鬼臼毒素 | 518-28-5

• 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
• 中文名称: 鬼臼毒素
• 中文别名: 鬼臼脂毒；(5R,5aR,8aR,9R)-5R-5,8,8a,9-四氢-9-羟-5-(3,4,5-三甲氧苯基)呋喃(3",4":6,7)萘并-[2,3-d]-1,3-；鬼臼酯素；足叶草毒素；普达非伦毒素；(5R,5aR,8aR,9R)-5R-5,8,8a,9-四氢-9-羟-5-(3,4,5-三甲氧苯基)呋喃(3',4':6,7)萘并-[2,3-d]-1,3-间二氧杂环烯-6(5aH)-酮
• 英文名称: podofilox
• 英文别名: (-)-podophyllotoxin；PPT；PDT；podo；(5R,5aR,8aR,9R)-5-hydroxy-9-(3,4,5-trimethoxyphenyl)-5a,6,8a,9-tetrahydro-5H-[2]benzofuro[5,6-f][1,3]benzodioxol-8-one
• CAS: 518-28-5
• 化学式: C₂₂H₂₂O₈
• mdl: MFCD00075290
• 分子量: 414.412
• InChiKey: YJGVMLPVUAXIQN-XVVDYKMHSA-N

物化性质

• 熔点：
  183-184 °C (lit.)
• 比旋光度：
  -110.7 º (c=1, CHCl3)
• 沸点：
  453.31°C (rough estimate)
• 密度：
  1.2649 (rough estimate)
• 溶解度：
  DMSO:15.0(最大浓度 mg/mL);36.2(最大浓度 mM)
• LogP：
  2.010
• 物理描述：
  Solid
• 颜色/状态：
  Solvated crystals
• 蒸汽压力：
  8.3X10-15 mm Hg at 25 °C /Estimated/
• 旋光度：
  Specific optical rotation = -132.7 deg @ 20 °C/D, chloroform, 2%
• 碰撞截面：
  190.1 Ų [M+H-H2O]+ [CCS Type: TW, Method: calibrated with polyalanine and drug standards]

计算性质

• 辛醇/水分配系数(LogP)：
  2
• 重原子数：
  30
• 可旋转键数：
  4
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.409
• 拓扑面积：
  92.7
• 氢给体数：
  1
• 氢受体数：
  8

ADMET

代谢

半衰期：1.0至4.5小时。

Half Life: 1.0 to 4.5 hours.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 毒性总结

