teniposide | 29767-20-2

• 物质功能分类: 原料药 - 抗肿瘤药 - 天然来源类抗肿瘤药
• 分子结构分类: 有机化合物 - 木脂素、新木脂素和相关化合物 - 木脂素内酯
• 英文名称: teniposide
• 英文别名: VM-26；4'-Demethyl-1-O-<4,6-O-(2-thenyliden)-β-D-glucopyranosyl>-epipodophyllotoxin；4'-Demethyl-1-O-[4,6-O-(2-thenyliden)-β-D-glucopyranosyl]-epipodophyllotoxin；Teniposidum；(5S,5aR,8aR,9R)-5-[[(4aR,6R,7R,8R,8aS)-7,8-dihydroxy-2-thiophen-2-yl-4,4a,6,7,8,8a-hexahydropyrano[3,2-d][1,3]dioxin-6-yl]oxy]-9-(4-hydroxy-3,5-dimethoxyphenyl)-5a,6,8a,9-tetrahydro-5H-[2]benzofuro[6,5-f][1,3]benzodioxol-8-one
• CAS: 29767-20-2；35317-60-3；53956-10-8；89301-94-0；132880-84-3
• 化学式: C₃₂H₃₂O₁₃S
• 分子量: 656.664
• InChiKey: NRUKOCRGYNPUPR-PSZSYXFXSA-N

物化性质

• 熔点：
  244-247°C
• 比旋光度：
  D20 -107° (9:1 chloroform/methanol)
• 沸点：
  650.86°C (rough estimate)
• 密度：
  1.2568 (rough estimate)
• 溶解度：
  DMSO：可溶10mg/mL，澄清
• 最大波长(λmax)：
  283nm(MeOH)(lit.)
• 物理描述：
  Solid
• 颜色/状态：
  Crystals from absolute ethanol
• 蒸汽压力：
  6.8X10-26 mm Hg at 25 °C /Estimated/
• 旋光度：
  Specific optical rotation: -107 deg at 20 °C/D (9:1 chloroform/methanol)
• 分解：
  When heated to decomposition it emits very toxic fumes of /sulfur oxides/.
• 解离常数：
  pKa = 10.13

计算性质

• 辛醇/水分配系数(LogP)：
  1.2
• 重原子数：
  46
• 可旋转键数：
  6
• 环数：
  8.0
• sp3杂化的碳原子比例：
  0.47
• 拓扑面积：
  189
• 氢给体数：
  3
• 氢受体数：
  14

ADMET

代谢

在人离体肝脏制剂中，细胞色素P450混合功能同工酶催化了（悬挂）E环的代谢，生成O-去甲基化和儿茶酚代谢物。这种代谢主要归因于CYP3A4的活性，其次在较小程度上归因于CYP3A5。还报道了过氧化物酶介导的替尼泊苷的O-去甲基化。

In isolated human liver preparations, cytochrome P450 mixed-function isozymes catalysed metabolism of the (pendant) E-ring to O-demethylated and catechol metabolites. This metabolism was subsequently attributed primarily to CYP3A4 activity and to a lesser degree to CYP3A5. Peroxidase-mediated O-demethylation of teniposide has also been reported.

来源:Hazardous Substances Data Bank (HSDB)

代谢

在给予替尼泊苷的儿童中，血清和尿液中报告的主要代谢物是羟基酸，由内酯环的开环形成；还检测到了顺式异构体，可能是储存过程中形成的降解产物。没有检测到由葡萄糖苷部分丢失形成的苷元（Evans等人，1982年）。在其他使用高剂量替尼泊苷的研究中，没有在血浆或尿液中发现羟基酸，并且在与葡萄糖醛酸酶孵育后，这些样品中替尼泊苷的测量浓度没有变化，这表明形成少量或没有提出的葡萄糖醛酸苷代谢物（Holthuis等人，1987年）。然而，另一项研究中，给予的替尼泊苷剂量的6%在24小时内以母药形式从尿液中排出，另外8%以提出的苷元葡萄糖醛酸苷形式排出，后者没有正式鉴定。

In children given teniposide, the main metabolite in serum and urine was reported to be the hydroxy acid, formed by opening of the lactone ring; the cis-isomer, which may be a degradation product formed during storage, was also detected. The aglycone, formed by loss of the glucopyranoside moiety, was not detected (Evans et al., 1982). The hydroxy acid has not been found in plasma or urine in other studies with high doses of teniposide, and no changes in the measured concentration of teniposide in these samples was found after incubation with glucuronidase, indicating formation of little or none of the proposed glucuronide metabolites (Holthuis et al., 1987). In another study, however, 6% of the administered dose of teniposide was excreted in the urine as parent drug over 24 h, and a further 8% as a proposed aglycone glucuronide, which was not formally identified.

