2-N-(benzyloxycarbonyl)-4-N-(9-fluorenylmethyloxycarbonyl)-L-2,4-diaminobutyric acid tert-butyl ester | 291529-77-6

• 分子结构分类: 有机化合物 - 苯类化合物 - 芴
• 英文名称: 2-N-(benzyloxycarbonyl)-4-N-(9-fluorenylmethyloxycarbonyl)-L-2,4-diaminobutyric acid tert-butyl ester
• 英文别名: tert-butyl (2S)-4-(9H-fluoren-9-ylmethoxycarbonylamino)-2-(phenylmethoxycarbonylamino)butanoate
• CAS: 291529-77-6
• 化学式: C₃₁H₃₄N₂O₆
• 分子量: 530.621
• InChiKey: GSEURMJUOZKJDG-MHZLTWQESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.6
• 重原子数：
  39
• 可旋转键数：
  13
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  103
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  2-N-(benzyloxycarbonyl)-4-N-(9-fluorenylmethyloxycarbonyl)-L-2,4-diaminobutyric acid tert-butyl ester 在 5percent Pd/C 哌啶 、 氢气 、 1-羟基苯并三唑 、 1-(3-二甲基氨基丙基)-3-乙基碳二亚胺 作用下， 以 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 0.01h， 生成 L-Arg NO2-L-Dbu-OC(CH3)3
  参考文献：
  名称：

  Synthesis and Evaluation of Peptidomimetics as Selective Inhibitors and Active Site Probes of Nitric Oxide Synthases

  摘要：

  Nitric oxide synthase (NOS) catalyzes the conversion of L-arginine to L-citrilline and nitric oxide (NO). Selective inhibition of the isoforms of NOS could have great therapeutic potential in the treatment of certain disease states arising from pathologically elevated synthesis of NO. Recently, we reported dipeptide amides containing a basic amine side chain as potent and selective inhibitors of neuronal NOS (Huang, H.; Martasek, P.; Roman, L. J.; Masters, B. S. S.; Silverman, R. B. J. Med. Chem. 1999, 42, 3147). The mast potent nNOS inhibitor among these compounds is L-Arg(NO2)-L-Dbu-NH2 (1) (K-i = 130 nM), which also exhibits the highest selectivity over eNOS (>1500-fold) with excellent selectivity over iNOS (190-fold). Here we describe the design and synthesis of a series of peptidomimetic analogues of this dipeptide as potential selective inhibitors of nNOS. The biochemical evaluation of these compounds also revealed the binding requirements of the dipeptide inhibitors with NOS. Incorporation of protecting groups at the N-terminus of the dipeptide amide 1 (compounds 4 and 5) resulted in dramatic decreases in the inhibitory potency of nNOS. Masking the NH group of the peptide bond (peptoids 6-8 and N-methylated compounds 9-11) also gave much poorer nNOS inhibitors than I. Both of the results demonstrate the importance of the cl-amine of the dipeptide and the NH moiety of the peptide bond for binding at the active site. Modifications at the C-terminus of the peptide included converting the amide to the methyl ester (12), tert-butyl ester (13), and carboxylic acid (14) and also descarboxamide analogues (15-17), which revealed less restricted binding requirements for the C-terminus of the dipeptide. Further optimization should be possible when we learn more about the binding requirements at the active sites of NOSs.

  DOI：

  10.1021/jm000127z
• 作为产物：
  描述：

  氯甲酸-9-芴基甲酯 、 (S)-4-Amino-2-benzyloxycarbonylamino-butyric acid tert-butyl ester 在 sodium carbonate 作用下， 生成 2-N-(benzyloxycarbonyl)-4-N-(9-fluorenylmethyloxycarbonyl)-L-2,4-diaminobutyric acid tert-butyl ester
  参考文献：
  名称：

  Synthesis and Evaluation of Peptidomimetics as Selective Inhibitors and Active Site Probes of Nitric Oxide Synthases

