methyl 6-{(2S,3R,4S,5S)-3-[(2S)-1-benzyloxy-2-methylbutyl]-2-methyl-4-nitro-5-phenyl-prolylamino}hexanoate | 936712-91-3

• 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: methyl 6-{(2S,3R,4S,5S)-3-[(2S)-1-benzyloxy-2-methylbutyl]-2-methyl-4-nitro-5-phenyl-prolylamino}hexanoate
• 英文别名: methyl 6-[[(2S,3S,4S,5S)-2-methyl-3-[(1S,2S)-2-methyl-1-phenylmethoxybutyl]-4-nitro-5-phenylpyrrolidine-2-carbonyl]amino]hexanoate
• CAS: 936712-91-3
• 化学式: C₃₁H₄₃N₃O₆
• 分子量: 553.699
• InChiKey: KLMGFUUFXMKSFN-DUSRPOAASA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.8
• 重原子数：
  40
• 可旋转键数：
  15
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.55
• 拓扑面积：
  123
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  methyl 6-{(2S,3R,4S,5S)-3-[(2S)-1-benzyloxy-2-methylbutyl]-2-methyl-4-nitro-5-phenyl-prolylamino}hexanoate 在 水 、 lithium hydroxide 作用下， 以 乙二醇二甲醚 为溶剂， 反应 0.42h， 以77%的产率得到6-{(2S,3R,4S,5S)-3-[(2S)-1-(benzyloxy)-2-methylbutyl]-2-methyl-4-nitro-5-phenylpyrrolidine-2-carboxamido}hexanoic acid
  参考文献：
  名称：

  Design, Synthesis, and Functional Evaluation of Leukocyte Function Associated Antigen-1 Antagonists in Early and Late Stages of Cancer Development

  摘要：

  The integrin leukocyte function associated antigen 1 (LFA-1) binds the intercellular adhesion molecule 1 (ICAM-1) by its alpha(L)-chain inserted domain (I-domain). This interaction plays a key role in cancer and other diseases. We report the structure-based design, small-scale synthesis, and biological activity evaluation of a novel family of LFA-1 antagonists. The design led to the synthesis of a family of highly substituted homochiral pyrrolidines with antiproliferative and antimetastatic activity in a murine model of colon carcinoma, as well as potent antiadhesive properties in several cancer cell lines in the low micromolar range. NMR analysis of their binding to the isolated I-domain shows that they bind to the I-domain allosteric site (IDAS), the binding site of other allosteric LFA-1 inhibitors. These results provide evidence of the potential therapeutic value of a new set of LFA-1 inhibitors, whose further development is facilitated by a synthetic strategy that is versatile and fully stereocontrolled.

  DOI：

  10.1021/jm3016848
• 作为产物：
  描述：

  (2S,3R,4S,5S)-3-[(S)-1-(benzyloxy)-2-methybutyl]-2-methoxycarbonyl-2-methyl-4-nitro-5-phenylpyrrolidine 在 水 、 lithium hydroxide 作用下， 以 乙二醇二甲醚 、 N,N-二甲基甲酰胺 为溶剂， 反应 19.0h， 生成 methyl 6-{(2S,3R,4S,5S)-3-[(2S)-1-benzyloxy-2-methylbutyl]-2-methyl-4-nitro-5-phenyl-prolylamino}hexanoate
  参考文献：
  名称：

  Design, Synthesis, and Functional Evaluation of Leukocyte Function Associated Antigen-1 Antagonists in Early and Late Stages of Cancer Development

  摘要：

  The integrin leukocyte function associated antigen 1 (LFA-1) binds the intercellular adhesion molecule 1 (ICAM-1) by its alpha(L)-chain inserted domain (I-domain). This interaction plays a key role in cancer and other diseases. We report the structure-based design, small-scale synthesis, and biological activity evaluation of a novel family of LFA-1 antagonists. The design led to the synthesis of a family of highly substituted homochiral pyrrolidines with antiproliferative and antimetastatic activity in a murine model of colon carcinoma, as well as potent antiadhesive properties in several cancer cell lines in the low micromolar range. NMR analysis of their binding to the isolated I-domain shows that they bind to the I-domain allosteric site (IDAS), the binding site of other allosteric LFA-1 inhibitors. These results provide evidence of the potential therapeutic value of a new set of LFA-1 inhibitors, whose further development is facilitated by a synthetic strategy that is versatile and fully stereocontrolled.

  DOI：

  10.1021/jm3016848

文献信息

• Design, Synthesis, and Functional Evaluation of Leukocyte Function Associated Antigen-1 Antagonists in Early and Late Stages of Cancer Development
  作者：Eider San Sebastián、Tahl Zimmerman、Aizpea Zubia、Yosu Vara、Elyette Martin、Finton Sirockin、Annick Dejaegere、Roland H. Stote、Xabier Lopez、David Pantoja-Uceda、María Valcárcel、Lorea Mendoza、Fernando Vidal-Vanaclocha、Fernando P. Cossío、Francisco J. Blanco

  DOI：10.1021/jm3016848

  日期：2013.2.14

  The integrin leukocyte function associated antigen 1 (LFA-1) binds the intercellular adhesion molecule 1 (ICAM-1) by its alpha(L)-chain inserted domain (I-domain). This interaction plays a key role in cancer and other diseases. We report the structure-based design, small-scale synthesis, and biological activity evaluation of a novel family of LFA-1 antagonists. The design led to the synthesis of a family of highly substituted homochiral pyrrolidines with antiproliferative and antimetastatic activity in a murine model of colon carcinoma, as well as potent antiadhesive properties in several cancer cell lines in the low micromolar range. NMR analysis of their binding to the isolated I-domain shows that they bind to the I-domain allosteric site (IDAS), the binding site of other allosteric LFA-1 inhibitors. These results provide evidence of the potential therapeutic value of a new set of LFA-1 inhibitors, whose further development is facilitated by a synthetic strategy that is versatile and fully stereocontrolled.