来源:Hazardous Substances Data Bank (HSDB)

代谢

通常情况下，在哺乳动物体外细胞中，替尼泊苷的作用并不需要外源性代谢激活。已经鉴定出了替尼泊苷的各种代谢产物，但它们的致突变性质尚未进行研究。

In general, the effects of teniposide in mammalian cells in vitro occurred in the absence of exogenous metabolic activation. Various metabolic species of teniposide have been identified, but their mutagenic properties have not been studied.

来源:Hazardous Substances Data Bank (HSDB)

代谢

消除途径：4%至12%的剂量以原药形式通过尿液排出。给药后72小时内，放射性物质通过粪便排出的量占剂量的0%至10%。 半衰期：5小时

Route of Elimination: From 4% to 12% of a dose is excreted in urine as parent drug. Fecal excretion of radioactivity within 72 hours after dosing accounted for 0% to 10% of the dose. Half Life: 5 hours

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 毒性总结

作用机制似乎与抑制II型拓扑异构酶活性有关，因为替尼泊苷不插入DNA或与DNA强烈结合。替尼泊苷与DNA拓扑异构酶II结合并抑制其活性。替尼泊苷的细胞毒性效果与细胞中产生的双链DNA断裂的相对数量有关，这是拓扑异构酶II-DNA中间体稳定化的反映。

The mechanism of action appears to be related to the inhibition of type II topoisomerase activity since teniposide does not intercalate into DNA or bind strongly to DNA. Teniposide binds to and inhibits DNA topoisomerase II. The cytotoxic effects of teniposide are related to the relative number of double-stranded DNA breaks produced in cells, which are a reflection of the stabilization of a topoisomerase II-DNA intermediate.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 致癌性证据

评估：对于替尼泊苷对人类的致癌性，人类的证据有限。对于依托泊苷在实验动物中的致癌性，证据不足。总体评估：替尼泊苷可能对人类具有致癌性（2A组）。在得出这一评估时，工作组注意到依托泊苷能在白血病细胞中引起独特的细胞遗传学损伤，这些损伤可以轻易地与由烷化剂诱导的损伤区分开来。这些白血病的短暂潜伏期与由烷化剂诱导的白血病潜伏期形成对比。在体外的人细胞和体内动物细胞中，会发生强烈的蛋白质遮蔽DNA断裂和致裂变效应。

Evaluation: There is limited evidence in humans for the carcinogenicity of teniposide. There is inadequate evidence in experimental animals for the carcinogenicity of etoposide. Overall evaluation: Teniposide is probably carcinogenic to humans (Group 2A). In reaching this evaluation, the Working Group noted that etoposide causes distinctive cytogenetic lesions in leukemic cells that can be readily distinguished from those induced by alkylating agents. The short latency of these leukemias contrasts with that of leukemia induced by alkylating agents. Potent protein masked DNA breakage and clastogenic effects occur in human cells in vitro and animal cells in vivo.

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：替尼泊苷

IARC Carcinogenic Agent:Teniposide

来源:International Agency for Research on Cancer (IARC)

毒理性

• 致癌物分类

国际癌症研究机构（IARC）致癌物分类：2A组：可能对人类致癌

IARC Carcinogenic Classes:Group 2A: Probably carcinogenic to humans

来源:International Agency for Research on Cancer (IARC)

毒理性

• 致癌物分类

国际癌症研究机构专著：第76卷：（2000年）一些抗病毒和抗癌药物以及其他药物制剂

IARC Monographs:Volume 76: (2000) Some Antiviral and Antineoplastic Drugs, and Other Pharmaceutical Agents

来源:International Agency for Research on Cancer (IARC)

