(8R)-3-[(4S,5R)-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7,8-dihydro-4H-imidazo[4,5-d][1,3]diazepin-8-ol | 53910-25-1

• 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 - 有机杂环化合物 - 咪唑二氮卓类
• 英文名称: (8R)-3-[(4S,5R)-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7,8-dihydro-4H-imidazo[4,5-d][1,3]diazepin-8-ol
• CAS: 53910-25-1
• 化学式: C₁₁H₁₆N₄O₄
• 分子量: 268.27
• InChiKey: FPVKHBSQESCIEP-VCWZQCKKSA-N

物化性质

• 熔点：
  154-157?C
• 比旋光度：
  D25 +76.4° (c = 1 in water); D23 +73.0° (c = 1, pH 7 buffer)
• 沸点：
  411.43°C (rough estimate)
• 密度：
  1.2576 (rough estimate)
• 溶解度：
  在水中的溶解度为10mg/mL，澄清
• 颜色/状态：
  White crystals from methanol/water
• 稳定性/保质期：
  Commercially available pentostatin powder for injection should be stored at 2-8 °C. ... When stored at 2-8 °C, the manufacturer states that currently available pentostatin powder for injection is stable for 18 mo after the date of manufacture when stored as directed. ... Pentostatin is compatible with 5% dextrose injection, 0.9% sodium chloride injection, and lactated Ringer's. When reconstituted with 0.9% sodium chloride injection to a final concentration of 2 mg/ml, pentostatin solutions are physically and chemically stable for at least 72 hr at room temperature (22-25 °C). When diluted to a final concentration of 20 ug/ml, the drug is chemically compatible at room temperature with 0.9% sodium chloride or lactated Ringer's injection for at least 48 hr and with 5% dextrose injection for at least 24 hr. Up to an 8-10% loss in potency has been reported to occur within 48 hr in such solutions diluted in 5% dextrose, However, because such reconstituted and/or diluted pentostatin solutions contain no preservatives, the manufacturer recommends that they be used within 8 hr when stored at room temperature in ambient light, and that unused portions be discarded.
• 旋光度：
  Specific optical rotation: + 76.4 deg at 25 °C/D (concentration by volume = 1 g 100 ml water); specific optical rotation: + 73.0 deg at 23 °C/D (concentration by volume = 1 g in 100 ml water pH 7 buffer)
• 解离常数：
  pKa = 5.2 in water

计算性质

• 辛醇/水分配系数(LogP)：
  -2.1
• 重原子数：
  19
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.64
• 拓扑面积：
  112
• 氢给体数：
  4
• 氢受体数：
  6

ADMET

毒理性

• 毒性数据

毒性数据：小鼠（静脉注射）：LD50 122毫克/千克

ToxicityData:Mouse(iv): LD50 122 mg/kg

来源:NCI Investigational Drugs

毒理性

• 相互作用

有限的数据表明，同时使用喷托司汀（每两周4毫克/平方米）和氟达拉滨（主要是每隔28天连续4天每天10毫克/平方米），一种合成嘌呤核苷酸，可能与严重和/或致命的肺毒性（例如，肺炎）有关。在一项研究中，6名同时接受这两种药物治疗难治性慢性淋巴细胞性白血病的患者中，据报道有4名患者出现了这种毒性。

Limited data suggest that concomitant therapy with pentostatin (4 mg/sq m every 2 weeks) and fludarabine (principally 10 mg/sq m daily for 4 days at 28 day intervals), a synthetic purine nucleoside, may be associated with severe and/or fatal pulmonary toxicity (eg, pneumonitis). In one study, 4 of 6 patients receiving the drugs concomitantly for treatment of refractory chronic lymphocytic leukemia reportedly developed such toxicity.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