鉴定：足叶草是一种皮肤科药物。物质来源：北美品种的足叶草（Podophyllum peltatum，又称曼陀罗或五月苹果植物）的根和根状茎的干燥树脂；活性成分包括木脂素，包括足叶毒素（20%）、α-足叶酸（10%）和β-足叶酸（5%）。它是一种淡棕色至绿黄色的可溶于水、酒精、氯仿、丙酮、温苯和冰醋酸的固体粉末。适应症：用于去除疣或鸡眼。描述：足叶草树脂具有抗有丝分裂作用，主要用于局部治疗生殖器疣（尖锐湿疣）。足叶草树脂曾被用于外阴、会阴和尿道内疣的治疗，但不应用于宫颈或尿道疣。必须小心避免应用到健康组织。足叶草树脂也用于治疗足底疣的软膏。足叶草树脂曾被用作泻药，但口服后会有明显的催吐作用，对肠粘膜极为刺激，并产生剧烈的蠕动。它已被更少毒性的泻药所替代。人体暴露：主要风险和靶器官：足叶草树脂的主要活性成分，足叶毒素，是一种脂溶性化合物，容易穿过细胞膜。足叶毒素及其衍生物是强大的细胞毒素，能够抑制细胞有丝分裂和脱氧核糖核酸（DNA）合成，其方式与秋水仙碱类似。细胞分裂被阻止，其他细胞过程受损，逐渐导致细胞破坏和组织破坏。局部足叶草容易被系统吸收，并能穿过胎盘。局部应用或口服摄入可能会导致多系统毒性效应。临床效应总结：系统性中毒的特征包括恶心和呕吐（可能是持续的）、呼吸急促、发热、昏迷、心动过速、低血压、麻痹性肠梗阻、少尿、肾衰竭、白细胞增多、白细胞减少、周围神经病和死亡。禁忌症：妊娠：局部足叶草被系统吸收并穿过胎盘屏障。它与人体的先天性畸形有关。暴露途径：口服：即使会引起恶心和呕吐，也容易被吸收。皮肤：局部应用后会被系统吸收，特别是如果皮肤表面不完整。眼睛：通过粘膜非常好吸收。暴露途径的吸收：口服吸收：足叶草摄入后非常好且快速吸收。在一例死亡病例中，病人在医生的办公室摄入了10到11克25%的足叶草溶液。他立即被给予艾佩卡糖浆并在摄入后45分钟呕吐。他还被给予活性炭和柠檬酸镁。尽管进行了血液灌流，他在摄入后39小时死亡。皮肤吸收：文献中有几例局部应用足叶草后发生系统性中毒的案例。在这种情况下，症状出现的延迟在2到24小时之间。暴露途径的分布：由于足叶毒素可溶于水，可以预测分布体积较小。此外，血液灌流后没有观察到反跳效应。代谢：无可用数据。在一例报告中，在血液灌流前、中、后检查了患者血浆中的足叶毒素。在开始血液灌流前的一段时间内，血浆中足叶毒素浓度迅速下降，提示快速代谢。在几例病例报告中症状出现的延迟可能表明足叶毒素的代谢物比足叶毒素本身更有毒。这项研究在血液灌流期间测量了一种代谢物，但在分析中发现并移除了几种其他可能的代谢物。作用方式：毒动力学：足叶草树脂是一种有效的有丝分裂毒素，能以与秋水仙碱类似的方式阻止有丝分裂中期。人类中毒是由于局部应用或摄入商业提取物所致。过度暴露会导致神经、胃肠和血液毒性，偶尔会导致死亡。很少情况下，食用未成熟果实或植物部分会导致腹泻，主要是腹泻。成熟果实不会产生毒性。足叶草是一种角质软化剂，具有腐蚀性和泻药作用。足叶草是一种抗有丝分裂剂。它结合到微管蛋白上，微管蛋白是微管蛋白亚单位，与秋水仙碱结合在同一位点或与秋水仙碱结合位点有较大重叠。足叶毒素的抗有丝分裂作用可能是由干扰染色体的运动引起的。足叶毒素的分子机制是通过足叶毒素与微管蛋白的结合破坏有丝分裂纺锤体的微管。足叶草具有腐蚀性，但其作用与大多数腐蚀剂不同，因为其效果既不是直接的也不是立即的：相反，细胞分裂被阻止和其他细胞过程受损后，细胞破坏和组织侵蚀会缓慢发生。人体毒性：成人：大多数局部应用足叶草后发生系统性中毒的病例涉及女性，其中一些是致命的。在足叶草应用于大面积或过量、或药物与皮肤或粘膜长时间接触后，会发生严重的系统性毒性。当足叶草应用于脆弱、出血或最近活检的疣，或药物意外应用于正常皮肤或受影响区域周围的粘膜时，系统性中毒的风险可能会增加。在局部应用或摄入足叶草后，可能会出现肾衰竭和肝毒性

