N-methyl-N-[(4-(S)-methyldithio)-1-oxopentyl]-S-alanine | 796073-78-4

• 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-[(4-(S)-methyldithio)-1-oxopentyl]-S-alanine
• 英文别名: (2S)-2-[methyl-[(4S)-4-(methyldisulfanyl)pentanoyl]amino]propanoic acid
• CAS: 796073-78-4
• 化学式: C₁₀H₁₉NO₃S₂
• 分子量: 265.398
• InChiKey: WRWDSBICYUMRCW-YUMQZZPRSA-N

物化性质

• 沸点：
  425.9±30.0 °C(Predicted)
• 密度：
  1.199±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.1
• 重原子数：
  16
• 可旋转键数：
  7
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.8
• 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-[(4-(S)-methyldithio)-1-oxopentyl]-S-alanine 、 maytansinol 在 N,N'-二环己基碳二亚胺 、 zinc(II) chloride 作用下， 以 乙醚 、 二氯甲烷 为溶剂， 反应 2.0h， 生成 N^2'-deacetyl-N^2'-[4-(S)-(methyldithio)-1-oxopentyl]maytansine 、 N^2'-deacetyl-N^2'-[4-(S)-(methyldithio)-1-oxopentyl]-D-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
• 作为产物：
  描述：

  R-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 作用下， 以 四氢呋喃 、 乙二醇二甲醚 、 乙醇 、 二氯甲烷 、 水 为溶剂， 反应 6.5h， 生成 N-methyl-N-[(4-(S)-methyldithio)-1-oxopentyl]-S-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 new maytansinoids
  申请人：IMMUNOGEN, INC.

  公开号：US20040235840A1

  公开（公告）日：2004-11-25

  New thiol and disulfide-containing maytansinoids bearing a mono or di-alkyl substitution on the &agr;-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.

  揭示了具有α-碳原子上带有硫原子的单烷基或双烷基取代基的新硫醇和二硫化物含有马坦西诺伊德。还公开了合成这些新马坦西诺伊德的方法以及将这些新马坦西诺伊德连接到细胞结合剂的方法。马坦西诺伊德-细胞结合剂结合物可用作治疗剂，专门传递到靶细胞并具有细胞毒性。与先前描述的药物相比，这些结合物在动物肿瘤模型中显示出大大改善的治疗效果。
• CYTOTOXIC AGENTS COMPRISING NEW MAYTANSINOIDS
  申请人：Chari V. J. Ravi

  公开号：US20070264266A1

  公开（公告）日：2007-11-15

  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.

  公开了一种新的含有巯基和二硫键的马丹霉素衍生物，其α-碳原子上带有硫原子的位置上具有单烷基或双烷基取代。还公开了制备这些新马丹霉素衍生物的方法以及将这些新马丹霉素衍生物与细胞结合剂连接的方法。马丹霉素-细胞结合剂共轭物作为治疗剂具有特异性地传递到目标细胞并具有细胞毒性。与先前描述的药物相比，这些共轭物在动物肿瘤模型中显示出极大的治疗效果。
• CYTOTOXIC AGENTS COMPRISING NEW MAYTANSINOIDS (DM4)
  申请人：ImmunoGen, Inc.

  公开号：US20150071949A1

  公开（公告）日：2015-03-12

  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.

  本文介绍了一种新的含巯基和二硫键的马丹霉素衍生物，其α-碳原子上的硫原子带有单烷基或双烷基取代基。同时，还揭示了合成这些新马丹霉素衍生物和将其与细胞结合剂连接的方法。马丹霉素-细胞结合剂结合物可作为治疗剂，专门传递到靶细胞并具有细胞毒性。与先前描述的治疗剂相比，这些结合物在动物肿瘤模型中显示出极大的治疗效果。
• MAYTANSINOID-CELL-BINDING AGENT CONJUGATES
  申请人：ImmunoGen, Inc.

  公开号：EP3851126A1

  公开（公告）日：2021-07-21

  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.

  本发明公开了在含硫原子的α-碳原子上具有单烷基或二烷基取代的新的含硫醇和二硫化物的类 maytansinoids。此外，还公开了合成这些新的 maytansinoids 的方法以及将这些新的 maytansinoids 与细胞结合剂连接的方法。这种 maytansinoids-细胞结合剂共轭物可用作治疗剂，能特异性地输送到靶细胞并具有细胞毒性。与之前描述的药物相比，这些共轭物在动物肿瘤模型中的疗效大大提高。
• IMPROVED CYTOTOXIC AGENTS COMPRISING NEW MAYTANSINOIDS
  申请人：ImmunoGen, Inc.

  公开号：EP1651162B1

  公开（公告）日：2015-10-21