尽管使用pentostatin或allopurinol单药治疗已与皮疹发展有关，但有限的证据表明，与单独使用pentostatin治疗相比，患有难治性毛细胞白血病的患者同时使用这两种药物，并未与皮疹发生率的增加有关。然而，其他毒性反应，包括肾脏或肝脏功能异常，在少数同时接受pentostatin和allopurinol治疗的患者中已被观察到。……据报道，一名患者在同时接受pentostatin和allopurinol治疗期间发展出了致命的超敏性血管炎；然而，尚未确定与药物的因果关系。

Although therapy with either pentostatin or allopurinol alone has been associated with the development of skin rash, limited evidence suggests that concomitant use of the drugs, compared with pentostatin therapy alone, in patients with refractory hairy cell leukemia is not associated with an increased incidence of rash. However, other toxicities, including abnormalities in renal or hepatic function, have been observed in a few patients receiving concomitant pentostatin and allopurinol. ... One patient reportedly developed a fatal hypersensitivity vasculitis while receiving pentostatin and allopurinol concurrently; however, a causal relationship to the drugs has not been established.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

彭托司坦抑制了阿糖腺苷的降解，并在细胞培养和实验性诱导的白血病动物中增强了其细胞毒性。此外，对急性白血病患者有限的资料显示，与彭托司坦单药治疗相比，联合治疗可能与增加的血浆阿糖腺苷浓度和/或半衰期以及更大的毒性相关。尽管有报道称，在接受阿糖腺苷和彭托司坦同时治疗的急性T细胞淋巴细胞性白血病患者中，有少数患者出现了改善和/或缓解。

Pentostatin inhibits the degradation of vidarabine and enhances its cytotoxicity in cell culture and in animals with experimentally induced leukemia. In addition, limited data in patients with acute leukemia suggest that combined therapy with the drugs may be associated with increased plasma vidarabine concentrations and/or half-life and greater toxicity compared with pentostatin therapy alone. Although improvement and/or remission has been reported in a few patients with acute T cell lymphoblastic leukemia who received vidarabine and pentostatin concomitantly.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

没有已知的针对喷托司汀过量的特效解毒剂。使用剂量高于目前推荐剂量（20-50 mg/平方米，连续5天，而不是每两周4 mg/平方米）的喷托司汀与严重的肾脏、肝脏、肺和中枢神经系统毒性有关，这些毒性是不可预测的，偶尔是致命的。在过量情况下，管理应包括停止使用该药物，并开始适当的支持性措施，以应对观察到的毒性类型。

No specific antidote for pentostatin overdosage is known. Administration of pentostatin in dosages higher than those currently recommended (20-50 mg/sq m over 5 days as compared with 4 mg/sq m every other week, respectively) has been associated with severe renal, hepatic, pulmonary, and CNS toxicity, which was unpredictable and occasionally fatal. In case of overdosage, management should include discontinuance of the drug and initiation of supportive measures appropriate to the type of toxicity observed.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

经静脉注射0.25 mg/kg剂量的戊多司坦，每日一次，连续4或5天，对少数晚期、难治性癌症患者进行监测，其血药浓度范围大约在3.2-9.7 ng/ml。血药浓度似乎随剂量增加而线性增加；在一项针对白血病患者的研究中，药物以30分钟静脉输注0.25或1 mg/kg给药后1小时测定的血药浓度平均值分别约为0.4或1.26 ug/ml。

Plasma concentrations of pentostatin following direct iv injection of 0.25 mg/kg daily for 4 or 5 days in a limited number of patients with advanced, refractory cancer ranged from approximately 3.2-9.7 ng/ml. Plasma concentrations appear to increase linearly with dose; in a study in patients with leukemia, plasma pentostatin concentrations determined 1 hour after administration of 0.25 or 1 mg/kg of the drug as a 30 min iv infusion averaged approximately 0.4 or 1.26 ug/ml, respectively.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