IDENTIFICATION: Podophyllum is a dermatological medication. Origin of the substance: Dried resin from the roots and rhizomes of Podophyllum peltatum (Mandrake or May apple plant) the North American variety; active ingredients are lignans including podophyllotoxins (20%), alpha-peltatin (10%) and beta-peltatin (5%). It is a light brown to greenish yellow solid powder soluble in water, alcohol, chloroform, acetone, warm benzene and glacial acetic acid. Indications: Wart or corn removal preparation. Description: Podophyllum resin has an antimitotic action and is used principally as a topical treatment for ano-genital warts (condylomata acuminata). Podophyllum resin has been used on external genital, perianal and intrameatal warts, but should not be used on cervical or urethral warts. Care must be taken to avoid application to healthy tissue. Podophyllum resin is also used in an ointment for plantar warts. Podophyllum resin has been used as a laxative, but when taken by mouth, it has a marked purging action and it is highly irritating to the intestinal mucosa and produces violent peristalsis. It has been superseded by less toxic laxatives. HUMAN EXPOSURE: Main risk and target organs: Podophyllum resin's major active constituent, podophyllotoxin, is a lipid soluble compound that readily crosses cell membranes. Podophyllotoxin and its derivatives are potent cytotoxic agents that inhibit cell mitosis and deoxyribonucleic acid (DNA) synthesis in a manner similar to that of colchicine. Cell division is arrested and other cellular processes are impaired, gradually resulting in the disruption of cells and destruction of the tissue. Topical podophyllum is easily absorbed systemically and can cross the placenta. Either local application or oral ingestion may produce multisystem toxic effects. Summary of clinical effects: Features of systemic toxicity include nausea and vomiting (which may be persistent), tachypnea, fever, stupor, coma, tachycardia, hypotension, paralytic ileus, oliguria, renal failure, leukocytosis, leucopenia, peripheral neuropathy and death. Contraindications: Pregnancy: topical podophyllum is absorbed systemically and crosses the placental barrier. It has been associated with the induction of congenital malformations in humans. Routes of exposure: Oral: Easily absorbed even if it induces nausea and vomiting. Dermal: It is absorbed systemically after topical application especially if the skin surface is not intact. Eye: Very well absorbed through mucous membranes. Absorption by route of exposure: Oral absorption: Podophyllum is very well and rapidly absorbed after ingestion. In a fatal case, the patient ingested between 10 and 11 gm of a 25% podophyllum solution in benzoin tincture in the physician's office. He was immediately given syrup of Ipecac and vomited 45 minutes after ingestion. He was also given activated charcoal and magnesium citrate. He died 39 hours after ingestion despite hemoperfusion. Dermal absorption: There are several cases of systemic poisoning following topical application of podophyllum in the literature. In such cases, the onset of symptoms is delayed between two and 24 hours. Distribution by route of exposure: Since podophyllum toxin is water soluble, a small volume of distribution may be predicted. Furthermore, no rebound effects were observed after hemoperfusion. Metabolism: No data available. In a case report, podophyllum toxin in the patient's plasma before, during and after hemoperfusion was examined. A rapid fall in plasma concentration of podophyllum toxin occurred in the period before hemoperfusion was started suggesting rapid metabolism. The delay of onset of symptoms in several case reports may suggest that the metabolized of podophyllum toxin are more toxic than podophyllum toxin itself. This study measured a metabolite during hemoperfusion but several other possible metabolites were found on analysis and removed by hemoperfusion. Mode of action: Toxicodynamics: Podophyllum resin is a potent spindle poison that blocks mitosis metaphase in a manner similar to colchicine. Human poisoning results from either topical application or ingestion of the commercial extract. Overexposure causes neurological, gastrointestinal and hematological toxicity that occasionally results in fatalities. Rarely, poisoning results from consumption of unripe fruit or plant parts and causes primarily diarrhea. The ripe fruit does not produce toxicity. Podophyllum is a keratolytic agent with caustic and cathartic actions. Podophyllum is an antimitotic agent. It binds to tubulin, the protein subunit of the spindle micro-tubules, at the same site or greatly overlapping the same site as colchicine. The antimitotic action of podophyllum toxin probably results from interference with the movement of the chromosomes. The molecular mechanism of mitosis blockade is the disruption of the micro-tubules of the mitotic spindle via binding of podophyllum toxin to tubulin. Podophyllum is caustic but its action differs from those of most caustics in that its effect is neither direct nor immediate: rather, the disruption of cells and erosion of tissue occur slowly subsequent to arrest of cell division and impairment of other cellular processes. Human toxicity: Adults: Most systemic poisoning cases following topical application of podophyllum involved women and some of these were fatal. Serious systemic toxicity has occurred following topical application of podophyllum to large areas or in excessive amounts, or when the medication was allowed to remain in contact with the skin or mucous membranes for a prolonged period of time. The risk of systemic toxicity may be increased when podophyllum is applied to friable bleeding, or recently biopsied warts, or when the medication is inadvertently applied to normal skin or mucous membranes surrounding the affected area. Renal failure and hepatotoxicity (increased serum concentrations of lactate dehydrogenase (LDH), aspartate aminotransferase (AST; SGOT) and alkaline phosphase have occurred following topical application or ingestion