吸收、分配和排泄

替尼泊苷在11名接受100-150 mg/平方米替尼泊苷治疗的患者的大脑内肿瘤中检测到的浓度为0.05-1.12微克/克组织，这些患者在肿瘤切除前1.5-3小时接受了治疗。在3名患者中，邻近的正常脑组织中的浓度较低（< 0.9微克/克组织），而在其他患者中则检测不到（< 0.05微克/克组织）。

Teniposide was detected in intracerebral tumors at concentrations of 0.05-1.12 ug/g tissue in 11 patients given 100-150 mg/sq m teniposide 1.5-3 hr before tumor resection. The concentrations in adjacent normal brain tissue were low (< 0.9 ug/g tissue) in three patients and undetectable (< 0.05 ug/g tissue) in the others

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

替尼泊苷在一个患者体内被检测到，该患者在累计静脉给药576毫克后三天死亡，最高浓度出现在脾脏、前列腺、心脏、大肠、肝脏和胰腺。

Teniposide was detected in one patient who died three days after a cumulative intravenous dose of 576 mg, the highest concentrations occurring in the spleen, prostate, heart, large bowel, liver and pancreas.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

替尼泊苷是否分布进入乳汁尚不清楚。

It is not known whether teniposide is distributed into breast milk.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

消除：肾脏：4%至12%的剂量以未改变的依托泊苷形式。在一项使用氚标记的依托泊苷对成人的研究中，给药后120小时内，尿液中有44%的放射性标记（母化合物和代谢物）被回收。粪便：0%至10%的剂量。

Elimination: Renal: 4 to 12% of a dose as unchanged teniposide. In a study of tritium-labeled teniposide in adults, 44% of the radiolabel (parent compound and metabolites) was recovered in urine within 120 hours after dosing. Fecal: 0 to 10% of a dose.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险品标志：
  Xi
• 安全说明：
  S26,S36
• 危险类别码：
  R36/37/38
• WGK Germany：
  3
• 海关编码：
  29349990
• 危险标志：
  GHS08
• 危险品运输编号：
  3276
• 危险性描述：
  H350
• 危险性防范说明：
  P201,P308 + P313

制备方法与用途

药理作用 替尼泊苷是一种鬼臼毒素的半合成衍生物，为周期特异性细胞毒药物。它主要作用于细胞周期S后期或G2前期的细胞，通过阻止细胞进入有丝分裂而起作用。此外，该药物还会引起DNA单链断裂，其断裂数量是VP-16的5倍，其机制是抑制I型拓扑异构酶。替尼泊苷的主要代谢物包括羟基酸、苦味酸内酯衍生物及其糖苷基，其中糖基对DNA具有活性。约39.5%从尿中排泄，43.1%从粪便排出。

药代动力学 在一定剂量范围内，替尼泊苷的药代动力学参数呈线性，药物在体内不发生蓄积。静脉注射后，药物从中央室1相清除，分布相半衰期约为1小时。该药物与蛋白的结合率高，并能通过血脑屏障，在脑脊液中的浓度低于血药浓度。替尼泊苷的肾脏清除率仅占总清除率的10%，其清除半衰期约为6～20小时。

用途 替尼泊苷临床主要用于治疗白血病、恶性淋巴瘤、神经母细胞瘤、脑瘤、何杰金病、膀胱癌和小细胞肺癌等。

不良反应 替尼泊苷的主要毒副反应为骨髓抑制，表现为血小板减少和较轻的白细胞下降。常见的其他不良反应包括恶心、呕吐、脱发、腹泻、腹痛、皮疹、发热和静脉炎等。偶见转氨酶升高，使用本品可能导致过敏反应，引发支气管痉挛、皮肤潮红、荨麻疹、呼吸困难及低血压等，罕见口炎、头痛及精神混乱现象。

用途 替尼泊苷是一种鬼臼毒素的半合成衍生物，具有抗肿瘤活性。它是拓扑异构酶II的抑制剂，并能形成三元复合物与该酶和DNA结合，导致剂量依赖性的单链和双链断裂、DNA：蛋白交叉连接、DNA链重接抑制及细胞毒性作用。

