(3E,5S,8S)-8-amino-5-propan-2-yl-1,6-diazacyclododec-3-ene-2,7-dione | 1350879-58-1

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 大环内酰胺类
• 英文名称: (3E,5S,8S)-8-amino-5-propan-2-yl-1,6-diazacyclododec-3-ene-2,7-dione
• CAS: 1350879-58-1
• 化学式: C₁₃H₂₃N₃O₂
• 分子量: 253.345
• InChiKey: LFLNIIGEVDYWHM-FQLSZKSXSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.31
• 重原子数：
  18.0
• 可旋转键数：
  1.0
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.69
• 拓扑面积：
  84.22
• 氢给体数：
  3.0
• 氢受体数：
  3.0

反应信息

• 作为反应物：
  描述：

  (3E,5S,8S)-8-amino-5-propan-2-yl-1,6-diazacyclododec-3-ene-2,7-dione 、 (S)-methyl 2-(3-((S)-1-((2,5-dioxopyrrolidin-1-yl)oxy)-1-oxo-3-phenylpropan-2-yl)ureido)-3-methylbutanoate 在 MP-carbonate resin 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 18.33h， 生成 (S)-methyl 2-(3-((S)-1-(((5S,8S,E)-5-isopropyl-2,7-dioxo-1,6-diazacyclododec-3-en-8-yl)amino)-1-oxo-3-phenylpropan-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：

  N-alpha-Cbz-L-赖氨酸 在 四甲基乙二胺 、 benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate 、 氢溴酸 、 zinc trifluoromethanesulfonate 、 sodium carbonate 、 1-羟基苯并三唑 、 戴斯-马丁氧化剂 、 溶剂黄146 、 三乙胺 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 二氯甲烷 、 水 为溶剂， 反应 40.33h， 生成 (3E,5S,8S)-8-amino-5-propan-2-yl-1,6-diazacyclododec-3-ene-2,7-dione
  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

文献信息

• [EN] NOVEL SYRINGOLIN ANALOGUES AND METHODS OF MAKING AND USING SAME<br/>[FR] NOUVEAUX ANALOGUES DE SYRINGOLINE ET PROCÉDÉS DE FABRICATION ET D'UTILISATION DE CEUX-CI
  申请人：UNIV BROWN

  公开号：WO2016182968A1

  公开（公告）日：2016-11-17

  The present invention provides, in certain aspects, novel syringolin analogues, In certain embodiments, the compounds of the invention are proteasome inhibitors, In other embodiments, the compounds treat or prevent a cancer such as, but not limited to, leukemia in a subject,

  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。
• Total Synthesis of Syringolin A and B
  作者：Michael C. Pirrung、Goutam Biswas、Tannya R. Ibarra-Rivera

  DOI：10.1021/ol100761z

  日期：2010.5.21

  Total syntheses of two recently discovered proteasome inhibitors, syringolin A and B, are reported. The key to our approach was creation of the α,β-unsaturated 12-membered lactam via intramolecular Horner−Wadsworth−Emmons reaction. Such reactions have been broadly used to prepared macrolactones, but this work presents a rarer example of its application to macrolactams. The final steps involved attachment

  据报道，两种最近发现的蛋白酶体抑制剂丁香脂素A和丁香酚B的总合成。我们方法的关键是通过分子内Horner-Wadsworth-Emmons反应生成α，β-不饱和12元内酰胺。这种反应已被广泛用于制备大内酯，但是这项工作为大内酰胺提供了一个罕见的例子。最终步骤包括使用肽偶联方法，包括基于未保护的缬氨酸N-羧酸酐的方法连接双（戊烯基）脲侧链。通过交叉复分解产生了丁香环素A的另外的烯烃。