(2S,3R)-3-hydroxy-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-(1-tritylimidazol-4-yl)propanoic acid | 160054-25-1

• 分子结构分类: 有机化合物 - 苯类化合物 - 三苯基化合物
• 英文名称: (2S,3R)-3-hydroxy-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-(1-tritylimidazol-4-yl)propanoic acid
• CAS: 160054-25-1
• 化学式: C₃₀H₃₁N₃O₅
• 分子量: 513.593
• InChiKey: SQLCDSQAWYVQGH-UIOOFZCWSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.3
• 重原子数：
  38
• 可旋转键数：
  10
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.23
• 拓扑面积：
  114
• 氢给体数：
  3
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  (2S,3R)-3-hydroxy-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-(1-tritylimidazol-4-yl)propanoic acid 在 二苯基膦叠氮化物 、 (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate 、 N,N-二异丙基乙胺 、 三氟乙酸 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 24.5h， 生成 N^β-[1-amino-3(S)-[4-amino-6-[[[1(S)-[({4(S)-[({1(S)-[({2-[4'-({[(3-dimethylsulfonio)-1-propyl]amino}carbonyl)-2',4-bithiazol-2-yl]-1-ethyl}amino)carbonyl]-2(R)-hydroxy-1-propyl}amino)carbonyl]-2(R)-butyl}amino)carbonyl]-2(R)-hydroxy-2-(imidazol-4-yl)
  参考文献：
  名称：

  Definition of the Effect and Role of the Bleomycin A₂ Valerate Substituents:  Preorganization of a Rigid, Compact Conformation Implicated in Sequence-Selective DNA Cleavage

  摘要：

  The synthesis and a comparative study of deglycobleomycin A(2) analogues containing key modifications in the valerate subunit are described in efforts that define the role of the linker length and its substituents. In addition to demonstrating that the C3-hydroxy group exhibits only a modest effect (1-2x) that may be attributed to an intermolecular H-bond with DNA and that the length of the linker is important (C4 > C5 > C3 > C2), the studies illustrate that the substantial impact of the C4-methyl group is linked to the presence of the C2-methyl group, while the modest impact of the C2-methyl group itself (ca. 2x) is not coupled to the presence of the C4-methyl group. These effects may be explained by the conformational properties of the agents resulting from the substitutions and beautifully fit the models of DNA-bound Co(III)OOH bleomycin A(2) and deglycobleomycin A(2). The magnitude of the effects suggests that an important functional role of the linker region is to facilitate adoption of a rigid, compact conformation productive for DNA cleavage. The studies also identify a second potential site that may adopt two nearly equivalent conformations which may constitute a swivel point that permits access to a class of related bound structures adaptable to the conformational characteristics of the multiple cleavage sites or access to both strands of DNA from a common intercalation site important for both primary (single strand) and secondary (double strand) cleavage.

  DOI：

  10.1021/ja9816640
• 作为产物：
  描述：

  1-三苯甲基咪唑-4-甲醛 在 lithium hydroxide 、 sodium azide 、 三氟甲磺酸二丁硼 、 硫化氢 、 双氧水 、 sodium methylate 、 三乙胺 作用下， 以 四氢呋喃 、 甲醇 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 53.08h， 生成 (2S,3R)-3-hydroxy-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-(1-tritylimidazol-4-yl)propanoic acid
  参考文献：
  名称：

  Total Synthesis of Bleomycin A2 and Related Agents. 1. Synthesis and DNA Binding Properties of the Extended C-Terminus: Tripeptide S, Tetrapeptide S, Pentapeptide S, and Related Agents

  摘要：

  Full details of concise, diastereocontrolled syntheses of 2-5 and their incorporation into tri-, tetra-, and pentapeptide S, the C-terminus of bleomycin Alt are described. The extension of the studies to the synthesis of a complete set of tri- and tetrapeptide S structural analogs 29a,b and 43b-j is detailed, and their DNA binding constants (apparent K-B, calf thymus DNA) and apparent binding site sizes were determined. Consistent with past observations, the studies highlight the fact that the majority of the DNA binding affinity for bleomycin A(2) (1.0 X 10(5) M(-1)) and deglycobleomycin Aa (1.1 x 10(5) M(-1)) is embodied within N-BOC-tripeptide S (0.26 X 10(5) M(-1)). The additional comparisons of 29a (O.18 x 10(5) M(-1)), N-BOC-tetrapeptide S (0.21 x 10(5) M(-1)), 43h (0.20 x 10(5) M(-1)), and N-BOC-pentapeptide S (0.23 X 10(5) M(-1)) versus N-BOC-dipeptide S (0.10 x 10(5) M(-1)) indicate productive stabilizing binding interactions for the tripeptide S L-threonine subunit and substituent, illustrate that the entire pentanoic acid subunit of tetrapeptide S and its substituents do not significantly contribute to DNA binding affinity, and indicate that the entire beta-hydroxy-L-histidine subunit of pentapeptide S does not contribute to DNA binding affinity. With the exception of the L-threonine side chain substituent, the observations suggest that the tri- and tetrapeptide S substituent effects on the bleomycin A(2) DNA cleavage reaction are not due to substantial stabilizing binding interactions with duplex DNA. In addition, the measured apparent binding site sizes for bleomycin A(2)(3.8 base pairs), deglycobleomycin A(2) (3.9 base pairs), N-BOC-tripeptide S (3.6 base pairs), N-BOC-tetrapeptide S (3.7 base pairs), 43h (3.5 base pairs), and N-BOC-pentapeptide S (4.2 base pairs) versus N-BOC-dipeptide S (2.2 base pairs) and 29a (2.7 base pairs) suggest that it is the tripeptide S subunit of bleomycin A(2) that is fully bound to duplex DNA, that the tripeptide S L-threonine hydroxyethyl substituent detectably affects the agent interaction with duplex DNA, but that the presence or absence of the other tetrapeptide S and pentapeptide S backbone substituents do not substantially alter the binding site size or tripeptide S binding mode.