of podophyllum. Podophyllum can cause severe systemic toxicity, which may result from topical application and ingestion. The toxic effects are usually reversible but in some instances, they have been fatal. Children: Fever and convulsions seem to be more frequent in children. Most reported cases followed accidental ingestion. Carcinogenicity: Podophyllum is a suspected human carcinogen. Teratogenicity: Podophyllum may be a teratogenic agent in humans. At least two cases of possible teratogenic effects of podophyllum have been described. Interactions: Other keratolytic agents may stimulate dermal absorption of podophyllum. Main adverse effects: The risk of systemic toxicity may be increased when podophyllum is applied to friable, bleeding or recently biopsied warts, or when the medication is inadvertently applied to normal skin or mucous membranes surrounding the affected area. Adverse effects on the nervous system may occur following topical application of podophyllum; these are usually delayed in onset and prolonged in duration. Cerebral toxicity (manifested by altered sensorium ranging from mild confusion to coma) may occur following topical application of podophyllum and continue for 7 to 10 days during which the electorencephalogram (EEG) may show generalized slowing. The following side/adverse effects have been selected on the basis of their potential clinical significance. Skin rash or itching: allergic reaction to benzoin, which may be present in some preparations. Redness, burning or other irritation of the skin has been noted. Abdominal pain, nausea or vomiting. Diarrhea, sometimes severe and prolonged. Clumsiness or unsteadiness. Confusion and reduced reflexes. Excitement, irritability, nervousness and hallucinations. Muscle weakness, leucopenia (sore throat and fever) and thrombocytopenia Autonomic neuropathy (difficult or painful urination; dizziness or lightheadedness, especially when getting from a lying or sitting position; fast heartbeat). Difficulty in breathing. Drowsiness. Paralytic ileus (constipation, nausea and vomiting; pain in upper abdomen or stomach, mild dull and continuing) Peripheral neuropathy (numbness, tingling, pain or weakness in hands or feet). If peripheral neuropathy occurs, it usually appears about 2 weeks after podophyllum application, may worsen progressively for up to 3 months and may persist for up to 9 months or longer. Seizures have been noted. Clinical effects: Acute poisoning: Ingestion: Ingestion may cause: nausea and vomiting, which may be severe and persistent and occur rapidly after ingestion. Abdominal pain, ileus (paralytic), lethargy, coma, tachypnea, respiratory failure, tachycardia, hypotension, cardiac arrhythmia, cardiovascular collapse, oliguria, renal failure, fever, metabolic acidosis, leukocytosis, leucopenia, thrombocytopenia, pancytopenia, peripheral neuropathy, death. Skin exposure: In contrast to ingestion, there will be a delay of up to 24 hours before appearance of signs. These are similar to those occurring after ingestion. Eye contact: Podophyllum may be absorbed through this route but severe systemic poisoning seldom occurs. Local irritation and lesions of cornea and conjunctiva may occur. Chronic poisoning: Ingestion: This type of poisoning occurred when podophyllum was used as a cathartic or slimming aid. It has not been reported in recent years. In such cases, poisoning was sometimes difficult to diagnose since the clinical picture did not resemble that of acute poisoning. The first clinical signs are either hematological, gastro-intestinal or peripheral neuropathy. Skin exposure: Repeated local treatment of warts or condyloma may produce systemic poisoning or local lesions of the skin (erosion, pain, bleeding, infection). Course, prognosis, cause of death: The precise course following overdose is difficult to predict since we seldom have good indicators of the absorbed dose. It should be noted that some severely intoxicated patients (especially children) have survived while others either died or developed permanent sequelae (peripheral neuropathy) with lower doses. Death generally results from the cerebral; cardiovascular; renal; or hematological complications. Systematic description of clinical effects: Cardiovascular: Tachycardia, cardiac, arrhythmias, hypotension and cardiovascular collapse. Respiratory: Tachypnea and respiratory failure. Pneumonitis (resembling chemical pneumonitis) and pulmonary edema (rarely). Neurological: Central Nervous System (CNS): Confusion, lethargy, coma and convulsions. Peripheral nervous system: Peripheral neuropathy which develops over several days and may take weeks or months to regress. There may be permanent sequelae. Autonomic nervous system: Paralytic ileus. Skeletal and smooth muscle: Rhabdomyolysis may occur with myoglobinuria. This may aggravate the renal failure. Phosphokinase (CPK) should be monitored. Gastrointestinal: Nausea and vomiting which may be persistent and severe; abdominal pain; paralytic ileus and diarrhea which may produce water and electrolyte imbalance. Hepatic: Elevation of hepatic enzymes. Urinary: Renal: Oliguria and renal insufficiency. Other: Cystitis and painful micturition. Endocrine and reproductive system: Fetal death, abortion, premature labor and fetal malformations. Dermatologic: Pruritus around the treated sites especially if the skin has not been protected by petroleum jelly. Irritation, urticaria, skin necrosis and bleeding. Scarring of tissue, especially of anogenital regions, paraphimosis that may require circumcision and pseudo epitheliomatosis hyperplasia. Eye, ear, nose, throat: local effects: Irritation of skin or mucous membrane, necrosis, scarring of tissues, bleeding and corneal erosion. Hematological: Leucocytosis followed by leucopenia, anemia, thrombocytopenia and pancytopenia. Special risks: The use of podophyllum is contraindicated in pregnant or lactating women. ANIMAL STUDIES: Mutagenicity: Podophyllum is mutagenic in Salmonella typhimurium. /Podophyllum/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

