他比特啶 | 114899-77-3

• 物质功能分类: 原料药
• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 中文名称: 他比特啶
• 中文别名: 他比特定；曲贝替定
• 英文名称: ecteinascidin 743
• 英文别名: trabectedin；ET-743；yondelis；[(1R,2R,3R,11S,12S,14R,26R)-5,6',12-trihydroxy-6,7'-dimethoxy-7,21,30-trimethyl-27-oxospiro[17,19,28-trioxa-24-thia-13,30-diazaheptacyclo[12.9.6.13,11.02,13.04,9.015,23.016,20]triaconta-4(9),5,7,15,20,22-hexaene-26,1'-3,4-dihydro-2H-isoquinoline]-22-yl] acetate
• CAS: 114899-77-3
• 化学式: C₃₉H₄₃N₃O₁₁S
• 分子量: 761.85
• InChiKey: PKVRCIRHQMSYJX-AIFWHQITSA-N

物化性质

• 熔点：
  >143°C (dec.)
• 比旋光度：
  D25 +114° (c = 0.1 in methanol)
• 密度：
  1.55±0.1 g/cm3 (20 ºC 760 Torr)
• 溶解度：
  可溶于氯仿（少许）、甲醇（少许）
• 物理描述：
  Solid

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  54
• 可旋转键数：
  4
• 环数：
  10.0
• sp3杂化的碳原子比例：
  0.49
• 拓扑面积：
  194
• 氢给体数：
  4
• 氢受体数：
  15

ADMET

毒理性

• 肝毒性

血清氨基转移酶水平升高几乎发生在所有接受曲贝替丁治疗的患者中，超出正常上限5倍以上的升高发生在20%至50%的患者中。治疗前使用地塞米松似乎可以减少酶升高的程度和频率。升高通常在静脉输注后的2到5天内出现，在5到9天之间达到最高水平，并在3到4周内普遍降至基线值。血清碱性磷酸酶和胆红素的轻微升高也很常见。然而，由于曲贝替丁引起的临床上明显的肝损伤并伴有黄疸是罕见的。另一方面，患有基础肝病的患者似乎有增加败血症和多器官衰竭的风险，建议在治疗前后监测肝功能测试。肝损伤通常模仿基础肝硬化的急性失代偿，血清酶轻度升高，黄疸和肝合成功能障碍加重。免疫过敏和自身免疫特征不常见。死亡通常是由于败血症和多器官衰竭。

Elevations in serum aminotransferase levels arise in almost all patients treated with trabectedin and elevations above 5 times the upper limit of normal occur 20% to 50% of patients. Pretreatment with dexamethasone appears to decrease the degree and frequency of enzyme elevations. The elevations arise within 2 to 5 days of the intravenous infusion, rise to maximal levels between 5 and 9 days and generally fall to baseline values within 3 to 4 weeks. Minor elevations in serum alkaline phosphatase and bilirubin are also common. However, clinically apparent liver injury with jaundice from trabectedin is rare. On the other hand, patients with underlying liver disease appear to be at increased risk for septicemia and multiorgan failure, and monitoring of liver tests before and during therapy is recommended. The liver injury typically mimics acute decompensation of an underlying cirrhosis with modest elevations in serum enzymes and worsening jaundice and hepatic synthetic dysfunction. Immunoallergic and autoimmune features are uncommon. Fatalities are generally due to sepsis and multiorgan failure.

来源:LiverTox

毒理性

• 蛋白质结合

94% 到 98%

94 to 98%

来源:DrugBank

吸收、分配和排泄

• 吸收

静脉给药。

Administered intravenously.

来源:DrugBank

制备方法与用途

用途

曲贝替定是一种烷化剂药物适用为有不可切除或转移脂肪肉瘤或平滑肌肉瘤患者接受一个以前含蒽环类药物[anthracycline]-方案的治疗。

软组织肉瘤治疗新药-曲贝替定

2015年10月23日，美国FDA通过优先审批途径批准了美国强生旗下杨森（Janssen）公司的药物曲贝替定（Trabectedin）上市，商品名为Yondelis。用于不可切除或转移、曾接受过含一种蒽环类药物化疗的脂肪肉瘤和平滑肌肉瘤患者的治疗。曲贝替定为烷化剂属于细胞毒类药，2007年EMEA批准其在欧洲首次上市，用于治疗晚期软组织肉瘤。后又被批准在欧洲和加拿大等地区治疗复发卵巢癌；生产商是西班牙生物技术公司Zeltia和美国强生（Johnson and Johnson）。

生物活性

Trabectedin (Ecteinascidin 743; ET-743) 是一种四氢异喹啉生物碱，具有有效的抗肿瘤活性，从 Ecteinascidia turbinata 中分离出来。 Trabectedin 与 DNA 的小沟结合，阻断应激诱导的蛋白质的转录，诱导 DNA 骨架裂解和癌细胞凋亡 (apoptosis)，并增加 MCF-7 和 MDA-MB-453 细胞中 ROS 的生成。Trabectedin 可用于软组织肉瘤和卵巢癌的研究。

