Z-Aib-L-Phe-D-Pro-OtBu | 221186-91-0

• 英文名称: Z-Aib-L-Phe-D-Pro-OtBu
• 英文别名: tert-butyl (2R)-1-[(2S)-2-[[2-methyl-2-(phenylmethoxycarbonylamino)propanoyl]amino]-3-phenylpropanoyl]pyrrolidine-2-carboxylate
• CAS: 221186-91-0
• 化学式: C₃₀H₃₉N₃O₆
• 分子量: 537.656
• InChiKey: LUWDRFFAFUVLCC-BJKOFHAPSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.3
• 重原子数：
  39
• 可旋转键数：
  12
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.47
• 拓扑面积：
  114
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  Z-Aib-L-Phe-D-Pro-OtBu 在 palladium on activated charcoal 、 氢气 、 1-羟基苯并三唑 、 N,N'-二环己基碳二亚胺 作用下， 以 溶剂黄146 、 N,N-二甲基甲酰胺 为溶剂， 反应 27.0h， 生成
  参考文献：
  名称：

  Evaluation of functional groups on amino acids in cyclic tetrapeptides in histone deacetylase inhibition

  摘要：

  The naturally occurring cyclic tetrapeptide, chlamydocin, originally isolated from fungus , consists of alpha-aminoisobutyric acid, -phenylalanine, -proline and an unusual amino acid ()-2-amino-8-(()-oxiran-2-yl)-8-oxooctanoic acid (Aoe) and inhibits the histone deacetylases (HDACs), a class of regulatory enzymes. The epoxyketone moiety of Aoe is the key functional group for inhibition. The cyclic tetrapeptide scaffold is supposed to play important role for effective binding to the surface of enzymes. In place of the epoxyketone group, hydroxamic acid and sulfhydryl group have been applied to design inhibitor ligands to zinc atom in catalytic site of HDACs. In the research for more potent HDAC inhibitors, we replaced the epoxyketone moiety of Aoe with different functional groups and synthesized a series of chlamydocin analogs as HDAC inhibitors. Among the functional groups, methoxymethylketone moiety showed as potent inhibition as the hydroxamic acid. On the contrary, we confirmed that borate, trifruoromethylketone, and 2-aminoanilide are almost inactive in HDAC inhibition.

  DOI：

  10.1007/s00726-011-0947-6
• 作为产物：
  描述：

  N-苄氧羰基-L-苯丙氨酸 在 palladium on activated charcoal 、 氢气 、 1-羟基苯并三唑 、 N,N'-二环己基碳二亚胺 作用下， 以 溶剂黄146 、 N,N-二甲基甲酰胺 为溶剂， 反应 36.0h， 生成 Z-Aib-L-Phe-D-Pro-OtBu
  参考文献：
  名称：

  Evaluation of functional groups on amino acids in cyclic tetrapeptides in histone deacetylase inhibition

  摘要：

  The naturally occurring cyclic tetrapeptide, chlamydocin, originally isolated from fungus , consists of alpha-aminoisobutyric acid, -phenylalanine, -proline and an unusual amino acid ()-2-amino-8-(()-oxiran-2-yl)-8-oxooctanoic acid (Aoe) and inhibits the histone deacetylases (HDACs), a class of regulatory enzymes. The epoxyketone moiety of Aoe is the key functional group for inhibition. The cyclic tetrapeptide scaffold is supposed to play important role for effective binding to the surface of enzymes. In place of the epoxyketone group, hydroxamic acid and sulfhydryl group have been applied to design inhibitor ligands to zinc atom in catalytic site of HDACs. In the research for more potent HDAC inhibitors, we replaced the epoxyketone moiety of Aoe with different functional groups and synthesized a series of chlamydocin analogs as HDAC inhibitors. Among the functional groups, methoxymethylketone moiety showed as potent inhibition as the hydroxamic acid. On the contrary, we confirmed that borate, trifruoromethylketone, and 2-aminoanilide are almost inactive in HDAC inhibition.

  DOI：

  10.1007/s00726-011-0947-6

文献信息

• Chlamydocin–hydroxamic acid analogues as histone deacetylase inhibitors
  作者：Norikazu Nishino、Binoy Jose、Ryuzo Shinta、Tamaki Kato、Yasuhiko Komatsu、Minoru Yoshida

  DOI：10.1016/j.bmc.2004.08.041

  日期：2004.11

  Chlamydocin-hydroxamic acid analogues were designed and synthesized as histone deacetylase (HDAC) inhibitors based on the structure and HDAC inhibitory activity of chlamydocin and trichostatin A. Chlamydocin is a cyclic tetrapeptide containing an epoxyketone moiety in the side chain that makes it an irreversible inhibitor of HDAC. We replaced the epoxyketone moiety of chlamydocin with hydroxamic acid to