尚未有文献记载平均或绝对血浆腺苷或脱氧腺苷浓度与喷托司汀治疗反应或毒性反应之间存在明显的相关性；然而，有限的数据表明，药物反应可能与淋巴细胞中脱氧腺苷三磷酸与腺苷三磷酸的比率有关。另外，据报道，血浆中脱氧腺苷的增加与红细胞和淋巴细胞中脱氧腺苷三磷酸的积累平行，并且红细胞中脱氧腺苷三磷酸与腺苷三磷酸的比率与毒性之间存在相关性。

No apparent correlation has been documented between mean or absolute plasma adenosine or deoxyadenosine concentrations and therapeutic or toxic responses to pentostatin; however, limited data suggest that there may be a correlation between response to the drug and the ratio of deoxyadenosine triphosphate to adenosine triphosphate in lymphoblasts. In addition, increases in plasma deoxyadenosine reportedly parallel the accumulation of deoxyadenosine triphosphate in erythrocytes and lymphoblasts, and there appears to be a correlation between toxicity and the ratio of deoxyadenosine triphosphate to adenosine triphosphate in erythrocytes.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

动物研究表明，喷托司汀能够迅速分布到所有身体组织中，但药物在不同组织中的积累程度似乎因物种而异。在给小鼠进行腹腔注射后，发现药物在肾脏、肝脏和脾脏中的浓度最高。在狗中，喷托司汀的给药后组织浓度与组织的腺苷脱氨酶活性成正比，以肺、脾、胰腺、心脏、肝脏和空肠中的浓度最高。据报道，喷托司汀通过一种与其他核苷类似的促进运输系统或简单的扩散进入红细胞；尽管喷托司汀的效果（例如，腺苷脱氨酶的抑制作用）在不同类型的细胞（例如，淋巴细胞、红细胞）中的时间过程不同，但药物从细胞中流出的特性尚未被描述。

Studies in animals indicate that pentostatin distributes rapidly to all body tissues, but the extent of drug accumulation in different tissues appears to vary among species. Following intraperitoneal injection in mice, the highest concentrations of the drug were found in the kidneys, liver, and spleen. In dogs, pentostatin tissue concentrations following iv administration were proportional to tissue adenosine deaminase activity, with the highest concentrations in the lungs, spleen, pancreas, heart, liver, and jejunum. Pentostatin reportedly enters erythrocytes via a facilitated transport system common to other nucleosides or by simple diffusion; efflux of the drug from cells has not been characterized, although the time course of pentostatin's effects (eg, adenosine deaminase inhibition) varies among different types of cells (eg, lymphocytes, erythrocytes).

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

动物和人类中的有限数据表明，喷托司汀进入脑脊液（CSF）的分布相对较差，CSF中的峰浓度平均大约为同期血浆浓度的10%。在一项针对6岁白血病患者的实验中，患者通过直接静脉注射连续三天每天接受0.25毫克/公斤的喷托司汀治疗，首次给药后4小时，通过酶抑制滴定法测得的血清和脑脊液（通过腰椎穿刺获得）中的喷托司汀浓度分别约为147和19纳克/毫升；在第三次给药后1小时，相应的血清和脑脊液浓度分别约为241和35纳克/毫升。

Limited data in animals and humans indicate that pentostatin distributes relatively poorly into CSF, with peak CSF concentrations averaging approximately 10% of concurrent plasma concentrations. In a 6 yr old leukemia patient receiving pentostatin 0.25 mg/kg daily for 3 successive days by direct iv injection, serum and CSF (via lumbar puncture) pentostatin concentrations 4 hr after the initial dose were approximately 147 and 19 ng/ml, respectively, using an enzyme-inhibition titration assay; one hour after the third dose, corresponding serum and CSF concentrations were approximately 241 and 35 ng/ml, respectively.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险品标志：
  Xn
• 危险类别码：
  R22
• WGK Germany：
  3
• 危险品运输编号：
  UN 2811 6.1 / PGIII
• 海关编码：
  2934999090
• 包装等级：
  III
• 危险类别：
  6.1
• 危险性防范说明：
  P264,P270,P301+P310,P321,P330,P405,P501
• 危险性描述：
  H301,H350,H360