反应信息

• 作为反应物：
  描述：

  teniposide 生成 (5S,5aR,8aR,9R)-9-(5-Methoxy-3,4-dioxo-1,5-cyclohexadien-1-yl)-8-oxo-5,5a,6,8,8a,9-hexahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-5-yl 4,6-O-(2-thienylmethylene)-beta-D-glucopyranoside
  参考文献：
  名称：

  摘要：

  DOI：
• 作为产物：
  描述：

  4’-去甲基表鬼臼毒素-Β-D-葡萄糖甙 、 2-噻吩甲醛 生成 teniposide
  参考文献：
  名称：

  摘要：

  DOI：

文献信息

• ANTIBODIES
  申请人：Sathyanarayanan Sriram

  公开号：US20120058112A1

  公开（公告）日：2012-03-08

  The combination of an IGF-1R antagonist such as a humanized antibody and an anti-proliferative drug is described. In a preferred embodiment, the present invention describes the combination of an IGF-1R antibody and an anti-proliferative drug belonging to the EGFR-inhibitor class, which is preferably erlotinib. The combination according to the present invention is useful for the treatment of tumours, including IGF-1R and/or EGFR mediated or dependent tumours.

  本发明描述了IGF-1R拮抗剂（例如人源化抗体）和抗增殖药物的组合。在一种优选实施方案中，本发明描述了IGF-1R抗体和属于EGFR抑制剂类的抗增殖药物（优选为厄洛替尼）的组合。根据本发明的组合对于治疗肿瘤，包括IGF-1R和/或EGFR介导或依赖的肿瘤是有用的。
• METHODS AND COMPOSITIONS FOR TREATING CANCER
  申请人：Kolhe Parag

  公开号：US20100143340A1

  公开（公告）日：2010-06-10

  The present invention provides methods for preventing or treating a medical disorder in a subject comprising administering to the subject an effective amount of a stable pharmaceutical formulation comprising an antibody or antigen-binding fragment thereof.

  本发明提供了一种预防或治疗受试者医疗障碍的方法，包括向受试者投与一种包含抗体或其抗原结合片段的稳定药物制剂的有效量。
• BIOMARKERS FOR SENSITIVITY TO ANTI-IGF1R THERAPY
  申请人：Wang Yan

  公开号：US20110091524A1

  公开（公告）日：2011-04-21

  The present invention provides, for example, methods for conveniently determining if a cancerous condition in a subject will be responsive to an IGF1R inhibitor. The invention includes patient selection methods and methods of treatment.

  本发明提供了方便确定受试者的癌症状况是否对IGF1R抑制剂具有响应的方法。该发明包括患者选择方法和治疗方法。
• FDG-PET EVALUATION OF EWING'S SARCOMA SENSITIVITY
  申请人：MERCK SHARP & DOHME CORP.

  公开号：US20130243692A1

  公开（公告）日：2013-09-19

  This invention relates to methods for evaluating the efficacy of an IGF1R inhibitor, such as an anti-IGF1R antibody, for the treatment of an Ewing's sarcoma tumor by determining the level of tumoral glucose metabolism. Tumoral glucose metabolism is determining at an early point in the treatment regimen by any of several methods known in the art including FDG-PET/CT scan.

  本发明涉及一种评估IGF1R抑制剂（如抗IGF1R抗体）对Ewing肉瘤肿瘤治疗疗效的方法，通过确定肿瘤葡萄糖代谢水平来进行。肿瘤葡萄糖代谢可以通过艺术中已知的几种方法之一（包括FDG-PET/CT扫描）在治疗方案的早期阶段进行确定。
• IGFBP2 Biomarker
  申请人：Wang Yan

  公开号：US20150168424A1

  公开（公告）日：2015-06-18

  The present invention provides method for quickly and conveniently determining if a given treatment regimen of IGF1R inhibitor is sufficient, e.g., to saturate IGF1R receptors in the body of a subject. Several clinically relevant determinations may be made based on this point, including, for example, whether the dosage of the regimen is sufficient or should be increased.

  本发明提供了一种快速方便的方法，用于确定给定的IGF1R抑制剂治疗方案是否足够，例如，饱和受试者体内的IGF1R受体。可以基于这一点进行几个临床相关的决定，包括例如，治疗方案的剂量是否足够或应该增加。