N-methyl-N-[(3-methyldithio)-1-oxobutyl]-L-alanine | 138148-63-7

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: N-methyl-N-[(3-methyldithio)-1-oxobutyl]-L-alanine
• 英文别名: N-methyl-N-(4-methyldithio-butanoyl)-L-alanine；(2S)-2-[methyl-[4-(methyldisulfanyl)butanoyl]amino]propanoic acid
• CAS: 138148-63-7
• 化学式: C₉H₁₇NO₃S₂
• 分子量: 251.371
• InChiKey: GKWCBGAPNBWUFS-ZETCQYMHSA-N

物化性质

• 熔点：
  92-93 °C
• 沸点：
  422.0±30.0 °C(Predicted)
• 密度：
  1.229±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0.7
• 重原子数：
  15
• 可旋转键数：
  7
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.78
• 拓扑面积：
  108
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  N-methyl-N-[(3-methyldithio)-1-oxobutyl]-L-alanine 、 maytansinol 在 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)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'-[3-(methyldithio)-1-oxobutyl]maytansine
  参考文献：
  名称：

  Ado-trastuzumab Emtansine (T-DM1): An Antibody–Drug Conjugate (ADC) for HER2-Positive Breast Cancer

  摘要：

  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.

  DOI：

  10.1021/jm500766w
• 作为产物：
  描述：

  4-(甲基二硫烷基)丁酸 在 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 作用下， 以 乙二醇二甲醚 、 二氯甲烷 、 水 为溶剂， 反应 4.0h， 生成 N-methyl-N-[(3-methyldithio)-1-oxobutyl]-L-alanine
  参考文献：
  名称：

  Semisynthetic Maytansine Analogues for the Targeted Treatment of Cancer

  摘要：

  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.

  DOI：

  10.1021/jm060319f

文献信息

• Cytotoxic agents comprising maytansinoids and their therapeutic use
  申请人：ImmunoGen Inc.

  公开号：US05208020A1

  公开（公告）日：1993-05-04

  A cytotoxic agent comprising one or more maytansinoids linked to a cell binding agent. A therapeutic agent for killing selected cell populations comprising: (a) a cytotoxic amount of one or more maytansinoids linked to a cell binding agent, and (b) a pharmaceutically acceptable carrier diluent or excipient. A method for killing selected cell populations comprising contacting a cell population or tissue suspected of containing cells from said selected cell population with a cytotoxic amount of a cytotoxic agent comprising one or more maytansinoids linked to a cell binding agent. An N-methyl-alanine-containing ester of maytansinol or an analogue of maytansinol, said N-methyl-alanine-containing ester comprising a linking group capable of linking an N-methyl-alanine-containing maytansinoid ester to a chemical moiety. N-methyl-cysteine-containing ester of maytansinol or an analogue of maytansinol.

  一种细胞毒性剂，包括与细胞结合剂连接的一种或多种梅坦西酮类化合物。一种用于杀灭选定细胞群体的治疗剂，包括：(a) 与细胞结合剂连接的一种或多种梅坦西酮类化合物的细胞毒性量，以及(b) 一种药用可接受的载体稀释剂或赋形剂。一种用于杀灭选定细胞群体的方法，包括将疑似含有来自所述选定细胞群体的细胞的细胞群体或组织与包括与细胞结合剂连接的一种或多种梅坦西酮类化合物的细胞毒性剂的细胞毒性量接触。一种甲基-丙氨酸酯基梅坦西酮或梅坦西酮类似物，所述甲基-丙氨酸酯基包括一种能够将甲基-丙氨酸酯基梅坦西酮与化学基团连接的连接基团。梅坦西酮的甲基-半胱氨酸酯基或梅坦西酮类似物。
• Process for the preparation and purification of thiol-containing maytansinoids
  申请人：Immunogen, Inc.