靶点

IC50: 0.1 nM (MX-1 cells), 1.5 nM (MCF7 cells) and 3.7 nM (MCF7/DXR cells)
Reactive oxygen species (ROS)
Apoptosis

体外研究

Trabectedin (ET-743; 10 nM; 24-72 hours; MCF7 cells) treatment cells accumulate in late S to G2 phase.
Trabectedin (Ecteinascidin 743) inhibits cell growth of MX-1, MCF7 and MCF7/DXR cells with IC ₅₀ values of 0.1 nM, 1.5 nM and 3.7 nM, respectively.
Trabectedin induces cytotoxicity and apoptosis in both breast cancer cells in a time and concentration-dependent manner. The expression levels of the death receptor pathway molecules, TRAIL-R1/DR4, TRAIL-R2/DR5, FAS/TNFRSF6, TNF RI/TNFRSF1A, and FADD are significantly increased by 2.6-, 3.1-, 1.7-, 11.2- and 4.0-fold by Trabectedin treatment in MCF-7 cells. In MDA-MB-453 cells, the mitochondrial pathway related pro-apoptotic proteins Bax, Bad, Cytochrome c, Smac/DIABLO, and Cleaved Caspase-3 expressions are induced by 4.2-, 3.6-, 4.8-, 4.5-, and 4.4-fold, and the expression levels of anti-apoptotic proteins Bcl-2 and Bcl-XL are reduced by 4.8- and 5.2-fold in MDA-MB-453 cells.
In vitro treatment with noncytotoxic concentrations of Trabectedin selectively inhibits the production of CCL2, CXCL8, IL-6, VEGF, and PTX3 by myxoid liposarcoma (MLS) primary tumor cultures and/or cell lines.

Cell Cycle Analysis

Cell Line:	MCF7 cells
Concentration:	10 nM
Incubation Time:	24 hours, 48 hours, 72 hours
Result:	Led to pronounced S-G2-M accumulation.

体内研究

Trabectedin (ET-743; 30-50 μg/kg; intravenous injection; every three days; female athymic nude mice) treatment increases the antitumor effects in nude mice bearing MX-1 mammary carcinoma xenografts without increasing toxicity.
A xenograft mouse model of human myxoid liposarcoma (MLS) shows marked reduction of CCL2, CXCL8, CD68+ infiltrating macrophages, CD31+ tumor vessels, and partial decrease of PTX3 after Trabectedin treatment.

Animal Model:	Female athymic nude mice bearing the nu/nu gene (5-6 weeks old, 18-20 g) injected with MX-1 cells
Dosage:	30 μg/kg, 40 μg/kg, 50 μg/kg
Administration:	Intravenous injection; every three days
Result:	Increased the antitumor effects in nude mice bearing MX-1 mammary carcinoma xenografts without increasing toxicity.

反应信息

• 作为反应物：
  描述：

  他比特啶 在 sodium cyanoborohydride 、 溶剂黄146 作用下， 以 乙腈 为溶剂， 反应 0.5h， 以64%的产率得到ET-745
  参考文献：
  名称：

  Synthesis of Natural Ecteinascidins (ET-729, ET-745, ET-759B, ET-736, ET-637, ET-594) from Cyanosafracin B

  摘要：

  The semisynthetic process initially described for the synthesis of 1 (ET-743) has been extended to the preparation of other natural ecteinascidins. For the synthesis of 2 (ET-729) a demethylation of a N-Me intermediate was carried out by a selective oxidation with MCPBA. Other natural ecteinascidins (ET-745, ET-759B, ET-736, ET-637, ET-594) were accessible from key intermediate 25. The described methodologies allow for the preparation of a wide variety of ecteinascidins by procedures that can be easily scaled up.

  DOI：

  10.1021/jo034547i
• 作为产物：
  描述：

  (1'R,6R,6aR,7R,13S,14R,16R)-5-(acetyloxy)-3',4',6,6a,7,13,14,16-octahydro-6'-hydroxy-7',9-dimethoxy-8-(methoxymethoxy)-4,10,23-trimethyl-19-oxo-spiro[6,16-(epithiopropanoxymethano)-7,13-imino-12H-1,3-dioxolo[7,8]isoquino[3,2-b][3]benzazocine-20,1'(2'H)-isoquinoline]-14-carbonitrile 在 三氟乙酸 、 silver nitrate 作用下， 以 四氢呋喃 、 水 、 乙腈 为溶剂， 反应 34.0h， 生成 他比特啶
  参考文献：
  名称：

  [EN] PROCESS FOR THE PREPARATION OF ECTEINASCIDIN DERIVATIVE AND ITS INTERMEDIATE
  [FR] PROCÉDÉ DE PRÉPARATION D'UN DÉRIVÉ D'ECTÉINASCIDINE ET DE SON INTERMÉDIAIRE

