(5S,5aR,8aR,9R)-5-[(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 | 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: (5S,5aR,8aR,9R)-5-[(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
• 化学式: C₃₂H₃₂O₁₃S
• 分子量: 656.7
• InChiKey: NRUKOCRGYNPUPR-CRZAWEBOSA-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.)
• 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，其次是由于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。未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，并未在血浆或尿液中发现羟基酸，且在用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，这表明形成很少或没有提出的葡萄糖醛酸苷代谢物（Holthuis等人，1987年）。然而，另一项研究发现，给予的替尼泊苷剂量的6%在24小时内以原药形式排出尿液，另外8%以提出的苷元葡萄糖醛酸苷形式排出，后者未被正式鉴定。

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)

毒理性

• 致癌性证据

评估：对于替尼泊苷在人类中的致癌性，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相比有所不同。在体外的人细胞和体内动物细胞中，会发生强烈的蛋白遮蔽DNA断裂和致裂效应。

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)

毒理性

• 相互作用

环孢素以5 mg/kg bw的剂量在2小时内给药，随后以30 mg/kg bw的剂量在48小时内静脉给药，使替尼泊苷的曲线下面积（AUC）增加了50%，这是由于清除率降低所致。相反，同时给予苯妥英钠，使替尼泊苷的清除率从对照患者的13 mL/min/平方米增加到32 mL/min/平方米。

Concurrent administration of ciclosporin at 5 mg/kg bw over 2 h, followed by 30 mg/kg bw over 48 h intravenously, increased the AUC for teniposide by 50%, due to a reduction in clearance. Conversely, concurrent administration of phenytoin increased the clearance rate of teniposide to 32 mL/min per m2 from 13 mL/min per m2 for control patients.

来源:Hazardous Substances Data Bank (HSDB)

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，并在肿瘤切除前1.5-3小时给药的患者脑内肿瘤中的浓度范围为0.05-1.12微克/克组织。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），在其他患者中未检测到（<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%的剂量以未改变的替尼泊苷形式。在一项对成年人进行的氚标记替尼泊苷研究中，给药后120小时内，44%的放射性标记（母化合物和代谢物）在尿液中回收。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。

文献信息

• [EN] STEREOSELECTIVE SYNTHESIS OF PHOSPHORUS CONTAINING ACTIVES<br/>[FR] SYNTHÈSE STÉRÉOSÉLECTIVE D'AGENTS ACTIFS CONTENANT DU PHOSPHORE
  申请人：PHARMASSET INC

  公开号：WO2011123668A2

  公开（公告）日：2011-10-06

  Disclosed herein are phosphorus-containing actives, their use as actives for treating diseases, and a stereoselective process for preparing the same. Also disclosed herein are useful synthetic intermediates and processes for preparing the same. A process for preparing a composition comprising an enantiomerically- or a diastereomerically-enriched phosphorus-containing active, salt, or pharmaceutically acceptable salt thereof, of formula I is disclosed: 1 which comprises a) reacting a protected or unprotected Active with a base to form a salt of said active and then reacting said salt with an enantiomerically- or a diastereomerically enriched compound of formula II wherein Group is as defined herein, W is an aryl or -CCH2)nSC(O)C(CH3)m(CH2OH)3-m, where n is 2 or 3 and m is 0, 1, 2, or 3, and LG is a leaving group; b) optionally deprotecting the compound obtained in step a) and c) optionally subjecting the compound obtained in step a) or the compound obtained in step b) to chromatography, extraction, or crystallization to obtain the active.

  本文披露了含磷活性物质及其作为治疗疾病的活性成分的用途，以及制备它们的立体选择性过程。此外，本文还披露了有用的合成中间体及其制备过程。本文披露了一种制备式I中的对映体或二对映异构体富集的含磷活性物质、盐或药用可接受盐的组合物的过程：1 包括a)将受保护或未受保护的活性物质与碱反应，形成所述活性物质的盐，然后将所述盐与式II的对映体或二对映异构体富集化合物反应，其中Group如本文所定义，W为芳基或-CCH2)nSC(O)C(CH3)m(CH2OH)3-m，其中n为2或3，m为0、1、2或3，LG为离去基团；b)可选择性地去保护步骤a)中获得的化合物，c)可选择性地将步骤a)或步骤b)中获得的化合物进行色谱、萃取或结晶处理，以获得活性物质。
• Stereoselective synthesis of phosphorus containing actives
  申请人：Gilead Pharmasset LLC

  公开号：EP2752422A1

  公开（公告）日：2014-07-09

  Disclosed herein is a process for preparing an enantiomerically- or a diastereomerically enriched phosphorus-containing active, salt, or pharmaceutically acceptable salt thereof, of formula I-1 , which comprises the steps of: (a) reacting a protected or unprotected Active with a base to form a salt of said active and then reacting said salt with an enantiomerically- or a diastereomerically enriched compound of formula II-1 wherein the Active is a nucleoside, a nucleoside-analog, or a non-nucleoside.

  本文公开了一种制备式 I-1 的对映体或非对映异构体富集的含磷活性物质、盐或其药学上可接受的盐的方法 ，其步骤包括(a) 使受保护或未受保护的活性物质与碱反应，形成所述活性物质的盐，然后使所述盐与富含对映体或非对映异构体的式 II-1 化合物反应； (b) 使受保护或未受保护的活性物质与碱反应，形成所述活性物质的盐，然后使所述盐与富含对映体或非对映异构体的式 II-1 化合物反应。 其中活性物质为核苷、核苷类似物或非核苷。
• STEREOSELECTIVE SYNTHESIS OF PHOSPHORUS CONTAINING ACTIVES
  申请人：Gilead Pharmasset LLC

  公开号：EP2552931B1

  公开（公告）日：2014-07-23
• US7645747B2
  申请人：——

  公开号：US7645747B2

  公开（公告）日：2010-01-12
• US8859756B2
  申请人：——

  公开号：US8859756B2

  公开（公告）日：2014-10-14