(5R)-7-[(1R)-1-benzyloxycarbonyl-3-methylbutyl]-6-oxo-1-pyruvyl-1,7-diazaspiro[4.4]nonane | 387823-69-0

• 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: (5R)-7-[(1R)-1-benzyloxycarbonyl-3-methylbutyl]-6-oxo-1-pyruvyl-1,7-diazaspiro[4.4]nonane
• 英文别名: benzyl (2R)-4-methyl-2-[(5R)-6-oxo-1-(2-oxopropanoyl)-1,7-diazaspiro[4.4]nonan-7-yl]pentanoate
• CAS: 387823-69-0
• 化学式: C₂₃H₃₀N₂O₅
• 分子量: 414.502
• InChiKey: UMTCLJCBIGJMEY-AUSIDOKSSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  30
• 可旋转键数：
  8
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.57
• 拓扑面积：
  84
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (5R)-7-[(1R)-1-benzyloxycarbonyl-3-methylbutyl]-6-oxo-1-pyruvyl-1,7-diazaspiro[4.4]nonane 在 palladium on activated charcoal N-甲基吗啉 、 N-羟基-7-氮杂苯并三氮唑 、 氢气 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 作用下， 以 甲醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， -5.0~20.0 ℃ 、101.33 kPa 条件下， 反应 17.0h， 生成 (hydroxyisovaleric acid)-[(5R)-7-[(1R)-1-carbonyl-3-methylbutyl]-6-oxo-1-pyruvyl-1,7-diazaspiro[4.4]nonane^7-9]aplidine
  参考文献：
  名称：

  Synthesis, Conformational Analysis, and Cytotoxicity of Conformationally Constrained Aplidine and Tamandarin A Analogues Incorporating a Spirolactam β-Turn Mimetic

  摘要：

  With the aim of studying the contribution of the beta II turn conformation at the side chain of didemnins to the bioactive conformation responsible for their antitumoral activity, conformationally restricted analogues of aplidine and tamandarin A, where the side chain dipeptide Pro(8)-N-Me-D-Leu(7) is replaced with the spirolactam beta II turn mimetic (5R)-7-[(1R)-1-carbonyl-methylbutyl]-6-oxo-1,7-diazaspiro[4.4]nonane, were prepared. Additionally, restricted analogues, where the aplidine (pyruvyl(9)) or tamandarin A [(S)-Lac(9)] acyl groups are replaced with the isobutyryl, Boc, and 2-methylacryloyl groups, were also prepared. These structural modifications were detrimental to cytotoxic activity, leading to a decrease of 1-2 orders of magnitude with respect to that exhibited by aplidine and tamandarin A. The conformational analysis of one of these spirolactam aplidine analogues, by NMR and molecular modeling methods, showed that the conformational restriction caused by the spirolactam. does not produce significant changes in the overall conformation of aplidine, apart from preferentially stabilizing the trans rotamer at the pyruvyl(9)-spirolactam amide bond, whereas in aplidine both cis and trans rotamers at the pyruvyl(9)-Pro(8) amide bond are more or less equally stabilized. These results seem to indicate a preference for the cis form at that amide bond in the bioactive conformation of aplidine. The significant influence of this cis/trans isomerism upon the cytotoxicity suggests a possible participation of a peptidylprolyl cis/trans isomerase in the mechanism of action of aplidine.

  DOI：

  10.1021/jm040788m
• 作为产物：
  描述：

  丙酮酸 、 (5R)-7-[(1R)-1-benzyloxycarbonyl-3-methylbutyl]-6-oxo-1,7-diazaspiro[4.4]nonane trifluoroacetate 在 N-甲基吗啉 、 N-羟基-7-氮杂苯并三氮唑 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 作用下， 以 二氯甲烷 为溶剂， 反应 24.0h， 以47%的产率得到(5R)-7-[(1R)-1-benzyloxycarbonyl-3-methylbutyl]-6-oxo-1-pyruvyl-1,7-diazaspiro[4.4]nonane
  参考文献：
  名称：

  Synthesis, Conformational Analysis, and Cytotoxicity of Conformationally Constrained Aplidine and Tamandarin A Analogues Incorporating a Spirolactam β-Turn Mimetic

