(3-(benzyloxy)-4-methyl-2-nitrobenzoyl)threonyl-D-phenylalaninylprolylsarcosyl-N-methylvaline lactone | 158680-41-2

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 肽模拟物
• 英文名称: (3-(benzyloxy)-4-methyl-2-nitrobenzoyl)threonyl-D-phenylalaninylprolylsarcosyl-N-methylvaline lactone
• 英文别名: N-[(3R,6S,7R,10S,16S)-3-benzyl-7,11,14-trimethyl-2,5,9,12,15-pentaoxo-10-propan-2-yl-8-oxa-1,4,11,14-tetrazabicyclo[14.3.0]nonadecan-6-yl]-4-methyl-2-nitro-3-phenylmethoxybenzamide
• CAS: 158680-41-2
• 化学式: C₄₂H₅₀N₆O₁₀
• 分子量: 798.893
• InChiKey: PQXVBKQLLHOWGK-FJMVDQBBSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.19
• 重原子数：
  58.0
• 可旋转键数：
  9.0
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  197.8
• 氢给体数：
  2.0
• 氢受体数：
  10.0

反应信息

• 作为反应物：
  描述：

  (3-(benzyloxy)-4-methyl-2-nitrobenzoyl)threonyl-D-phenylalaninylprolylsarcosyl-N-methylvaline lactone 在 palladium on activated charcoal 氢气 作用下， 以 甲醇 为溶剂， 反应 2.0h， 生成 2-Amino-N-((5R,8S,9R,12S,17aS)-5-benzyl-12-isopropyl-9,13,16-trimethyl-4,7,11,14,17-pentaoxo-hexadecahydro-10-oxa-3a,6,13,16-tetraaza-cyclopentacyclohexadecen-8-yl)-3-hydroxy-4-methyl-benzamide
  参考文献：
  名称：

  Role of D-Valine Residues in the Antitumor Drug Actinomycin D:Replacement of D-Valines with Other D-Amino Acids Changes the DNA Binding Characteristics and Transcription Inhibitory Activities

  摘要：

  D-valine analogues of the antitumor drug actinomycin D, in which D-valine residues were replaced with D-threonine, D-tyrosine, D-phenylalanine, and D-O-methyltyrosine residues, have been totally synthesized. The crystal structure of the D-O-methyltyrosine analogue has been determined (a = b = 21.352(6), c = 44.525(9) Angstrom space group P4(1)2(1)2; R = 0.19 for 803 out of 1114 reflections at 1.8 Angstrom resolution data). Replacements of D-valines did not change the overall conformation of the molecule, and the substituted groups were located on the side opposite to the DNA binding site, suggesting that the analogues can bind intercalatively at 5'-GC-3' sequences of DNA like actinomycin D does. In the crystals, the analogue molecules constitute a tight dimer, and a pair of stacked chromophores of the dimer was further sandwiched by two methoxyphenyl groups of neighboring molecules. These strong aromatic-aromatic stacking forces among the molecules appear to reduce very much the water solubility of the aromatic analogues. The characteristics of binding of the analogues to various DNA's including d(GAAGCTTC)(2), d(GTTGCAAC)(2), poly(dA-dT), poly(dG-dC), and calf thymus DNA have been examined by using the visible spectrum methods. Difference spectra of actinomycin D and the analogues with oligonucleotides indicated that the analogues bind intercalatively to the DNA, as actinomycin D does, but the association constants were reduced to approximately one-half that of actinomycin D. The spectra of the aromatic analogues titrated with calf thymus DNA indicated that the aromatic analogues bound somehow differently to the longer DNA's. A simple profile analysis of the spectra suggested that the aromatic analogues bound to calf thymus DNA not only with intercalation, as actinomycin D does, but also with side binding. Nevertheless, the association constants of the aromatic analogues to calf thymus DNA with the intercalation mode were found to be quite similar to those of the short oligonucleotides. This conclusion has been supported by the melting behaviors of the DNA with the aromatic analogues, in which the melting curves of the analogues were superimposable on the melting curve of DNA with actinomycin D, suggesting that the aromatic analogue molecules were intercalated into the DNA. The inhibitory activities of actinomycin D and analogues on RNA polymerase in vitro were examined using calf thymus DNA and E. coli RNA polymerase. All actinomycin D analogues severely inhibited RNA synthesis at relatively low drug concentrations. In general, inhibitory activities of the analogues on the RNA synthesis were found to be correlated with those of DNA binding characteristics. However, the analogue in which D-phenylalanine replaced D-valines inhibited RNA synthesis more strongly than actinomycin D itself, but this-analogue bound to the DNA's much more weakly than actinomycin D. In this study, the D-valine residues in the cyclic depsipeptides of actinomycin D were found not to be directly involved in DNA binding, but this amino acid residue was found to be an important biological modulator of the antibiotic. Although the D-valine is a hydrophobic amino acid residue, this amino acid residue appears to play an important role in increasing the water solubility of the antibiotic. Replacements of D-valine residues reduced drastically the water solubility of the analogues, and consequently; this physical character of the analogues reduced their capacities for binding to DNA. As a result, the biological activities of the analogues were generally decreased.