  摘要：

  本发明涉及一种改进的、工业上可行的Trabectedin制备过程。本发明还涉及一种改进的、工业上可行的公式-A的Trabectedin中间化合物制备过程。本发明使用成本更低的试剂、溶剂，并且工艺条件可以很容易地适用于商业规模。

  公开号：

  WO2020105068A1

文献信息

• A Scalable Total Synthesis of the Antitumor Agents Et‐743 and Lurbinectedin
  作者：Weiming He、Zhigao Zhang、Dawei Ma

  DOI：10.1002/anie.201900035

  日期：2019.3.18

  An efficient and scalable approach is described for the total synthesis of the marine natural product Et‐743 and its derivative lubinectedin, which are valuable antitumor compounds. The method delivers 1.6 % overall yield in 26 total steps from Cbz‐protected (S)‐tyrosine. It features the use of a common advanced intermediate to create the right and left parts of these compounds, and a light‐mediated

  描述了一种有效且可扩展的方法，用于海洋天然产物Et-743及其衍生物lubinectin的全合成，这是有价值的抗肿瘤化合物。该方法可从Cbz保护的（S）酪氨酸分26个步骤中获得1.6％的总收率。它的特点是使用常见的高级中间体来创建这些化合物的左右部分，并使用光介导的远程C H键活化来组装含苯并[1,3]二恶唑的中间体。
• [EN] SYNTHETIC PROCESS FOR THE MANUFACTURE OF ECTEINASCIDIN COMPOUNDS<br/>[FR] PROCÉDÉ DE SYNTHÈSE POUR LA PRÉPARATION DE COMPOSÉS ECTEINASCIDINES
  申请人：PHARMA MAR SA

  公开号：WO2011147828A1

  公开（公告）日：2011-12-01

  This invention relates to compounds of formula II: wherein R1, R2, ProtSH, and ProtNH are as defined, to processes for the synthesis of ectainascidins of formula I from compounds of formula II, and to processes for the synthesis of compounds of formula II.

  这项发明涉及到式子II的化合物：其中R1、R2、ProtSH和ProtNH的定义如下，以及从式子II的化合物合成式子I的ectainascidins的过程，以及合成式子II的化合物的过程。
• Total Synthesis of Ecteinascidin 743
  作者：Atsushi Endo、Arata Yanagisawa、Masanao Abe、Shigemitsu Tohma、Toshiyuki Kan、Tohru Fukuyama

  DOI：10.1021/ja026216d

  日期：2002.6.1

  A straightforward synthesis of ecteinascidin 743 was accomplished from readily available l-glutamic acid as a single chiral source. Our novel synthesis features a concise and convergent approach for construction of the B-ring, consisting of a sequence involving a stereoselective Heck reaction between a diazonium salt and an enamide, oxidative cleavage of the resulting alkene, and intramolecular ortho

  海鞘素 743 的直接合成是从容易获得的 l-谷氨酸作为单一手性来源完成的。我们的新合成具有构建 B 环的简洁和收敛的方法，包括一个序列，涉及重氮盐和烯酰胺之间的立体选择性 Heck 反应、所得烯烃的氧化裂解以及苯酚的分子内邻位取代醛。
• Intermediate and process of preparation of ecteinascidin using such intermediate
  申请人：Centre National de la Recherche Scientifique (CNRS)

  公开号：EP1792904A1

  公开（公告）日：2007-06-06

  The present invention concerns an intermediate of the following formula I in which R1 and R2 represent independently of each other a C1-C12 alkyl group, a (C1-C12 alkoxy)carbonyl group, optionally substituted by one, two or three halogen atom, a (C2-C12 alkenyloxy) carbonyl group, an acyl group, a aryl(C1-C12)alkyl group, an arylalkoxy carbonyl group, a (C1-C12 alkyl)sulfonyle group or an arylsulfonyl group and R3 represents a O-protecting group. The present invention concerns also a process of preparation of the intermediate and its use for the preparation of Ecteinascidin 743 and Ecteinascidin-770.

  本发明涉及以下式I的中间体，其中R1和R2分别独立地表示C1-C12烷基，(C1-C12烷氧基)羰基，可选地被一个、两个或三个卤素原子取代的(C2-C12烯氧基)羰基，酰基，芳基(C1-C12)烷基，芳基氧羰基，(C1-C12烷基)磺酰基或芳基磺酰基，R3表示O-保护基。本发明还涉及中间体的制备方法及其用于制备Ecteinascidin 743和Ecteinascidin-770。
• 天然产物Trabectedin的制备
  申请人：浙江中科创越药业有限公司

  公开号：CN109912629B

  公开（公告）日：2021-12-24

  本发明提供了一种天然产物Trabectedin的制备方法，具体地，本发明提供了一种Et‑743的制备方法，所述方法以酪氨酸为起始底物，经过26步反应即可完成合成，且合成路线中采用的原料和试剂都较易获得，反应条件也比较温和，可实现大规模的制备。