依托泊苷，是一种半合成的足叶草毒素衍生物，通过抑制拓扑异构酶II来诱导DNA断裂。该药物在细胞周期的晚S期和早G2期最为活跃。替尼泊苷是一种具有非常相似药理特性的类似物。足叶草毒素衍生物在晚S期和早G2期显示出对拓扑异构酶II的绑定活性。例如，依托泊苷可以绑定并稳定由该酶引起的临时断裂，破坏断裂的修复过程，从而阻止双链DNA的通过，最终停止DNA的解旋和复制。已经在中国仓鼠细胞中描述了足叶草毒素、或者其拓扑异构酶II抑制衍生物如依托泊苷（VP-16）的耐药突变体。这些突变体的相互排斥的交叉耐药模式提供了一个高度特异性的手段来区分这两种足叶草毒素衍生物。对足叶草毒素耐药的中国仓鼠细胞受到了一个后来被识别为哺乳动物HSP60或伴侣蛋白的P1蛋白的影响。（维基百科）

Etoposide, a semisynthetic derivative of podofilox, induces DNA breakage through its inhibition of topoisomerase II. The drug is most active in the late S and early G2 phases of the cell cycle. Teniposide is an analog with very similar pharmacologic characteristics. Podofilox derivatives display binding activity to the enzyme topoisomerase II during the late S and early G2 stage. For instance, etoposide binds and stabilizes the temporary break caused by the enzyme, disrupts the reparation of the break through which the double-stranded DNA passes, and consequently stops DNA unwinding and replication. Mutants resistant to either podofilox, or to its topoisomerase II inhibitory derivatives such as etoposide (VP-16), have been described in Chinese hamster cells. The mutually exclusive cross-resistance patterns of these mutants provide a highly specific mean to distinguish the two kinds of podofilox derivatives. Mutant Chinese hamster cells resistant to podofilox are affected in a protein P1 that was later identified as the mammalian HSP60 or chaperonin protein. (Wikipedia)

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 致癌物分类

对人类无致癌性（未列入国际癌症研究机构IARC清单）。

No indication of carcinogenicity to humans (not listed by IARC).

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 暴露途径

将0.05毫升0.5%足叶草毒素溶液涂抹在外阴部不会导致可检测的血清水平。涂抹0.1到1.5毫升后，涂抹后一至两小时内的血清水平峰值达到1至17纳克/毫升。

Topical application of 0.05 mL of 0.5% podofilox solution to external genitalia did not result in detectable serum levels. Applications of 0.1 to 1.5 mL resulted in peak serum levels of 1 to 17 ng/mL one to two hours after application.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 解毒与急救

治疗全身毒性或意外摄入主要是支持性的。为了减少吸收：清洗皮肤上残留的药物。支持性护理：已知或疑似故意过量服用的患者应转诊进行精神科咨询。

Treatment of systemic toxicity or accidental ingestion is essentially supportive. To decrease absorption: Wash the skin free of any remaining drug. Supportive care: Patients in whom intentional overdose is known or suspected should be referred for psychiatric consultation.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

• 吸收

外阴部涂抹0.05毫升0.5%足叶草毒素溶液后，未检测到可检测的血清水平。涂抹0.1至1.5毫升后，血清水平在涂抹后一至两小时达到峰值，为1至17纳克/毫升。

Topical application of 0.05 mL of 0.5% podofilox solution to external genitalia did not result in detectable serum levels. Applications of 0.1 to 1.5 mL resulted in peak serum levels of 1 to 17 ng/mL one to two hours after application.