  DOI：

  10.1021/ja00092a011

文献信息

• Assessment of the Role of the Bleomycin A₂ Pyrimidoblamic Acid C4 Amino Group
  作者：Dale L. Boger、Timothy M. Ramsey、Hui Cai、Silvia T. Hoehn、John W. Kozarich、JoAnne Stubbe

  DOI：10.1021/ja971889v

  日期：1998.1.1

  The preparation and examination of 3 and 4 and their unnatural epimers 6 and 7 by following a new and alternative synthesis of 2 was conducted to assess the role of the pyrimidine C4 amine of bleomycin A2 (1) and deglycobleomycin A2 (2). The agent 3 bearing a pyrimidine C4 dimethylamino substituent exhibited a substantially diminished DNA cleavage efficiency (10−15×) relative to 2 and the loss of the

  3 和 4 及其非天然差向异构体 6 和 7 的制备和检查遵循 2 的新的替代合成，以评估博来霉素 A2 (1) 和去甘博莱霉素 A2 (2) 的嘧啶 C4 胺的作用。带有嘧啶 C4 二甲氨基取代基的试剂 3 表现出相对于 2 显着降低的 DNA 切割效率（10-15 倍）和特征 5'-GC/5'-GT 切割选择性的丧失。与2相比，去除嘧啶C4氨基的试剂4表现出更大的DNA切割效率降低（30倍）。对于该试剂，特征切割选择性根据测定条件略微或显着降低。即使在没有实质性改变的情况下，检测它的能力需要 4 与 25-37 °C 的温度。此信息和温度依赖性表明结合相互作用减少，并且与嘧啶 C4 a...
• A Systematic Evaluation of the Bleomycin A₂ <scp>l</scp>-Threonine Side Chain:  Its Role in Preorganization of a Compact Conformation Implicated in Sequence-Selective DNA Cleavage
  作者：Dale L. Boger、Timothy M. Ramsey、Hui Cai、Silvia T. Hoehn、JoAnne Stubbe

  DOI：10.1021/ja9816638

  日期：1998.9.1

  The preparation and examination of 3-7 are detailed and constitute analogues of deglycobleomycin A(2) (2) containing systematic modifications in the L-threonine side chain. The studies revealed a substantial impact of the substituent on the DNA cleavage efficiency and ratio of double strand/single strand (ds/ss) cleavage without affecting the characteristic 5'-GPy selectivity. The results of the comparisons proved consistent with conformational effects of the substituent within the linker domain which restrict the number of accessible conformations (Phi congruent to -120 degrees, Psi = 60-180 degrees) and favor adoption of a compact conformation (Phi congruent to -120 degrees, Psi congruent to 180 degrees) implicated in sequence-selective DNA cleavage. The studies also identify one potential site that may adopt two nearly equivalent turn conformations. This site may constitute one swivel point in the structure that permits access to a class of related bound structures (Psi = 60-180 degrees) adaptable to variable conformational characteristics required of multiple cleavage sites, including access to both strands of duplex DNA from a single intercalation site important for both primary and secondary DNA cleavage.
• N-methyl threonine analogues of deglycobleomycin A2: Synthesis and evaluation
  作者：Dale L. Boger、Shuji Teramoto、Hui Cai