  DOI：

  10.1021/ja00097a003
• 作为产物：
  描述：

  N-(benzyloxycarbonyl)threonyl-D-phenylalaninylprolylsarcosine tert-butyl ester 在 palladium on activated charcoal 4-二甲氨基吡啶 、 N,N-bis[2-oxo-3-oxazolidinyl]phosphorodiamidic chloride 、 氢气 、 三乙胺 、 N,N'-二环己基碳二亚胺 、 三氟乙酸 作用下， 以 甲醇 、 二氯甲烷 为溶剂， -10.0~25.0 ℃ 、101.33 kPa 条件下， 反应 23.0h， 生成 (3-(benzyloxy)-4-methyl-2-nitrobenzoyl)threonyl-D-phenylalaninylprolylsarcosyl-N-methylvaline lactone
  参考文献：
  名称：

  Role of D-Valine Residues in the Antitumor Drug Actinomycin D:Replacement of D-Valines with Other D-Amino Acids Changes the DNA Binding Characteristics and Transcription Inhibitory Activities

  摘要：

  D-valine analogues of the antitumor drug actinomycin D, in which D-valine residues were replaced with D-threonine, D-tyrosine, D-phenylalanine, and D-O-methyltyrosine residues, have been totally synthesized. The crystal structure of the D-O-methyltyrosine analogue has been determined (a = b = 21.352(6), c = 44.525(9) Angstrom space group P4(1)2(1)2; R = 0.19 for 803 out of 1114 reflections at 1.8 Angstrom resolution data). Replacements of D-valines did not change the overall conformation of the molecule, and the substituted groups were located on the side opposite to the DNA binding site, suggesting that the analogues can bind intercalatively at 5'-GC-3' sequences of DNA like actinomycin D does. In the crystals, the analogue molecules constitute a tight dimer, and a pair of stacked chromophores of the dimer was further sandwiched by two methoxyphenyl groups of neighboring molecules. These strong aromatic-aromatic stacking forces among the molecules appear to reduce very much the water solubility of the aromatic analogues. The characteristics of binding of the analogues to various DNA's including d(GAAGCTTC)(2), d(GTTGCAAC)(2), poly(dA-dT), poly(dG-dC), and calf thymus DNA have been examined by using the visible spectrum methods. Difference spectra of actinomycin D and the analogues with oligonucleotides indicated that the analogues bind intercalatively to the DNA, as actinomycin D does, but the association constants were reduced to approximately one-half that of actinomycin D. The spectra of the aromatic analogues titrated with calf thymus DNA indicated that the aromatic analogues bound somehow differently to the longer DNA's. A simple profile analysis of the spectra suggested that the aromatic analogues bound to calf thymus DNA not only with intercalation, as actinomycin D does, but also with side binding. Nevertheless, the association constants of the aromatic analogues to calf thymus DNA with the intercalation mode were found to be quite similar to those of the short oligonucleotides. This conclusion has been supported by the melting behaviors of the DNA with the aromatic analogues, in which the melting curves of the analogues were superimposable on the melting curve of DNA with actinomycin D, suggesting that the aromatic analogue molecules were intercalated into the DNA. The inhibitory activities of actinomycin D and analogues on RNA polymerase in vitro were examined using calf thymus DNA and E. coli RNA polymerase. All actinomycin D analogues severely inhibited RNA synthesis at relatively low drug concentrations. In general, inhibitory activities of the analogues on the RNA synthesis were found to be correlated with those of DNA binding characteristics. However, the analogue in which D-phenylalanine replaced D-valines inhibited RNA synthesis more strongly than actinomycin D itself, but this-analogue bound to the DNA's much more weakly than actinomycin D. In this study, the D-valine residues in the cyclic depsipeptides of actinomycin D were found not to be directly involved in DNA binding, but this amino acid residue was found to be an important biological modulator of the antibiotic. Although the D-valine is a hydrophobic amino acid residue, this amino acid residue appears to play an important role in increasing the water solubility of the antibiotic. Replacements of D-valine residues reduced drastically the water solubility of the analogues, and consequently; this physical character of the analogues reduced their capacities for binding to DNA. As a result, the biological activities of the analogues were generally decreased.

  DOI：

  10.1021/ja00097a003