来源:DrugBank

吸收、分配和排泄

小量足叶草毒素可能会在局部应用后被系统吸收。在一项针对由人类乳头瘤病毒引起的外生殖器疣成年患者的研究中，将0.05毫升0.5%足叶草毒素溶液应用于外生殖器并未导致可检测的血清药物浓度；然而，局部应用0.1-1.5毫升的溶液后，在涂抹后1-2小时达到了1-17纳克/毫升的血清峰值浓度。

Small amounts of podofilox may be absorbed systemically following topical application. In a study in adults with anogenital warts caused by human papillomavirus, topical application of 0.05 mL of podofilox 0.5% solution to external genitalia did not result in detectable serum concentrations of the drug; however, topical application of 0.1-1.5mL of the solution resulted in peak serum concentrations of 1-17 ng/mL at 1-2 hours after application.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险等级：
  6.1(a)
• 危险品标志：
  T
• 安全说明：
  S36/37/39,S45
• 危险类别码：
  R23/25
• WGK Germany：
  3
• 海关编码：
  2942000000
• 危险品运输编号：
  UN 3462 6.1/PG 2
• 危险类别：
  6.1(a)
• RTECS号：
  LV2500000
• 包装等级：
  II
• 危险标志：
  GHS06
• 危险性描述：
  H301,H310,H315,H319,H335
• 危险性防范说明：
  P261,P280,P302 + P350,P305 + P351 + P338,P310

制备方法与用途

鬼臼毒素简介

鬼臼毒素，又称普达非洛，是一种非生物碱类木脂素类毒素，从鬼臼的根茎中提取。其乙醇溶液和软膏的商品名分别为慷定来和化疣敌，主要用于治疗由人类乳头瘤病毒引起的尖锐湿疣。鬼臼毒素及其合成衍生物如依托泊苷和替尼泊苷等在抗病毒和抗肿瘤制剂的应用上展现出广泛的选择性。其抗癌活性已被广泛研究，并在肺癌、淋巴瘤和生殖系统肿瘤的化疗中使用。

适应症

鬼臼毒素局部外用主要治疗男性或女性生殖器或肛门部位的尖锐湿疣，也可用于其他类型的病毒疣。

副作用

局部外用后常有灼热感、疼痛、红斑；疣体脱落后可能出现浅表溃疡或糜烂面。少数男性患者在用药治疗生殖器周围尖锐湿疣时会出现明显水肿和糜烂现象。如使用过程中有任何不适，请及时咨询医师或药师，必要时应立即就医。

禁忌症

鬼臼毒素与普达非洛同一种物质，其化学性质为白色针状结晶，易溶于甲醇、氯仿，来源于小檗科植物桃儿七属的桃儿七根茎部及小蘖科鬼臼属的华鬼臼根和茎。

用途 化学性质与用途

• 微管组装抑制剂：一种强力的微管装配抑制剂，结合在微管蛋白的秋水仙碱位点。
• 抗肿瘤药：作为抗癌药物，主要用于治疗尖锐湿疣和其他病毒性疣病。
• Topo II 抑制剂：鬼臼毒素及其衍生物是拓扑异构酶II和微管蛋白抑制剂。

临床应用

• 主要用于治疗尖锐湿疣及其它病毒性疣病。
• 抑制微管（microtubule）组装；具有抗肿瘤作用，临床上适用于急性单核细胞型和粒单核细胞型白血病、急性粒细胞白血病、嗜酸性粒细胞性白血病、小细胞肺癌、非何杰金氏恶性淋巴瘤及睾丸癌等。

生产方法

从小檗科植物中华山荷叶（Diphylleia sinensis）的根茎中提取。

反应信息

• 作为反应物：
  描述：

  鬼臼毒素 在 sodium tetrahydroborate 、 三氟乙酸 作用下， 以 四氢呋喃 为溶剂， 反应 2.0h， 以68%的产率得到去氧鬼臼毒素
  参考文献：
  名称：