  DOI：10.1016/s0968-0896(97)00107-7

  日期：1997.8

  The synthesis of 5 and its D-allo-threonine epimer 6 and the comparison of their DNA cleavage efficiency and selectivity with that of deglycobleomycin A(2) (3) are detailed. The studies illustrate that N-methylation of the L-threonine subunit within deglycobleomycin A(2) dramatically reduces the DNA cleavage efficiency (10-15-fold), weakens and nearly abolishes the inherent DNA cleavage selectivity, but has little effect on the inherent oxidation capabilities of the activated Fe(III) complexes. The results are consistent with a previously unrecognized prominent role for the threonine NH and the potential importance of a hydrogen bond to the Fe(III) hydroperoxide complex of bleomycin or a subsequent activated complex implicated in recent structural models. (C) 1997 Elsevier Science Ltd.
• Total Synthesis of Bleomycin A2 and Related Agents. 1. Synthesis and DNA Binding Properties of the Extended C-Terminus: Tripeptide S, Tetrapeptide S, Pentapeptide S, and Related Agents
  作者：Dale L. Boger、Steven L. Colletti、Takeshi Honda、Royce F. Menezes

  DOI：10.1021/ja00092a011

  日期：1994.6

  Full details of concise, diastereocontrolled syntheses of 2-5 and their incorporation into tri-, tetra-, and pentapeptide S, the C-terminus of bleomycin Alt are described. The extension of the studies to the synthesis of a complete set of tri- and tetrapeptide S structural analogs 29a,b and 43b-j is detailed, and their DNA binding constants (apparent K-B, calf thymus DNA) and apparent binding site sizes were determined. Consistent with past observations, the studies highlight the fact that the majority of the DNA binding affinity for bleomycin A(2) (1.0 X 10(5) M(-1)) and deglycobleomycin Aa (1.1 x 10(5) M(-1)) is embodied within N-BOC-tripeptide S (0.26 X 10(5) M(-1)). The additional comparisons of 29a (O.18 x 10(5) M(-1)), N-BOC-tetrapeptide S (0.21 x 10(5) M(-1)), 43h (0.20 x 10(5) M(-1)), and N-BOC-pentapeptide S (0.23 X 10(5) M(-1)) versus N-BOC-dipeptide S (0.10 x 10(5) M(-1)) indicate productive stabilizing binding interactions for the tripeptide S L-threonine subunit and substituent, illustrate that the entire pentanoic acid subunit of tetrapeptide S and its substituents do not significantly contribute to DNA binding affinity, and indicate that the entire beta-hydroxy-L-histidine subunit of pentapeptide S does not contribute to DNA binding affinity. With the exception of the L-threonine side chain substituent, the observations suggest that the tri- and tetrapeptide S substituent effects on the bleomycin A(2) DNA cleavage reaction are not due to substantial stabilizing binding interactions with duplex DNA. In addition, the measured apparent binding site sizes for bleomycin A(2)(3.8 base pairs), deglycobleomycin A(2) (3.9 base pairs), N-BOC-tripeptide S (3.6 base pairs), N-BOC-tetrapeptide S (3.7 base pairs), 43h (3.5 base pairs), and N-BOC-pentapeptide S (4.2 base pairs) versus N-BOC-dipeptide S (2.2 base pairs) and 29a (2.7 base pairs) suggest that it is the tripeptide S subunit of bleomycin A(2) that is fully bound to duplex DNA, that the tripeptide S L-threonine hydroxyethyl substituent detectably affects the agent interaction with duplex DNA, but that the presence or absence of the other tetrapeptide S and pentapeptide S backbone substituents do not substantially alter the binding site size or tripeptide S binding mode.
• Definition of the Effect and Role of the Bleomycin A₂ Valerate Substituents:  Preorganization of a Rigid, Compact Conformation Implicated in Sequence-Selective DNA Cleavage
  作者：Dale L. Boger、Timothy M. Ramsey、Hui Cai、Silvia T. Hoehn、JoAnne Stubbe

  DOI：10.1021/ja9816640

  日期：1998.9.1

  The synthesis and a comparative study of deglycobleomycin A(2) analogues containing key modifications in the valerate subunit are described in efforts that define the role of the linker length and its substituents. In addition to demonstrating that the C3-hydroxy group exhibits only a modest effect (1-2x) that may be attributed to an intermolecular H-bond with DNA and that the length of the linker is important (C4 > C5 > C3 > C2), the studies illustrate that the substantial impact of the C4-methyl group is linked to the presence of the C2-methyl group, while the modest impact of the C2-methyl group itself (ca. 2x) is not coupled to the presence of the C4-methyl group. These effects may be explained by the conformational properties of the agents resulting from the substitutions and beautifully fit the models of DNA-bound Co(III)OOH bleomycin A(2) and deglycobleomycin A(2). The magnitude of the effects suggests that an important functional role of the linker region is to facilitate adoption of a rigid, compact conformation productive for DNA cleavage. The studies also identify a second potential site that may adopt two nearly equivalent conformations which may constitute a swivel point that permits access to a class of related bound structures adaptable to the conformational characteristics of the multiple cleavage sites or access to both strands of DNA from a common intercalation site important for both primary (single strand) and secondary (double strand) cleavage.