N^2'-deacetyl-N^2'-[4-(R,S)-(methyldithio)-1-oxopentyl]maytansine | 796073-70-6

• 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-(R,S)-(methyldithio)-1-oxopentyl]maytansine
• 英文别名: [(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-(methyldisulfanyl)pentanoyl]amino]propanoate
• CAS: 796073-70-6
• 化学式: C₃₈H₅₄ClN₃O₁₀S₂
• 分子量: 812.446
• InChiKey: YCOIJPSIDUQDNN-UQJMXLCASA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  54
• 可旋转键数：
  11
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.63
• 拓扑面积：
  207
• 氢给体数：
  2
• 氢受体数：
  12

反应信息

• 作为反应物：
  描述：

  N^2'-deacetyl-N^2'-[4-(R,S)-(methyldithio)-1-oxopentyl]maytansine 在 1,4-二巯基-2,3-丁二醇 作用下， 生成 N^2'-deacetyl-N^2'-(4-mercapto-1-oxopentyl)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：

  3-O-p-toluenesulfonyl-pentanenitrile 在 sodium hydroxide 、 NaH₂PO₃ buffer 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 、 N,N'-二环己基碳二亚胺 、 zinc(II) chloride 作用下， 以 四氢呋喃 、 乙二醇二甲醚 、 乙醚 、 乙醇 、 二氯甲烷 、 水 为溶剂， 反应 6.0h， 生成 N^2'-deacetyl-N^2'-[4-(R,S)-(methyldithio)-1-oxopentyl]maytansine
  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