  摘要：

  Nitric oxide synthase (NOS) catalyzes the conversion of L-arginine to L-citrilline and nitric oxide (NO). Selective inhibition of the isoforms of NOS could have great therapeutic potential in the treatment of certain disease states arising from pathologically elevated synthesis of NO. Recently, we reported dipeptide amides containing a basic amine side chain as potent and selective inhibitors of neuronal NOS (Huang, H.; Martasek, P.; Roman, L. J.; Masters, B. S. S.; Silverman, R. B. J. Med. Chem. 1999, 42, 3147). The mast potent nNOS inhibitor among these compounds is L-Arg(NO2)-L-Dbu-NH2 (1) (K-i = 130 nM), which also exhibits the highest selectivity over eNOS (>1500-fold) with excellent selectivity over iNOS (190-fold). Here we describe the design and synthesis of a series of peptidomimetic analogues of this dipeptide as potential selective inhibitors of nNOS. The biochemical evaluation of these compounds also revealed the binding requirements of the dipeptide inhibitors with NOS. Incorporation of protecting groups at the N-terminus of the dipeptide amide 1 (compounds 4 and 5) resulted in dramatic decreases in the inhibitory potency of nNOS. Masking the NH group of the peptide bond (peptoids 6-8 and N-methylated compounds 9-11) also gave much poorer nNOS inhibitors than I. Both of the results demonstrate the importance of the cl-amine of the dipeptide and the NH moiety of the peptide bond for binding at the active site. Modifications at the C-terminus of the peptide included converting the amide to the methyl ester (12), tert-butyl ester (13), and carboxylic acid (14) and also descarboxamide analogues (15-17), which revealed less restricted binding requirements for the C-terminus of the dipeptide. Further optimization should be possible when we learn more about the binding requirements at the active sites of NOSs.

  DOI：

  10.1021/jm000127z

文献信息

• Synthesis and Evaluation of Peptidomimetics as Selective Inhibitors and Active Site Probes of Nitric Oxide Synthases
  作者：Hui Huang、Pavel Martásek、Linda J. Roman、Richard B. Silverman

  DOI：10.1021/jm000127z

  日期：2000.7.1

  Nitric oxide synthase (NOS) catalyzes the conversion of L-arginine to L-citrilline and nitric oxide (NO). Selective inhibition of the isoforms of NOS could have great therapeutic potential in the treatment of certain disease states arising from pathologically elevated synthesis of NO. Recently, we reported dipeptide amides containing a basic amine side chain as potent and selective inhibitors of neuronal NOS (Huang, H.; Martasek, P.; Roman, L. J.; Masters, B. S. S.; Silverman, R. B. J. Med. Chem. 1999, 42, 3147). The mast potent nNOS inhibitor among these compounds is L-Arg(NO2)-L-Dbu-NH2 (1) (K-i = 130 nM), which also exhibits the highest selectivity over eNOS (>1500-fold) with excellent selectivity over iNOS (190-fold). Here we describe the design and synthesis of a series of peptidomimetic analogues of this dipeptide as potential selective inhibitors of nNOS. The biochemical evaluation of these compounds also revealed the binding requirements of the dipeptide inhibitors with NOS. Incorporation of protecting groups at the N-terminus of the dipeptide amide 1 (compounds 4 and 5) resulted in dramatic decreases in the inhibitory potency of nNOS. Masking the NH group of the peptide bond (peptoids 6-8 and N-methylated compounds 9-11) also gave much poorer nNOS inhibitors than I. Both of the results demonstrate the importance of the cl-amine of the dipeptide and the NH moiety of the peptide bond for binding at the active site. Modifications at the C-terminus of the peptide included converting the amide to the methyl ester (12), tert-butyl ester (13), and carboxylic acid (14) and also descarboxamide analogues (15-17), which revealed less restricted binding requirements for the C-terminus of the dipeptide. Further optimization should be possible when we learn more about the binding requirements at the active sites of NOSs.