(2S,3R)-3-((1-(tert-butoxycarbonyl)-1H-indol-3-yl)methyl)pyrrolidine-2-carboxylic acid

• 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: (2S,3R)-3-((1-(tert-butoxycarbonyl)-1H-indol-3-yl)methyl)pyrrolidine-2-carboxylic acid
• 英文别名: (2S,3R)-3-[[1-[(2-methylpropan-2-yl)oxycarbonyl]indol-3-yl]methyl]pyrrolidine-2-carboxylic acid
• 化学式: C₁₉H₂₄N₂O₄
• 分子量: 344.411
• InChiKey: JCSGYPTVUCKVKQ-LRDDRELGSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.8
• 重原子数：
  25
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.47
• 拓扑面积：
  80.6
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (2S,3R)-3-((1-(tert-butoxycarbonyl)-1H-indol-3-yl)methyl)pyrrolidine-2-carboxylic acid 、 9-芴甲基-N-琥珀酰亚胺基碳酸酯 在 potassium carbonate 作用下， 以 1,4-二氧六环 、 水 为溶剂， 以78%的产率得到(2S,3R)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-3-((1-(tert-butoxycarbonyl)-1H-indol-3-yl)methyl)pyrrolidine-2-carboxylic acid
  参考文献：
  名称：

  氨基-锌-烯-烯酸酯环化：短距离获得顺式3取代的脯氨酰-高色氨酸衍生物。

  摘要：

  脯氨酸嵌合体是用于药物化学和/或生物学应用的有用工具。顺式-3-取代的脯氨酸的不对称合成可通过氨基-锌-烯-烯酸酯环化，然后对环状锌中间体进行重金属化以进一步官能化来轻松实现。通过锌中间体与吲哚环的Negishi交叉偶联来实现脯氨酰-高色氨酸衍生物的合成。需要使用衍生自Fu的[（t-Bu3）PH] -BF4的Pd催化剂，以避免不希望的β-氢化物消除。获得易于用于肽合成的光学纯和正交保护的化合物。

  DOI：

  10.1021/jo801006a
• 作为产物：
  描述：

  1-Boc-3-碘吲哚 在 palladium 10% on activated carbon 、 氢气 、 zinc dibromide 、 lithium diisopropyl amide 作用下， 以 四氢呋喃 、 甲醇 、 乙醚 为溶剂， -78.0~20.0 ℃ 、500.01 kPa 条件下， 反应 168.0h， 生成 (2S,3R)-3-((1-(tert-butoxycarbonyl)-1H-indol-3-yl)methyl)pyrrolidine-2-carboxylic acid
  参考文献：
  名称：

  Synthesis and Evaluation of Analogues of N-Phthaloyl-l-tryptophan (RG108) as Inhibitors of DNA Methyltransferase 1

  摘要：

  DNA methyltransferases (DNMT) are promising drug targets in cancer provided that new, more specific, and chemically stable inhibitors are discovered. Among the non-nucleoside DNMT inhibitors, N-phthaloyl-L-tryptophan 1 (RG108) was first identified as inhibitor of DNMT1. Here, 1 analogues were synthesized to understand its interaction with DNMT. The indole, carboxylate, and phthalimide moieties were modified. Homologated and conformationally constrained analogues were prepared. The latter were synthesized from prolinohomotryptophan derivatives through a methodology based amino-zinc-ene-enolate cyclization. All compounds were tested for their ability to inhibit DNMT1 in vitro. Among them, constrained compounds 16-18 and NPys derivatives 10-11 were found to be at least 10-fold more potent than the reference compound. The cytotoxicity on the tumor, DU145 cell line of the most potent inhibitors was correlated to their inhibitory potency. Finally, docking studies were conducted in order to understand their binding mode. This study provides insights for the design of the next-generation of DNMT inhibitors.

  DOI：

  10.1021/jm401419p

文献信息

• Amino-Zinc-Ene-Enolate Cyclization: A Short Access to <i>cis</i>-3-Substituted Prolino-homotryptophane Derivatives
  作者：Céline Mothes、Solange Lavielle、Philippe Karoyan

  DOI：10.1021/jo801006a

  日期：2008.9.1

  Proline chimeras are useful tools for medicinal chemistry and/or biological applications. The asymmetric synthesis of cis-3-substituted prolines can be easily achieved via amino-zinc-ene-enolate cyclization followed by transmetalation of the cyclic zinc intermediate for further functionalization. Syntheses of prolino-homotryptophane derivatives were achieved through Negishi cross-coupling of the zinc

  脯氨酸嵌合体是用于药物化学和/或生物学应用的有用工具。顺式-3-取代的脯氨酸的不对称合成可通过氨基-锌-烯-烯酸酯环化，然后对环状锌中间体进行重金属化以进一步官能化来轻松实现。通过锌中间体与吲哚环的Negishi交叉偶联来实现脯氨酰-高色氨酸衍生物的合成。需要使用衍生自Fu的[（t-Bu3）PH] -BF4的Pd催化剂，以避免不希望的β-氢化物消除。获得易于用于肽合成的光学纯和正交保护的化合物。
• Synthesis and Evaluation of Analogues of <i>N</i>-Phthaloyl-<scp>l</scp>-tryptophan (RG108) as Inhibitors of DNA Methyltransferase 1
  作者：Saâdia Asgatay、Christine Champion、Gaël Marloie、Thierry Drujon、Catherine Senamaud-Beaufort、Alexandre Ceccaldi、Alexandre Erdmann、Arumugam Rajavelu、Philippe Schambel、Albert Jeltsch、Olivier Lequin、Philippe Karoyan、Paola B. Arimondo、Dominique Guianvarc’h

  DOI：10.1021/jm401419p

  日期：2014.1.23

  DNA methyltransferases (DNMT) are promising drug targets in cancer provided that new, more specific, and chemically stable inhibitors are discovered. Among the non-nucleoside DNMT inhibitors, N-phthaloyl-L-tryptophan 1 (RG108) was first identified as inhibitor of DNMT1. Here, 1 analogues were synthesized to understand its interaction with DNMT. The indole, carboxylate, and phthalimide moieties were modified. Homologated and conformationally constrained analogues were prepared. The latter were synthesized from prolinohomotryptophan derivatives through a methodology based amino-zinc-ene-enolate cyclization. All compounds were tested for their ability to inhibit DNMT1 in vitro. Among them, constrained compounds 16-18 and NPys derivatives 10-11 were found to be at least 10-fold more potent than the reference compound. The cytotoxicity on the tumor, DU145 cell line of the most potent inhibitors was correlated to their inhibitory potency. Finally, docking studies were conducted in order to understand their binding mode. This study provides insights for the design of the next-generation of DNMT inhibitors.