N^2'-deacetyl-N^2'-[4-methyl-4-(methyldithio)-1-oxopentyl]maytansine | 796073-68-2

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 大环内酰胺类
• 英文名称: N^2'-deacetyl-N^2'-[4-methyl-4-(methyldithio)-1-oxopentyl]maytansine
• 英文别名: DM4-Sme；[(1S,2R,3S,5S,6S,16E,18E,20R,21S)-11-chloro-21-hydroxy-12,20-dimethoxy-2,5,9,16-tetramethyl-8,23-dioxo-4,24-dioxa-9,22-diazatetracyclo[19.3.1.110,14.03,5]hexacosa-10,12,14(26),16,18-pentaen-6-yl] (2S)-2-[methyl-[4-methyl-4-(methyldisulfanyl)pentanoyl]amino]propanoate
• CAS: 796073-68-2
• 化学式: C₃₉H₅₆ClN₃O₁₀S₂
• 分子量: 826.473
• InChiKey: LTLNAIFGVAUBEJ-SIDGEOBYSA-N

物化性质

• 沸点：
  963.8±65.0 °C(Predicted)
• 密度：
  1.30±0.1 g/cm3(Predicted)
• 溶解度：
  溶于二甲基亚砜

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  55
• 可旋转键数：
  11
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.64
• 拓扑面积：
  207
• 氢给体数：
  2
• 氢受体数：
  12

安全信息

• 储存条件：
  -20°C，密闭保存，干燥环境

制备方法与用途

DM4-SMe 是一种代谢产物，属于抗体-美登素偶联物 (AMC) 的范畴，能抑制微管蛋白（tubulin）并作为细胞毒性部分存在于抗体-药物偶联物 (ADCs) 中，通过二硫键或稳定的硫醚键与抗体相连。DM4-SMe 能有效抑制 KB 细胞的增殖，其 IC50 值为 0.026 nM。

反应信息

• 作为反应物：
  描述：

  N^2'-deacetyl-N^2'-[4-methyl-4-(methyldithio)-1-oxopentyl]maytansine 在 氘 作用下， 以 醋酸异丙酯 为溶剂， 反应 3.0h， 以80%的产率得到
  参考文献：
  名称：

  脂肪族酰胺的高选择性定向铱催化氢同位素交换反应

  摘要：

  首次，我们描述了未活化的C（sp 3）的高选择性均相铱催化的氢同位素交换（HIE））以脂肪族酰胺为中心。当使用市售的Kerr催化剂时，带有一系列常见抗体-药物偶联物（ADC）接头侧链的HIE的收率高，区域选择性高，并且氘的掺入率高达99％。该方法可完全转化为of化学的特定要求，并且通过直接may标记美登木素生物碱来证明其有效性。该方法的范围可以扩展到简单氨基酸，对甘氨酸和丙氨酸具有很高的HIE活性。在二肽和三肽中，观察到非常有趣的依赖保护基团的可调选择性。DFT计算使人们深入了解了过渡态的能量，从而解释了观察到的选择性和氨基酸保护基团的影响。

  DOI：

  10.1002/anie.201804010
• 作为产物：
  描述：

  安丝菌素 P 3 在 Lithium-tri-methoxy-alanat 、 N,N'-二环己基碳二亚胺 、 zinc(II) chloride 作用下， 以 二氯甲烷 为溶剂， 生成 N^2'-deacetyl-N^2'-[4-methyl-4-(methyldithio)-1-oxopentyl]maytansine
  参考文献：
  名称：

  Uses of immunoconjugates targeting CD138

  摘要：

  揭示了一种用于治疗与表达CD138的靶细胞相关的疾病的方法和组合物，采用多剂量方案。包括一种工程靶向抗体靶向CD138表达细胞和一种效应分子的免疫结合物在多剂量方案中被给予。多剂量方案包括至少两剂，而在一个活性治疗周期内给予的总剂量是总体最大可耐受剂量（AMTD）或AMTD的一个分数。当免疫结合物作为单剂量给予时，AMTD和/或所述分数超过导致剂量限制毒性（DLT）的剂量和/或超过最大可耐受剂量（MTD），包括作为在所述活性治疗周期内的多个单剂量方案的一部分给予时。

  公开号：

  US10117932B2

文献信息

• Method for the preparation of maytansinoid esters
  申请人：Widdison C. Wayne

  公开号：US20060167245A1

  公开（公告）日：2006-07-27

  Improved processes for the preparation and purification of maytansinoid esters, especially thiol and disulfide-containing maytansinoids are described. In one aspect the process comprises a process of making a maytansinoid ester comprising forming an anion of maytansinol or a maytansinoid bearing a free C-3 hydroxyl moiety and reacting the anion with an activated carboxyl compound to thereby produce the maytansinoid ester.

