得批准。之后它一直使用商品名Zanosar。它被用于临床上治疗胰岛细胞瘤(β细胞或非β细胞癌)，对类癌肿瘤、霍奇金病、结肠癌及肝癌等有一定疗效，同时在医学研究中建立1型糖尿病的动物模型。

动物糖尿病诱发剂

糖尿病是一种常见的代谢内分泌疾病，发病原因主要是胰岛素相对或绝对不足所致，其特征为高血糖和糖尿。实验可利用药物（如四氧嘧啶和链脲菌素等）选择性地破坏胰腺β-细胞、使血糖水平升高从而造成小鼠实验性糖尿病模型。

链脲佐菌素(简称STZ)是一种动物糖尿病诱发剂，对一定种属动物的胰岛β细胞有选择性破坏作用，能诱发许多动物产生糖尿病。但在豚鼠和人中不引起。一般采用大鼠和小鼠制造动物模型，国外有学者报道选用雄性大鼠制造模型的成模率明显高于雌性大鼠。1型糖尿病与2型糖尿病动物模型胰岛素分泌细胞死亡的诱导，STZ通过低亲和力的GLUT 2葡萄糖转运体在胰岛β细胞中选择性积累。

用途

一种含N-亚硝基的化合物，在胰腺胰岛充当一氧化氮的供体；诱导产生糖尿病动物模型的胰岛素分泌细胞死亡。高效DNA甲基化试剂，能诱发染色体断裂。对表达GLUT2葡萄糖转运体（GLUT2 glucose transporter）的神经内分泌肿瘤细胞系具细胞毒性。医学研究上链脲佐菌素用于诱导1型糖尿病。

文献信息

• Compositions and methods for treating disease utilizing a combination of radioactive therapy and cell-cycle inhibitors
  申请人：Hunter L. William

  公开号：US20080058579A1

  公开（公告）日：2008-03-06

  Disclosed herein are therapeutic devices, compositions and methods for treating proliferative diseases. For example, within one aspect of the invention therapeutic devices are provided, comprising a device that locally administers radiation and a cell-cycle inhibitor
• Multifunctional Compounds for Forming Crosslinked Biomaterials and Methods of Preparation and Use
  申请人：Daniloff George Y.

  公开号：US20080312315A1

  公开（公告）日：2008-12-18

  Multifunctional compounds are provided that readily crosslink in situ to provide crosslinked biomaterials. The multifunctional compounds contain a single component having at least three reactive functional groups thereon, with the functional groups selected so as to be non-reactive in an initial environment and inter-reactive in a modified environment. Reaction of a plurality of the multifunctional compounds results in a three-dimensional crosslinked matrix. In one embodiment, a first functional group is nucleophilic, a second functional group is electrophilic, and at least one additional functional group is nucleophilic or electrophilic. Methods for preparing and using the multifunctional compounds, and kits including the multifunctional compounds are also provided. Exemplary uses for the multifunctional compounds include tissue augmentation, biologically active agent delivery, bioadhesion, and prevention of adhesions following surgery or injury.
• SOFT TISSUE IMPLANTS AND ANTI-SCARRING AGENTS
  申请人：Hunter William L.

  公开号：US20090214652A1

  公开（公告）日：2009-08-27

  Soft tissue implants (e.g., breast, pectoral, chin, facial, lip, and nasal implants) are used in combination with an anti-scarring agent in order to inhibit scarring that may otherwise occur when the implant is placed within an animal.
• COMPOSITIONS AND METHODS FOR TREATING CONTRACTURE
  申请人：Avelar Rui

  公开号：US20090203632A1

  公开（公告）日：2009-08-13

  A method for treating contracture is provided that includes administering to a patient in need thereof a composition that includes a therapeutic agent effective in treating contracture. Compositions, devices, and kits for use in treating contracture are also described.
• SUTURES AND ANTI-SCARRING AGENTS
  申请人：Avelar Rui

  公开号：US20090226500A1

  公开（公告）日：2009-09-10

  Sutures are used in combination with anti-scarring agents to inhibit fibrosis between the sutures and the host tissues into which the sutures are inserted. Compositions and methods are described for use in reducing excessive scarring, surgical adhesion, and other disorders.