  摘要：

  With the aim of studying the contribution of the beta II turn conformation at the side chain of didemnins to the bioactive conformation responsible for their antitumoral activity, conformationally restricted analogues of aplidine and tamandarin A, where the side chain dipeptide Pro(8)-N-Me-D-Leu(7) is replaced with the spirolactam beta II turn mimetic (5R)-7-[(1R)-1-carbonyl-methylbutyl]-6-oxo-1,7-diazaspiro[4.4]nonane, were prepared. Additionally, restricted analogues, where the aplidine (pyruvyl(9)) or tamandarin A [(S)-Lac(9)] acyl groups are replaced with the isobutyryl, Boc, and 2-methylacryloyl groups, were also prepared. These structural modifications were detrimental to cytotoxic activity, leading to a decrease of 1-2 orders of magnitude with respect to that exhibited by aplidine and tamandarin A. The conformational analysis of one of these spirolactam aplidine analogues, by NMR and molecular modeling methods, showed that the conformational restriction caused by the spirolactam. does not produce significant changes in the overall conformation of aplidine, apart from preferentially stabilizing the trans rotamer at the pyruvyl(9)-spirolactam amide bond, whereas in aplidine both cis and trans rotamers at the pyruvyl(9)-Pro(8) amide bond are more or less equally stabilized. These results seem to indicate a preference for the cis form at that amide bond in the bioactive conformation of aplidine. The significant influence of this cis/trans isomerism upon the cytotoxicity suggests a possible participation of a peptidylprolyl cis/trans isomerase in the mechanism of action of aplidine.

  DOI：

  10.1021/jm040788m

文献信息

• Synthetic methods for aplidine and new antitumoral derivatives, methods of making and using them
  申请人：——

  公开号：US20040097413A1

  公开（公告）日：2004-05-20

  The invention provides aplidine derivatives and synthetic methods.

  该发明提供了 aplidine 衍生物及其合成方法。
• SYNTHETIC METHODS FOR APLIDINE AND NEW ANTITUMORAL DERIVATIVES, METHODS OF MAKING AND USING THEM
  申请人：PHARMA MAR, S.A.

  公开号：EP1294747B1

  公开（公告）日：2008-04-30
• US7348310B2
  申请人：——

  公开号：US7348310B2

  公开（公告）日：2008-03-25
• US7678765B2
  申请人：——

  公开号：US7678765B2

  公开（公告）日：2010-03-16
• Synthesis, Conformational Analysis, and Cytotoxicity of Conformationally Constrained Aplidine and Tamandarin A Analogues Incorporating a Spirolactam β-Turn Mimetic
  作者：Marta Gutiérrez-Rodríguez、Mercedes Martín-Martínez、M. Teresa García-López、Rosario Herranz、Félix Cuevas、Concepción Polanco、Ignacio Rodríguez-Campos、Ignacio Manzanares、Francisco Cárdenas、Miguel Feliz、Paul Lloyd-Williams、Ernest Giralt

  DOI：10.1021/jm040788m

  日期：2004.11.1

  With the aim of studying the contribution of the beta II turn conformation at the side chain of didemnins to the bioactive conformation responsible for their antitumoral activity, conformationally restricted analogues of aplidine and tamandarin A, where the side chain dipeptide Pro(8)-N-Me-D-Leu(7) is replaced with the spirolactam beta II turn mimetic (5R)-7-[(1R)-1-carbonyl-methylbutyl]-6-oxo-1,7-diazaspiro[4.4]nonane, were prepared. Additionally, restricted analogues, where the aplidine (pyruvyl(9)) or tamandarin A [(S)-Lac(9)] acyl groups are replaced with the isobutyryl, Boc, and 2-methylacryloyl groups, were also prepared. These structural modifications were detrimental to cytotoxic activity, leading to a decrease of 1-2 orders of magnitude with respect to that exhibited by aplidine and tamandarin A. The conformational analysis of one of these spirolactam aplidine analogues, by NMR and molecular modeling methods, showed that the conformational restriction caused by the spirolactam. does not produce significant changes in the overall conformation of aplidine, apart from preferentially stabilizing the trans rotamer at the pyruvyl(9)-spirolactam amide bond, whereas in aplidine both cis and trans rotamers at the pyruvyl(9)-Pro(8) amide bond are more or less equally stabilized. These results seem to indicate a preference for the cis form at that amide bond in the bioactive conformation of aplidine. The significant influence of this cis/trans isomerism upon the cytotoxicity suggests a possible participation of a peptidylprolyl cis/trans isomerase in the mechanism of action of aplidine.