  公开号：US06333410B1

  公开（公告）日：2001-12-25

  The present invention provides a process for the preparation and purification of thiol-containing maytansinoids comprising the steps of: (1) reductive hydrolysis of a maytansinoid C-3 ester with a reducing agent selected from the group consisting lithium trimethoxyaluminum hydride (LiAl(OMe)3H), lithium triethoxyaluminum hydride (LiAl(OEt)3H), lithium tripropoxyaluminum hydride (LiAl(OPr)3H), sodium trimethoxyaluminum hydride (NaAl(OMe)3H), sodium triethoxyaluminum hydride (NaAl(OEt)3H) and sodium tripropoxyaluminum hydride (NaAl(OPr)3H) to yield a maytansinol; (2) purifying the maytansinol to remove side products when present; (3) esterifying the purified maytansinol with a carboxylic acid to yield a mixture of an L- and a D-aminoacyl ester of maytansinol; (4) separating the L-aminoacyl ester of maytansinol from the reaction mixture in (3); (5) reducing the L-aminoacyl ester of maytansinol to yield a thiol-containing maytansinoid; and (6) purifying the thiol-containing maytansinoid.

  本发明提供了一种制备和纯化含硫醇马坦西酮类化合物的方法，包括以下步骤：(1) 使用选择自锂三甲氧基铝氢化物（LiAl(OMe)3H）、锂三乙氧基铝氢化物（LiAl(OEt)3H）、锂三异丙氧基铝氢化物（LiAl(OPr)3H）、钠三甲氧基铝氢化物（NaAl(OMe)3H）、钠三乙氧基铝氢化物（NaAl(OEt)3H）和钠三异丙氧基铝氢化物（NaAl(OPr)3H）的还原剂对马坦西酮类化合物C-3酯进行还原水解，得到马坦西醇；(2) 纯化马坦西醇以去除可能存在的副产物；(3) 将纯化的马坦西醇与羧酸酯化，得到马坦西醇的L-和D-氨基酰酯混合物；(4) 从步骤(3)中的反应混合物中分离出马坦西醇的L-氨基酰酯；(5) 将马坦西醇的L-氨基酰酯还原，得到含硫醇的马坦西酮类化合物；(6) 纯化含硫醇的马坦西酮类化合物。
• IMPROVED CYTOTOXIC AGENTS COMPRISING NEW MAYTANSINOIDS
  申请人：ImmunoGen, Inc.

  公开号：EP3524611A1

  公开（公告）日：2019-08-14

  A maytansinoid-cell binding agent conjugate, wherein the maytansinoid is represented by formula 41: wherein the maytansinoid is linked to the cell-binding agent via a cleavable linker, and wherein Y1 is (CH2)2CR1R2S-, and R1 is methyl and R2 is H or R1 and R2 are methyl.

  一种 maytansinoid-细胞结合剂共轭物，其中 maytansinoid 由式 41 表示： 其中 maytansinoid 通过可裂解连接体与细胞结合剂连接，Y1 为 (CH2)2CR1R2S-，R1 为甲基，R2 为 H 或 R1 和 R2 为甲基。
• PROCESS FOR THE PREPARATION AND PURIFICATION OF THIOL-CONTAINING MAYTANSINOIDS
  申请人：Immunogen, Inc.

  公开号：EP1313738B1

  公开（公告）日：2005-12-21
• CYTOTOXIC AGENTS COMPRISING NEW MAYTANSINOIDS (DM4)
  申请人：IMMUNOGEN, INC.

  公开号：US20180043013A1

  公开（公告）日：2018-02-15

  New thiol and disulfide-containing maytansinoids bearing a mono or di-alkyl substitution on the α-carbon atom bearing the sulfur atom are disclosed. Also disclosed are methods for the synthesis of these new maytansinoids and methods for the linkage of these new maytansinoids to cell-binding agents. The maytansinoid-cell-binding agent conjugates are useful as therapeutic agents, which are delivered specifically to target cells and are cytotoxic. These conjugates display vastly improved therapeutic efficacy in animal tumor models compared to the previously described agents.