(3S,6S,10aS)-6-((S)-2-acetamido-3-(1H-indol-3-yl)propanamido)-5-oxo-N-((R)-1-phenylprop-2-ynyl)decahydropyrrolo[1,2-a]azocine-3-carboxamide | 1001060-47-4

• 英文名称: (3S,6S,10aS)-6-((S)-2-acetamido-3-(1H-indol-3-yl)propanamido)-5-oxo-N-((R)-1-phenylprop-2-ynyl)decahydropyrrolo[1,2-a]azocine-3-carboxamide
• CAS: 1001060-47-4
• 化学式: C₃₃H₃₇N₅O₄
• 分子量: 567.688
• InChiKey: DXBJRMOJOJQCES-AAAUCYHNSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.12
• 重原子数：
  42.0
• 可旋转键数：
  8.0
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.39
• 拓扑面积：
  123.4
• 氢给体数：
  4.0
• 氢受体数：
  4.0

反应信息

• 作为反应物：
  描述：

  1,4-bis-(4-azidobutyl)benzene 、 (3S,6S,10aS)-6-((S)-2-acetamido-3-(1H-indol-3-yl)propanamido)-5-oxo-N-((R)-1-phenylprop-2-ynyl)decahydropyrrolo[1,2-a]azocine-3-carboxamide 在 copper(II) sulfate 作用下， 以 水 、 叔丁醇 为溶剂， 以76%的产率得到(S,3S,3'S,6S,6'S,10aS,10a'S)-N,N'-((1S,1'S)-(1,1'-(4,4'-(1,4-phenylene)bis(butane-4,1-diyl))bis(1H-1,2,3-triazole-4,1-diyl))bis(phenylmethylene))bis(6-((S)-2-acetamido-3-(1H-indol-3-yl)propanamido)-5-oxodecahydropyrrolo[1,2-a]azocine-3-carboxamide)
  参考文献：
  名称：

  Design, Synthesis, and Characterization of a Potent, Nonpeptide, Cell-Permeable, Bivalent Smac Mimetic That Concurrently Targets Both the BIR2 and BIR3 Domains in XIAP

  摘要：

  XIAP is a central apoptosis regulator that inhibits apoptosis by binding to and inhibiting the effectors caspase-3/-7 and an initiator caspase-9 through its BIR2 and BIR3 domains, respectively. Smac protein in its dimeric form effectively antagonizes XIAP by concurrently, targeting both its BIR2 and BIR3 domains. We report the design, synthesis, and characterization of a nonpeptide, cell-permeable, bivalent small-molecule (SM-164) which mimics Smac protein for targeting XIAP. Our study shows that SM-164 binds to XIAP containing both BIR domains with an IC50 value of 1.39 nM, being 300 and 7000 times more potent than its monovalent counterparts and the natural Smac AVPI peptide, respectively. SM-164 concurrently interacts with both BIR domains in XIAP and functions as an ultrapotent antagonist of XIAP in both cell-free functional and cell-based assays. SM-164 targets cellular XIAP and effectively induces apoptosis at concentrations as low as 1 nM in the HL-60 leukemia cell line. The potency of bivalent SM-164 in binding, functional, and cellular assays is 2-3 orders of magnitude higher than its corresponding monovalent Smac mimetics.

  DOI：

  10.1021/ja074725f
• 作为产物：
  描述：

  、 乙酸酐 在 N,N-二异丙基乙胺 作用下， 以379 mg的产率得到(3S,6S,10aS)-6-((S)-2-acetamido-3-(1H-indol-3-yl)propanamido)-5-oxo-N-((R)-1-phenylprop-2-ynyl)decahydropyrrolo[1,2-a]azocine-3-carboxamide
  参考文献：
  名称：

  Design, Synthesis, and Characterization of a Potent, Nonpeptide, Cell-Permeable, Bivalent Smac Mimetic That Concurrently Targets Both the BIR2 and BIR3 Domains in XIAP

  摘要：

  XIAP is a central apoptosis regulator that inhibits apoptosis by binding to and inhibiting the effectors caspase-3/-7 and an initiator caspase-9 through its BIR2 and BIR3 domains, respectively. Smac protein in its dimeric form effectively antagonizes XIAP by concurrently, targeting both its BIR2 and BIR3 domains. We report the design, synthesis, and characterization of a nonpeptide, cell-permeable, bivalent small-molecule (SM-164) which mimics Smac protein for targeting XIAP. Our study shows that SM-164 binds to XIAP containing both BIR domains with an IC50 value of 1.39 nM, being 300 and 7000 times more potent than its monovalent counterparts and the natural Smac AVPI peptide, respectively. SM-164 concurrently interacts with both BIR domains in XIAP and functions as an ultrapotent antagonist of XIAP in both cell-free functional and cell-based assays. SM-164 targets cellular XIAP and effectively induces apoptosis at concentrations as low as 1 nM in the HL-60 leukemia cell line. The potency of bivalent SM-164 in binding, functional, and cellular assays is 2-3 orders of magnitude higher than its corresponding monovalent Smac mimetics.

  DOI：

  10.1021/ja074725f

文献信息

• Potent Bivalent Smac Mimetics: Effect of the Linker on Binding to Inhibitor of Apoptosis Proteins (IAPs) and Anticancer Activity
  作者：Haiying Sun、Liu Liu、Jianfeng Lu、Longchuan Bai、Xiaoqin Li、Zaneta Nikolovska-Coleska、Donna McEachern、Chao-Yie Yang、Su Qiu、Han Yi、Duxin Sun、Shaomeng Wang

  DOI：10.1021/jm101651b

  日期：2011.5.12

  We have synthesized and evaluated a series of nonpeptidic, bivalent Smac mimetics as antagonists of the inhibitor of apoptosis proteins and new anticancer agents. All these bivalent Smac mimetics bind to full-length XIAP with low nanomolar affinities and function as ultrapotent antagonists of XIAP. While these Smac mimetics bind to cIAP1/2 with similar low nanomolar affinities, their potencies to induce degradation of cIAP1/2 proteins in cells differ by more than 100-fold. The most potent bivalent Smac mimetics inhibit cell growth with IC(50) from 1 to 3 nM in the MDA-MB-231 breast cancer cell line and are 100 times more potent than the least potent compounds. Determination of intracellular concentrations for several representative compounds showed that the linkers in these bivalent Smac mimetics significantly affect their intracellular concentrations and hence the overall cellular activity. Compound 27 completely inhibits tumor growth in the MDA-MB-231 xenografts while causing no signs of toxicity in the animals.