methyl (2R)-2-amino-3-[4-(tert-butoxy)phenyl]propanoate | 764623-50-9

• 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 (2R)-2-amino-3-[4-(tert-butoxy)phenyl]propanoate
• 英文别名: methyl (2R)-2-amino-3-[4-[(2-methylpropan-2-yl)oxy]phenyl]propanoate
• CAS: 764623-50-9
• 化学式: C₁₄H₂₁NO₃
• 分子量: 251.326
• InChiKey: AORVWDJGVFCGOW-GFCCVEGCSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  18
• 可旋转键数：
  6
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  61.6
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  methyl (2R)-2-amino-3-[4-(tert-butoxy)phenyl]propanoate 在 甲酸 、 水 、 三乙胺 、 N,N'-二环己基碳二亚胺 、 三氟乙酸 作用下， 反应 2.0h， 生成 D-酪氨酸,D-酪氨酰-
  参考文献：
  名称：

  Substrate and Reaction Specificity of Mycobacterium tuberculosis Cytochrome P450 CYP121

  摘要：

  Cytochrome P450 CYP121 is essential for the viability of Mycobacterium tuberculosis. Studies in vitro show that it can use the cyclodipeptide cyclo(L-Tyr-L-Tyr) (cYY) as a substrate. We report an investigation of the substrate and reaction specificities of CYP121 involving analysis of the interaction between CYP121 and 14cYY analogues with various modifications of the side chains or the diketopiperazine (DKP) ring. Spectral titration experiments show that CYP121 significantly bound only cyclodipeptides with a conserved DKP ring carrying two aryl side chains in L-configuration. CYP121 did not efficiently or selectively transform any of the cYY analogues tested, indicating a high specificity for cYY. The molecular determinants of this specificity were inferred from both crystal structures of CYP121-analog complexes solved at high resolution and solution NMR spectroscopy of the analogues. Bound cYY or its analogues all displayed a similar set of contacts with CYP121 residues Asn(85), Phe(168), and Trp(182). The propensity of the cYY tyrosyl to point toward Arg(386) was dependent on the presence of the DKP ring that limits the conformational freedom of the ligand. The correct positioning of the hydroxyl of this tyrosyl was essential for conversion of cYY. Thus, the specificity of CYP121 results from both a restricted binding specificity and a fine-tuned P450 substrate relationship. These results document the catalytic mechanism of CYP121 and improve our understanding of its function in vivo. This work contributes to progress toward the design of inhibitors of this essential protein of M. tuberculosis that could be used for antituberculosis therapy.

  DOI：

  10.1074/jbc.m112.443853

文献信息

• Computer-Aided Identification and Lead Optimization of Dual Murine Double Minute 2 and 4 Binders: Structure–Activity Relationship Studies and Pharmacological Activity
  作者：Mariateresa Giustiniano、Simona Daniele、Sveva Pelliccia、Valeria La Pietra、Deborah Pietrobono、Diego Brancaccio、Sandro Cosconati、Anna Messere、Stefano Giuntini、Linda Cerofolini、Marco Fragai、Claudio Luchinat、Sabrina Taliani、Giuseppe La Regina、Federico Da Settimo、Romano Silvestri、Claudia Martini、Ettore Novellino、Luciana Marinelli

  DOI：10.1021/acs.jmedchem.7b00912

  日期：2017.10.12

  The function of p53 protein, also known as "genome guardian", might be impaired by the overexpression of its primary cellular inhibitor, the murine double minute 2 protein (MDM2). However, the recent finding that MDM2-selective inhibitors induce high levels of its homologue MDM4, prompt us to identify, through a receptor-based virtual screening on an in house database, dual MDM2/MDM4 binders. Compound 1 turned out to possess an IC50 of 93.7 and of 4.6 nM on MDM2 and MDM4, respectively. A series of compounds were synthesized to optimize its activity on MDM2. As a result, compound 12 showed low nanomolar IC50 for both targets. NMR studies confirmed the pocket of binding of 12 as predicted by the Glide docking software. Notably, 12 was able to cause concentration-dependent inhibition of cell proliferation, yielding an IC50 value of 356 +/- 21 nM in neuroblastoma SHSY5Y cells and proved even to efficiently block cancer stem cell growth.
• Substrate and Reaction Specificity of Mycobacterium tuberculosis Cytochrome P450 CYP121
  作者：Matthieu Fonvielle、Marie-Hélène Le Du、Olivier Lequin、Alain Lecoq、Mickaël Jacquet、Robert Thai、Steven Dubois、Guillaume Grach、Muriel Gondry、Pascal Belin

  DOI：10.1074/jbc.m112.443853

  日期：2013.6

  Cytochrome P450 CYP121 is essential for the viability of Mycobacterium tuberculosis. Studies in vitro show that it can use the cyclodipeptide cyclo(L-Tyr-L-Tyr) (cYY) as a substrate. We report an investigation of the substrate and reaction specificities of CYP121 involving analysis of the interaction between CYP121 and 14cYY analogues with various modifications of the side chains or the diketopiperazine (DKP) ring. Spectral titration experiments show that CYP121 significantly bound only cyclodipeptides with a conserved DKP ring carrying two aryl side chains in L-configuration. CYP121 did not efficiently or selectively transform any of the cYY analogues tested, indicating a high specificity for cYY. The molecular determinants of this specificity were inferred from both crystal structures of CYP121-analog complexes solved at high resolution and solution NMR spectroscopy of the analogues. Bound cYY or its analogues all displayed a similar set of contacts with CYP121 residues Asn(85), Phe(168), and Trp(182). The propensity of the cYY tyrosyl to point toward Arg(386) was dependent on the presence of the DKP ring that limits the conformational freedom of the ligand. The correct positioning of the hydroxyl of this tyrosyl was essential for conversion of cYY. Thus, the specificity of CYP121 results from both a restricted binding specificity and a fine-tuned P450 substrate relationship. These results document the catalytic mechanism of CYP121 and improve our understanding of its function in vivo. This work contributes to progress toward the design of inhibitors of this essential protein of M. tuberculosis that could be used for antituberculosis therapy.