制备方法与用途

生物活性

Pentostatin 是有效的腺苷脱氨酶抑制剂，在治疗多种恶性淋巴增生，尤其是毛细胞白血病中非常有效。它还能与某些抗肿瘤药物发挥协同作用，并具有免疫抑制活性。

化学性质

从甲醇-水混合溶液结晶得到白色晶体，熔点为204～209.5℃或220～225℃（>150℃时会变黑）。在pH 7的水中，最大紫外吸收波长为282nm（ε值约为8000）；在pH 11的水中，最大吸收波长为283nm（ε值约为7970）；在pH 2的水中，初始吸收波长为273nm（开始时ε值约为7570，在6.5小时后变为3143）。[α]D^23+ 值分别为+76.4°（水溶液中C=1）和+73.0°（pH 7的缓冲液中C=1）。水中pKa值为5.2。

用途

Pentostatin 是腺苷脱氨酶(ADA)抑制剂，主要用于α-干扰素治疗无效的毛细胞白血病。

生产方法

大规模生产可通过喷妥司汀产生菌 Streptomyces cetrivioticus 的浸入或深层培养来制备：

1. 发酵

   • 选择合适的培养基植入无菌水溶性营养液，在20～45℃（最佳为33～40℃）条件下进行充气和搅拌培育，直至培养液中出现喷妥司汀。
   • 发酵时间受设备类型、大小、搅拌速度及充气速率等因素影响。大规模工业发酵通常需3～7天可得最大收率；短时间发酵则收率较低。

2. 分离与提纯

   • 分离：采用压滤或离心分离，滤饼用水彻底洗涤后合并洗液和滤液，并调pH值至约9.2。减压浓缩并冷却析出沉淀，用硅藻土作助滤剂过滤除去。
   • 滤液用水稀释并调pH值至约8.3，然后吸附于活性炭或Darco G-60柱子上进行纯化。分批或连续操作均可。
   • 丙酮水溶液用于洗脱，浓缩后通过活性炭柱进一步纯化，得到喷妥司汀的固体产物。

以上方法确保了Pentostatin 的高效生产和高纯度。

文献信息

• ACTIVE SUBSTANCE COMBINATION WITH GEMCITABINE FOR THE TREATMENT OF EPITHELIAL CANCER
  申请人：HEESCHEN CHRISTOPHER

  公开号：US20110151020A1

  公开（公告）日：2011-06-23

  The present invention refers to active substance combinations comprising of a nucleoside analog or antimetabolic agent like Gemcitabine, and either a Nodal/Activin inhibitor or a SHH-Inhibitor and an mTOR-inhibitor, medicaments comprising the same and the use of the active substance combinations in the treatment of cancer, especially of epithelial cancer.
• [EN] TRANSFERRIN RECEPTOR APTAMERS AND APTAMER-TARGETED DELIVERY<br/>[FR] APTAMÈRES DU RÉCEPTEUR DE LA TRANSFERRINE ET ADMINISTRATION CIBLÉE D'APTAMÈRES
  申请人：EINSTEIN COLL MED

  公开号：WO2013163303A2

  公开（公告）日：2013-10-31

  Aptamers targeted to a human transferrin receptor which do not compete with transferrin for binding are provided. Compositions and methods for aptamer-targeted liposomal drug delivery are also provided.
• [EN] APTAMER-TARGETED ANTIGEN DELIVERY<br/>[FR] ADMINISTRATION D'ANTIGÈNE CIBLÉ À UN APTAMÈRE
  申请人：EINSTEIN COLL MED

  公开号：WO2014011465A2

  公开（公告）日：2014-01-16

  A composition is provided comprising an oligonucleotide aptamer conjugated to an antigen, wherein the aptamer is directed against a cell-surface target of an antigen- presenting cell. Also provided are methods of delivering an antigen to a dendritic cell and of eliciting an immune response in a subject.