  设计和合成新型4'-demethyl-4-deoxypodophyllotoxin衍生物作为潜在的抗癌药。

  摘要：

  通过将芳氧基乙酰苯胺部分与4'-demethyl-4-deoxypodophyllotoxin（DDPT）的4'-羟基缀合，合成了一组鬼臼毒素（PPT）衍生物（7a-j），并评估了它们的抗癌活性。发现最有效的化合物7d以微摩尔IC 50值低抑制了三种癌细胞系的增殖。此外，已证明7d诱导MGC-803细胞中G2 / M期的细胞周期停滞，并调节细胞周期检查点蛋白如细胞周期蛋白A，细胞周期蛋白B，CDK1，cdc25c和p21的表达。最后，4 mg / kg的7d减少了小鼠HepG2异种移植的重量和体积。我们的发现表明7d可能是一种潜在的抗癌药。

  DOI：

  10.1016/j.bmcl.2015.06.089
• 作为产物：
  描述：

  去氧鬼臼毒素 在 aspergillus niger sp 作用下， 以 乙醇 为溶剂， 反应 72.0h， 生成 鬼臼毒素
  参考文献：
  名称：

  Conversion of deoxypodophyllotoxin to podophyllotoxin-related compounds by microbes.

  摘要：

  青霉菌 F-0543（未鉴定）将 Hemandia ovigera L.种子的主要成分（2.4%）脱氧鬼臼毒素（DPT）转化为表鬼臼毒素（EPT），而表鬼臼毒素是优秀抗癌剂依托泊苷的基本骨架，转化率高达 100%。虽然转化率各不相同，但所测试的 8 种青霉培养物也能将 DPT 转化为 EPT。三种黑曲霉能将 DPT 转化为 PT，但产量很低。此外，研究还发现，许多微生物会将 DPT 转化为一种非活性物质，即广泛分布于高等植物中的脱氧丙基叶绿素（DPP）。

  DOI：

  10.1271/bbb1961.53.777
• 作为试剂：
  描述：

  oleanolic acid 3-O-α-L-rhamnopyranosyl-(1→6)-(2-O-isoferuloyl-β-D-glucopyranosyl)-(1→4)-β-D-ribopyranosyl-(1→3)-α-L-rhamnopyranosyl-(1→2)[β-D-glucopyranosyl(1→4)]-α-L-arabinopyranoside 在 盐酸 、 鬼臼毒素 作用下， 反应 2.0h， 生成 D-核糖 、 L-阿拉伯糖 、 L-鼠李糖 、 葡萄糖 、 齐墩果酸
  参考文献：
  名称：

  Triterpene Saponins from Clematis mandshurica and Their Antiproliferative Activity

  摘要：

  Six new triterpene saponins, clematomandshurica saponins F-K (1-6), together with a known compound (7), were isolated from the roots and rhizomes of Clematis mandshurica. Their structures were elucidated on the basis of spectroscopic evidence and hydrolysis. Compounds 5-7 exhibited antiproliferative effects against PC-3 human prostate cancer cells with GI(50) values of 1.29, 1.50, and 0.71 mu M, respectively.

  DOI：

  10.1055/s-0032-1328657

文献信息

• [EN] ACC INHIBITORS AND USES THEREOF<br/>[FR] INHIBITEURS DE L'ACC ET UTILISATIONS ASSOCIÉES
  申请人：GILEAD APOLLO LLC

  公开号：WO2017075056A1

  公开（公告）日：2017-05-04

  The present invention provides compounds I and II useful as inhibitors of Acetyl CoA Carboxylase (ACC), compositions thereof, and methods of using the same.

  本发明提供了化合物I和II，这些化合物可用作乙酰辅酶A羧化酶（ACC）的抑制剂，以及它们的组合物和使用方法。
• [EN] COMPOUNDS AND COMPOSITIONS COMPRISING CDK INHIBITORS AND METHODS FOR THE TREATMENT OF CANCER<br/>[FR] COMPOSÉS ET COMPOSITIONS COMPRENANT DES INHIBITEURS DES CDK ET MÉTHODES DE TRAITEMENT DU CANCER
  申请人：UNIV GEORGIA STATE RES FOUND

  公开号：WO2010129858A1

  公开（公告）日：2010-11-11

  Disclosed herein are compounds suitable for use as antitumor agents, methods for treating cancer wherein the disclosed compounds are used in making a medicament for the treatment of cancer, methods for treating a tumor comprising, administering to a subject a composition comprising one or more of the disclosed cytotoxic agents, and methods for preparing the disclosed antitumor agents.

