(S)-1-[(S)-2-((S)-2-amino-propionylamino)-3-methyl-butyryl]-pyrrolidine-2-carboxylic acid benzylamide | 642090-91-3

• 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)-1-[(S)-2-((S)-2-amino-propionylamino)-3-methyl-butyryl]-pyrrolidine-2-carboxylic acid benzylamide
• 英文别名: Smac peptido-mimetic 1；(2S)-1-[(2S)-2-[[(2S)-2-aminopropanoyl]amino]-3-methylbutanoyl]-N-benzylpyrrolidine-2-carboxamide
• CAS: 642090-91-3
• 化学式: C₂₀H₃₀N₄O₃
• 分子量: 374.483
• InChiKey: RFCQRRDVLMEWMG-XIRDDKMYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.4
• 重原子数：
  27
• 可旋转键数：
  7
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.55
• 拓扑面积：
  105
• 氢给体数：
  3
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  N-Boc-L-缬氨酸 、 (S)-1-[(S)-2-((S)-2-amino-propionylamino)-3-methyl-butyryl]-pyrrolidine-2-carboxylic acid benzylamide 在 三氟乙酸 、 1-羟基苯并三唑 、 O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 、 N,N-二异丙基乙胺 作用下， 以 二氯甲烷 、 DMF (N,N-dimethyl-formamide) 为溶剂， 反应 1.0h， 生成 [1-(2-tert-butoxycarbonylamino-3-methyl-butyryl)-5-phenethylcarbamoyl-pyrrolidin-3-yl]-carbamic acid 9H-fluoren-9-ylmethyl ester
  参考文献：
  名称：

  [EN] PEPTIDE INHIBITORS OF SMAC PROTEIN BINDING TO INHIBITOR OF APOPTOSIS PROTEINS (IAP)
  [FR] INHIBITEURS PEPTIDIQUES DE LA LIAISON DE LA PROTEINE SMAC AVEC LES PROTEINES INHIBITRICES DE L'APOPTOSE (IAP)

  摘要：

  本公开涉及式I（I）的XIAP抑制剂化合物，其中取代基如规范所述。这些创新化合物可用作治疗增殖性疾病，包括癌症的治疗剂。

  公开号：

  WO2004005248A1
• 作为产物：
  描述：

  L-脯氨酸苄酯盐酸盐 在 palladium on activated charcoal 盐酸 、 N-羟基-7-氮杂苯并三氮唑 、 PS-carbodiimide resin 、 三异丙基硅烷 、 N,N-二甲基乙酰胺 、 氢气 、 1-羟基苯并三唑 、 1-(3-二甲基氨基丙基)-3-乙基碳二亚胺 、 N,N-二异丙基乙胺 、 三氟乙酸 作用下， 以 1,4-二氧六环 、 甲醇 、 1,2-二氯乙烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 18.0h， 生成 (S)-1-[(S)-2-((S)-2-amino-propionylamino)-3-methyl-butyryl]-pyrrolidine-2-carboxylic acid benzylamide
  参考文献：
  名称：

  Discovery of Potent Antagonists of the Antiapoptotic Protein XIAP for the Treatment of Cancer

  摘要：

  Inhibitor of apoptosis (IAP) proteins are overexpressed in many cancers and have been implicated in tumor growth, pathogenesis, and resistance to chemo- or radiotherapy. On the basis of the NMR structure of a SMAC peptide complexed with the BIR3 domain of X-linked IAP (XIAP), a novel series of XIAP antagonists was discovered. The most potent compounds in this series bind to the baculovirus IAP repeat 3 (BIR3) domain of XIAP with single-digit nanomolar affinity and promote cell death in several human cancer cell lines. In a MDA-MB-231 breast cancer mouse xenograft model, these XIAP antagonists inhibited the growth of tumors. Close structural analogues that showed only weak binding to the XIAP-BIR3 domain were inactive in the cellular assays and showed only marginal in vivo activity. Our results are consistent with a mechanism in which ligands for the BIR3 domain of XIAP induce apoptosis by freeing up caspases. The present study validates the BIR3 domain of XIAP as a target and supports the use of small molecule XIAP antagonists as a potential therapy for cancers that overexpress XIAP.

  DOI：

  10.1021/jm040037k

文献信息

• SMAC Peptidomimetics and the Uses Thereof
  申请人：Wang Shaomeng

  公开号：US20100093645A1

  公开（公告）日：2010-04-15

  The invention relates to peptidomimetics of Smac which function as inhibitors of Inhibitor of Apoptosis Proteins. The invention also relates to the use of these peptidomimetics for inducing apoptotic cell death and for sensitizing cells to inducers of apoptosis.
• Discovery of Potent Antagonists of the Antiapoptotic Protein XIAP for the Treatment of Cancer
  作者：Thorsten K. Oost、Chaohong Sun、Robert C. Armstrong、Ali-Samer Al-Assaad、Stephen F. Betz、Thomas L. Deckwerth、Hong Ding、Steven W. Elmore、Robert P. Meadows、Edward T. Olejniczak、Andrew Oleksijew、Tilman Oltersdorf、Saul H. Rosenberg、Alexander R. Shoemaker、Kevin J. Tomaselli、Hua Zou、Stephen W. Fesik

  DOI：10.1021/jm040037k

  日期：2004.8.1

  Inhibitor of apoptosis (IAP) proteins are overexpressed in many cancers and have been implicated in tumor growth, pathogenesis, and resistance to chemo- or radiotherapy. On the basis of the NMR structure of a SMAC peptide complexed with the BIR3 domain of X-linked IAP (XIAP), a novel series of XIAP antagonists was discovered. The most potent compounds in this series bind to the baculovirus IAP repeat 3 (BIR3) domain of XIAP with single-digit nanomolar affinity and promote cell death in several human cancer cell lines. In a MDA-MB-231 breast cancer mouse xenograft model, these XIAP antagonists inhibited the growth of tumors. Close structural analogues that showed only weak binding to the XIAP-BIR3 domain were inactive in the cellular assays and showed only marginal in vivo activity. Our results are consistent with a mechanism in which ligands for the BIR3 domain of XIAP induce apoptosis by freeing up caspases. The present study validates the BIR3 domain of XIAP as a target and supports the use of small molecule XIAP antagonists as a potential therapy for cancers that overexpress XIAP.
• [EN] PEPTIDE INHIBITORS OF SMAC PROTEIN BINDING TO INHIBITOR OF APOPTOSIS PROTEINS (IAP)<br/>[FR] INHIBITEURS PEPTIDIQUES DE LA LIAISON DE LA PROTEINE SMAC AVEC LES PROTEINES INHIBITRICES DE L'APOPTOSE (IAP)
  申请人：NOVARTIS AG

  公开号：WO2004005248A1

  公开（公告）日：2004-01-15

  The present disclosure relates to XIAP inhibitor compounds of the formula I (I) wherein the substituents are as described in the specification. The inventive compounds are useful as therapeutic agents for the treatment of proliferative disorders, including cancer.

  本公开涉及式I（I）的XIAP抑制剂化合物，其中取代基如规范所述。这些创新化合物可用作治疗增殖性疾病，包括癌症的治疗剂。