(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) | 1001060-44-1

• 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: (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)
• 英文别名: (3S,6S,10aS)-N-[(S)-[1-[4-[4-[4-[4-[(S)-[[(3S,6S,10aS)-6-[[(2S)-2-acetamido-3-(1H-indol-3-yl)propanoyl]amino]-5-oxo-2,3,6,7,8,9,10,10a-octahydro-1H-pyrrolo[1,2-a]azocine-3-carbonyl]amino]-phenylmethyl]triazol-1-yl]butyl]phenyl]butyl]triazol-4-yl]-phenylmethyl]-6-[[(2S)-2-acetamido-3-(1H-indol-3-yl)propanoyl]amino]-5-oxo-2,3,6,7,8,9,10,10a-octahydro-1H-pyrrolo[1,2-a]azocine-3-carboxamide
• CAS: 1001060-44-1
• 化学式: C₈₀H₉₄N₁₆O₈
• 分子量: 1407.73
• InChiKey: KCRWCGKTNLNFIB-VUHFQLKMSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  8.7
• 重原子数：
  104
• 可旋转键数：
  28
• 环数：
  13.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  308
• 氢给体数：
  8
• 氢受体数：
  12

反应信息

• 作为产物：
  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

文献信息

• Design, Synthesis, and Characterization of a Potent, Nonpeptide, Cell-Permeable, Bivalent Smac Mimetic That Concurrently Targets Both the BIR2 and BIR3 Domains in XIAP
  作者：Haiying Sun、Zaneta Nikolovska-Coleska、Jianfeng Lu、Jennifer L. Meagher、Chao-Yie Yang、Su Qiu、York Tomita、Yumi Ueda、Sheng Jiang、Krzysztof Krajewski、Peter P. Roller、Jeanne A. Stuckey、Shaomeng Wang

  DOI：10.1021/ja074725f

  日期：2007.12.1

  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.