  描述了用于制备和纯化美坦西酯类化合物的改进过程，特别是含有硫醇和二硫键的美坦西酯类化合物。在一个方面，该过程包括制备美坦西酯类化合物的过程，其中包括形成美坦西醇或带有游离C-3羟基的美坦西酯类化合物的阴离子，并将该阴离子与活化的羧基化合物反应，从而产生美坦西酯类化合物。
• PREPARATION OF MAYTANSINOID ESTERS
  申请人：BIO-THERA SOLUTIONS, LTD., CO.

  公开号：US20140179917A1

  公开（公告）日：2014-06-26

  Provided are efficient methods for direct coupling of a maytansinoid with a carboxylic acid to prepare a maytansinoid C-3 ester in high yield using a rare earth metal-based or trifluoromethanesulfonate-based Lewis acid catalyst and a base together with a coupling reagent. Also provided are compositions used in such methods.

  提供了一种高效的方法，用于将马坦西酮与羧酸直接偶联，以制备高产率的马坦西酮C-3酯，使用基于稀土金属或三氟甲磺酸盐的路易斯酸催化剂和碱以及偶联试剂。还提供了在这种方法中使用的组合物。
• Semisynthetic Maytansine Analogues for the Targeted Treatment of Cancer
  作者：Wayne C. Widdison、Sharon D. Wilhelm、Emily E. Cavanagh、Kathleen R. Whiteman、Barbara A. Leece、Yelena Kovtun、Victor S. Goldmacher、Hongsheng Xie、Rita M. Steeves、Robert J. Lutz、Robert Zhao、Lintao Wang、Walter A. Blättler、Ravi V. J. Chari

  DOI：10.1021/jm060319f

  日期：2006.7.1

  Maytansine, a highly cytotoxic natural product, failed as an anticancer agent in human clinical trials because of unacceptable systemic toxicity. The potent cell killing ability of maytansine can be used in a targeted delivery approach for the selective destruction of cancer cells. A series of new maytansinoids, bearing a disulfide or thiol substituent were synthesized. The chain length of the ester side chain and the degree of steric hindrance on the carbon atom bearing the thiol substituent were varied. Several of these maytansinoids were found to be even more potent in vitro than maytansine. The targeted delivery of these maytansinoids, using monoclonal antibodies, resulted in a high, specific killing of the targeted cells in vitro and remarkable antitumor activity in vivo.
• Ado-trastuzumab Emtansine (T-DM1): An Antibody–Drug Conjugate (ADC) for HER2-Positive Breast Cancer
  作者：John M. Lambert、Ravi V. J. Chari

  DOI：10.1021/jm500766w

  日期：2014.8.28

  Ado-trastuzumab emtansine (T-DM1) is an antibody-drug conjugate that combines the antitumor properties of the humanized anti-human epidermal growth factor receptor 2 (HER2) antibody, trastuzumab, with the maytansinoid, DM1, a potent microtubule-disrupting agent, joined by a stable linker. Upon binding to HER2, the conjugate is internalized via receptor-mediated endocytosis, and an active derivative of DM1 is subsequently released by proteolytic degradation of the antibody moiety within the lysosome. Initial clinical evaluation led to a phase III trial in advanced HER2-positive breast cancer patients who had relapsed after prior treatment with trastuzumab and a taxane, which showed that T-DM1 significantly prolonged progression-free and overall survival with less toxicity than lapatinib plus capecitabine. In 2013, T-DM1 received FDA approval for the treatment of patients with HER2-positive metastatic breast cancer who had previously received trastuzumab and a taxane, separately or in combination, the first ADC to receive full approval based on a randomized study.
• [EN] CCR7 ANTIBODY DRUG CONJUGATES FOR TREATING CANCER<br/>[FR] CONJUGUÉS ANTICORPS-MÉDICAMENT CCR7 POUR LE TRAITEMENT DU CANCER
  申请人：NOVARTIS AG

  公开号：WO2021220199A1

  公开（公告）日：2021-11-04

  This application discloses compositions and methods of treating follicular lymphoma using CCR7 antibody drug conjugates. Also disclosed herein are methods of treating cancer in a subject in need thereof, comprising administering to said subject an antibody drug conjugate, wherein the cancer expresses CCR7, wherein the antibody drug conjugate is administered to said subject at about 0.1 mg/kg to about 10 mg/kg.