  根据衣原霉素和曲古抑菌素A的结构和HDAC抑制活性，设计并合成了衣原霉素-异羟肟酸类似物作为组蛋白脱乙酰基酶（HDAC）抑制剂。衣原霉素是环状四肽，在侧链中含有环氧酮部分，使其成为不可逆抑制剂。 HDAC。我们用异羟肟酸代替了衣原体的环氧酮部分，以设计有效且可逆的HDAC抑制剂。另外，对于一系列衣藻多菌素类似物系列，引入了许多氨基-环烷羧酸（Acc）而不是简单的氨基-异丁酸（Aib）。测试了所合成的化合物的HDAC抑制活性，结果表明其中许多是HDAC的有效抑制剂。用芳香族氨基酸代替衣原体的Aib残基增强了体内和体外的抑制活性。我们已经对衣原霉素-异羟肟酸类似物进行了圆二色性和分子模拟研究，并将其与衣原霉素的溶液结构进行了比较。
• Novel cyclic tetrapeptide derivatives and pharmaceutical uses thereof
  申请人：Japan Energy Corporation

  公开号：US20020120099A1

  公开（公告）日：2002-08-29

  The present invention provides a cyclic tetrapeptide derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof: 1 wherein each of R 21 and R 22 independently denotes hydrogen, a linear C 1 -C 6 -alkyl group to which a non-aromatic cycloalkyl group or an optionally substituted aromatic ring may be attached, or a branched C 3 -C 6 -alkyl group to which a non-aromatic cycloalkyl group or an optionally substituted aromatic ring may be attached; and each of R 1 and R 3 independently denotes a linear C 1 -C 5 -alkylene group which may have a C 1 -C 6 side chain, in which the side chain may form a condensed ring structure on the alkylene chain. The present invention also provides a histone deacetylase inhibitor, an MHC class-I molecule expression-promoting agent and a pharmaceutical composition, each of which comprises the above cyclic tetrapeptide derivative or pharmaceutically acceptable salt thereof as an active ingredient.

  本发明提供了以下通式（I）所表示的环状四肽衍生物或其药学上可接受的盐： 其中，R21和R22各自独立地表示氢、线性的C1-C6烷基，其中可以连接非芳香环烷基或可选取代芳香环，或者支链的C3-C6烷基，其中可以连接非芳香环烷基或可选取代芳香环；R1和R3各自独立地表示线性的C1-C5亚基，该亚基可以具有C1-C6侧链，其中侧链可以在烷基链上形成紧缩环结构。 本发明还提供一种组蛋白去乙酰化酶抑制剂、一种MHC-I分子表达促进剂和一种制药组合物，其中每种制剂包含上述环状四肽衍生物或其药学上可接受的盐作为活性成分。
• Cyclic tetrapeptide derivatives and pharmaceutical uses thereof
  申请人：Sumitomo Pharmaceuticals Company, Limited

  公开号：US06825317B2

  公开（公告）日：2004-11-30

  The present invention provides a cyclic tetrapeptide derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof: wherein each of R21 and R22 independently denotes hydrogen, a linear C1-C6-alkyl group to which a non-aromatic cycloalkyl group or an optionally substituted aromatic ring may be attached, or a branched C3-C6-alkyl group to which a non-aromatic cycloalkyl group or an optionally substituted aromatic ring may be attached; and each of R1 and R3 independently denotes a linear C1-C5-alkylene group which may have a C1-C6 side chain, in which the side chain may form a condensed ring structure on the alkylene chain. The present invention also provides a histone deacetylase inhibitor, an MHC class-I molecule expression-promoting agent and a pharmaceutical composition, each of which comprises the above cyclic tetrapeptide derivative or pharmaceutically acceptable salt thereof as an active ingredient.

  本发明提供了下列一般式(I)所表示的环四肽衍生物或其药学上可接受的盐：其中，R21和R22各自独立地表示氢、线性的C1-C6烷基，该烷基可以连接一个非芳香环烷基或一个可选择取代的芳香环；或者一个支链的C3-C6烷基，该烷基可以连接一个非芳香环烷基或一个可选择取代的芳香环；R1和R3各自独立地表示线性的C1-C5烷基，该烷基可以具有C1-C6侧链，在该侧链上可以形成缩合环结构的烷基链上。本发明还提供了一种组蛋白去乙酰化酶抑制剂、一种MHC-I分子表达促进剂和一种药物组合物，每种药物组合物都包括上述环四肽衍生物或药学上可接受的盐作为活性成分。
• Chlamydocin analogs bearing carbonyl group as possible ligand toward zinc atom in histone deacetylases
  作者：Mohammed P.I. Bhuiyan、Tamaki Kato、Tatsuo Okauchi、Norikazu Nishino、Satoko Maeda、Tomonori G. Nishino、Minoru Yoshida

  DOI：10.1016/j.bmc.2005.12.063

  日期：2006.5

  A series of chlamydocin analogs with various carbonyl functionalities were designed and synthesized as histone deacetylase (HDAC) inhibitors. Chlamyclocin is a cyclic tetrapeptide containing an epoxyketone surrogate in the side chain which makes it irreversible inhibitor of HDACs, whereas apicidins are a class of cyclic tetrapeptides that contain an ethylketone moiety as zinc ligand. We replaced the epoxyketone moiety of chlamydocin with several ketones and aldehyde to synthesize potent reversible and selective HDAC inhibitors. The inhibitory activity of the cyclic tetrapeptides against histone deacetylase enzymes were evaluated and the result showed most of them are potent inhibitors. Some of them have remarkable selectivity among the HDACs. (c) 2006 Published by Elsevier Ltd.