methyl (2S)-3-methyl-2-[[(2S)-3-methyl-1-[(2-methylpropan-2-yl)oxy]-1-oxobutan-2-yl]carbamoylamino]butanoate | 1163728-43-5

• 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 (2S)-3-methyl-2-[[(2S)-3-methyl-1-[(2-methylpropan-2-yl)oxy]-1-oxobutan-2-yl]carbamoylamino]butanoate
• CAS: 1163728-43-5
• 化学式: C₁₆H₃₀N₂O₅
• 分子量: 330.425
• InChiKey: RBRLLYIJBUBNAM-RYUDHWBXSA-N

物化性质

• 沸点：
  453.7±30.0 °C(Predicted)
• 密度：
  1.045±0.06 g/cm3(Temp: 20 °C; Press: 760 Torr)(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  23
• 可旋转键数：
  9
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.81
• 拓扑面积：
  93.7
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  methyl (2S)-3-methyl-2-[[(2S)-3-methyl-1-[(2-methylpropan-2-yl)oxy]-1-oxobutan-2-yl]carbamoylamino]butanoate 在 甲酸 、 水 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 50.33h， 生成 (S)-methyl 2-(3-((S)-1-(((5S,8S,E)-2,7-dioxo-5-(3-(trifluoromethyl)benzyl)-1,6-diazacyclododec-3-en-8-yl)amino)-3-methyl-1-oxobutan-2-yl)ureido)-3-methylbutanoate
  参考文献：
  名称：

  Substrate-guided optimization of the syringolins yields potent proteasome inhibitors with activity against leukemia cell lines

  摘要：

  Natural products that inhibit the proteasome have been fruitful starting points for the development of drug candidates. Those of the syringolin family have been underexploited in this context. Using the published model for substrate mimicry by the syringolins and knowledge about the substrate preferences of the proteolytic subunits of the human proteasome, we have designed, synthesized, and evaluated syringolin analogs. As some of our analogs inhibit the activity of the proteasome with second-order rate constants 5-fold greater than that of the methyl ester of syringolin B, we conclude that the substrate mimicry model for the syringolins is valid. The improvements in in vitro potency and the activities of particular analogs against leukemia cell lines are strong bases for further development of the syringolins as anti-cancer drugs. (c) 2015 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2015.07.041
• 作为产物：
  描述：

  L-缬氨酸叔丁酯盐酸盐 、 (S)-(-)-2-异氰酰基-3-甲基丁酸 在 N,N-二异丙基乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 16.0h， 生成 methyl (2S)-3-methyl-2-[[(2S)-3-methyl-1-[(2-methylpropan-2-yl)oxy]-1-oxobutan-2-yl]carbamoylamino]butanoate
  参考文献：
  名称：

  [EN] NOVEL SYRINGOLIN ANALOGUES AND METHODS OF MAKING AND USING SAME
  [FR] NOUVEAUX ANALOGUES DE SYRINGOLINE ET PROCÉDÉS DE FABRICATION ET D'UTILISATION DE CEUX-CI

  摘要：

  本发明在某些方面提供了新颖的西林类似物。在某些实施方式中，本发明的化合物是蛋白酶体抑制剂。在其他实施方式中，这些化合物用于治疗或预防主体中的癌症，如但不限于白血病。

  公开号：

  WO2016182968A1

文献信息

• Discovery of a potent and highly β1 specific proteasome inhibitor from a focused library of urea-containing peptide vinyl sulfones and peptide epoxyketones
  作者：Wouter A. van der Linden、Lianne I. Willems、Tamer B. Shabaneh、Nan Li、Mark Ruben、Bogdan I. Florea、Gijs A. van der Marel、Markus Kaiser、Alexei F. Kisselev、Herman S. Overkleeft

  DOI：10.1039/c1ob06554h

  日期：——

  Syringolins, a class of natural products, potently and selectively inhibit the proteasome and show promising antitumour activity. To gain insight in the mode of action of syringolins, the ureido structural element present in syringolins is incorporated in oligopeptide vinyl sulfones and peptide epoxyketones yielding a focused library of potent new proteasome inhibitors. The distance of the ureido linkage with respect to the electrophilic trap strongly influences subunit selectivity within the proteasome. Compounds 13 and 15 are β5 selective and their potency exceeds that of syringolin A. In contrast, 5 may well be the most potent β1 selective compound active in living cells reported to date.

  甾环蛋白(syringolin)是一类天然产物，能强效且特异性地抑制蛋白酶体，并展现出有前景的抗肿瘤活性。为了深入了解甾环蛋白的作用机制，我们在寡肽乙烯砜和肽环氧酮中引入甾环蛋白中存在的脲环结构单元，从而产生了一系列强效的新型蛋白酶体抑制剂。脲环连接位点相对于亲电陷阱的距离，强烈影响蛋白酶体亚基的选择性。化合物13和15对β5亚基具有选择性，其效力超过了甾环蛋白A。相比之下，化合物5可能是迄今为止报道的在活细胞中活性最强的β1亚基选择性化合物。
• DEVELOPMENT OF A SYNTHESIS OF SYRINGOLIN A AND B AND DERIVATIVES THEREOF
  申请人：Kaiser Markus

  公开号：US20100022767A1

  公开（公告）日：2010-01-28

  The synthesis of syringolin A and B and derivatives thereof as well as to pharmaceutical compositions containing the syringolin A or B or derivatives thereof and the use of syringolin A and B and derivatives thereof for prophylaxis and treatment of cancer.

  合成Syringolin A和B及其衍生物，以及含有Syringolin A或B或其衍生物的药物组合物的用途，以及Syringolin A和B及其衍生物用于预防和治疗癌症。
• Convergent Synthesis and Biological Evaluation of Syringolin A and Derivatives as Eukaryotic 20S Proteasome Inhibitors
  作者：Jérôme Clerc、Barbara Schellenberg、Michael Groll、André S. Bachmann、Robert Huber、Robert Dudler、Markus Kaiser

  DOI：10.1002/ejoc.201000317

  日期：2010.7

  A convergent synthesis of SylA was developed and consists of the synthesis of a fully functionalized macrocycle, which is subsequently coupled with a urea moiety. For cyclization, ring-closing metathesis of a conformationally preorganized precursor was employed. The established synthetic route was then applied to the synthesis of SylA derivatives by using various peptidic side chains for decoration

  开发了 SylA 的会聚合成，由全功能化大环的合成组成，随后与尿素部分偶联。对于环化，采用构象预组织前体的闭环复分解。然后通过使用各种肽侧链修饰SylA大环，将建立的合成路线应用于SylA衍生物的合成。对所得的 SylA 类似物集合进行了蛋白酶体抑制测试，表明聚乙二醇化 SylA 衍生物是最有效的蛋白酶体抑制剂。