  本文披露了适用作抗肿瘤药剂的化合物，用于治疗癌症的方法，其中所披露的化合物用于制备治疗癌症的药物，治疗肿瘤的方法包括向受试者施用包含一种或多种所披露的细胞毒性药剂的组合物，以及制备所披露的抗肿瘤药剂的方法。
• Cobalamin conjugates for anti-tumor therapy
  申请人：Weinshenker M. Ned

  公开号：US20050054607A1

  公开（公告）日：2005-03-10

  The present invention provides a cobalamin-drug conjugate suitable for the treatment of tumor related diseases. Cobalamin is indirectly covalently bound to an anti-tumor drug via a cleavable linker and one or more optional spacers. Cobalamin is covalently bound to a first spacer or the cleavable linker via the 5′-OH of the cobalamin ribose ring. The drug is bound to a second spacer of the cleavable linker via an existing or added functional group on the drug. After administration, the conjugate forms a complex with transcobalamin (any of its isoforms). The complex then binds to a receptor on a cell membrane and is taken up into the cell. Once in the cell, an intracellular enzyme cleaves the conjugate thereby releasing the drug. Depending upon the structure of the conjugate, a particular class or type of intracellular enzyme affects the cleavage. Due to the high demand for cobalamin in growing cells, tumor cells typically take up a higher percentage of the conjugate than do normal non-growing cells. The conjugate of the invention advantageously provides a reduced systemic toxicity and enhanced efficacy as compared to a corresponding free drug.

  本发明提供了一种适用于治疗肿瘤相关疾病的钴胺素-药物结合物。钴胺素通过可切割的连接剂间接共价结合到抗肿瘤药物上，还可以通过一个或多个可选的间隔物。钴胺素通过其核糖环的5'-OH与第一间隔物或可切割连接剂共价结合。药物通过其现有或添加的功能基团与可切割连接剂的第二间隔物结合。在给药后，结合物与转钴胺素（其任何同工异构体）形成复合物。然后，该复合物结合到细胞膜上的受体并被细胞摄取。一旦进入细胞，细胞内酶将切割结合物，从而释放药物。根据结合物的结构，特定类别或类型的细胞内酶影响切割。由于生长细胞对钴胺素的需求量较高，肿瘤细胞通常摄取结合物的比例高于正常非生长细胞。本发明的结合物与相应的游离药物相比，具有较低的全身毒性和增强的疗效。
• [EN] DERIVATIVES OF AMANITA TOXINS AND THEIR CONJUGATION TO A CELL BINDING MOLECULE<br/>[FR] DÉRIVÉS DE TOXINES D'AMANITES ET LEUR CONJUGAISON À UNE MOLÉCULE DE LIAISON CELLULAIRE
  申请人：HANGZHOU DAC BIOTECH CO LTD

  公开号：WO2017046658A1

  公开（公告）日：2017-03-23

  Derivatives of Amernita toxins of Formula (I), wherein, formula (a) R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9, R 10, X, L, m, n and Q are defined herein. The preparation of the derivatives. The therapeutic use of the derivatives in the targeted treatment of cancers, autoimmune disorders, and infectious diseases.

  Amernita毒素的衍生物的化学式（I），其中，化学式（a）中的R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、X、L、m、n和Q在此处被定义。这些衍生物的制备。这些衍生物在靶向治疗癌症、自身免疫性疾病和传染病中的治疗用途。
• [EN] A CONJUGATE OF A CYTOTOXIC AGENT TO A CELL BINDING MOLECULE WITH BRANCHED LINKERS<br/>[FR] CONJUGUÉ D'UN AGENT CYTOTOXIQUE À UNE MOLÉCULE DE LIAISON CELLULAIRE AVEC DES LIEURS RAMIFIÉS
  申请人：HANGZHOU DAC BIOTECH CO LTD

  公开号：WO2020257998A1

  公开（公告）日：2020-12-30

  Provided is a conjugation of cytotoxic drug to a cell-binding molecule with a side-chain linker. It provides side-chain linkage methods of making a conjugate of a cytotoxic molecule to a cell-binding ligand, as well as methods of using the conjugate in targeted treatment of cancer, infection and immunological disorders.

  提供了一种将细胞毒性药物与一个侧链连接分子结合的共轭物。它提供了制备细胞毒性分子与细胞结合配体的共轭物的侧链连接方法，以及在靶向治疗癌症、感染和免疫性疾病中使用该共轭物的方法。

表征谱图