hept-6-en-1-oyl-L-valine-L-phenylalanine-hexahydropyridazine-3S-carboxylic acid hexa-3,5-dienyl ester | 247186-18-1

• 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: hept-6-en-1-oyl-L-valine-L-phenylalanine-hexahydropyridazine-3S-carboxylic acid hexa-3,5-dienyl ester
• 英文别名: [(3E)-hexa-3,5-dienyl] (3S)-1-[(2S)-2-[[(2S)-2-(hept-6-enoylamino)-3-methylbutanoyl]amino]-3-phenylpropanoyl]diazinane-3-carboxylate
• CAS: 247186-18-1
• 化学式: C₃₂H₄₆N₄O₅
• 分子量: 566.741
• InChiKey: DMEWGRGGNMAWTQ-MTOYMOEQSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.7
• 重原子数：
  41
• 可旋转键数：
  18
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  117
• 氢给体数：
  3
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  hept-6-en-1-oyl-L-valine-L-phenylalanine-hexahydropyridazine-3S-carboxylic acid hexa-3,5-dienyl ester 在 Grubbs catalyst first generation 作用下， 以 二氯甲烷 为溶剂， 以57%的产率得到(13E,15E)-(3S,6S,21S)-3-benzyl-6-isopropyl-19-oxa-1,4,7,25-tetraaza-bicyclo[19.3.1]pentacosa-13,15-diene-2,5,8,20-tetraone
  参考文献：
  名称：

  Sanglifehrin−Cyclophilin Interaction:  Degradation Work, Synthetic Macrocyclic Analogues, X-ray Crystal Structure, and Binding Data

  摘要：

  Sanglifehrin A (SFA) is a novel immunosuppressive natural product isolated from Streptomyces sp. A92-308110. SFA has a very strong affinity for cyclophilin A (IC50 = 6.9 +/- 0.9 nM) but is structurally different from cyclosporin A (CsA) and exerts its immunosuppressive activity via a novel mechanism. SFA has a complex molecular structure consisting of a 22-membered macrocycle, bearing in position 23 a nine-carbon tether terminated by a highly substituted spirobicyclic moiety. Selective oxidative cleavage of the C-26=C-27 exocyclic double bond affords the spirolactam containing fragment 1 and macrolide 2. The affinity of 2 for cyclophilin (IC50 = 29 +/- 2.1 nM) is essentially identical to SFA, which indicates that the interaction between SFA and cyclophilin A is mediated exclusively by the macrocyclic portion of the molecule. This observation was confirmed by the X-ray crystal structure resolved at 2.1 Angstrom of cyclophilin A complexed to macrolide 16, a close analogue of 2. The X-ray crystal structure showed that macrolide 16 binds to the same deep hydrophobic pocket of cyclophilin A as CsA. Additional valuable details of the structure-activity relationship were obtained by two different chemical approaches: (1) degradation work on macrolide 2 or (2) synthesis of a library of macrolide analogues using the ring-closing metathesis reaction as the key step. Altogether, it appears that the complex macrocyclic fragment of SFA is a highly optimized combination of multiple functionalities including an (E,E)-diene, a short polypropionate fragment, and an unusual tripeptide unit, which together provide an extremely strong affinity for cyclophilin A.

  DOI：

  10.1021/ja021327y
• 作为产物：
  描述：

  6-庚烯酸 在 N-甲基吗啉 、 lithium hydroxide 、 三苯基膦 、 偶氮二甲酸二乙酯 作用下， 以 四氢呋喃 为溶剂， 反应 0.5h， 生成 hept-6-en-1-oyl-L-valine-L-phenylalanine-hexahydropyridazine-3S-carboxylic acid hexa-3,5-dienyl ester
  参考文献：
  名称：

  Sanglifehrin−Cyclophilin Interaction:  Degradation Work, Synthetic Macrocyclic Analogues, X-ray Crystal Structure, and Binding Data

  摘要：

  Sanglifehrin A (SFA) is a novel immunosuppressive natural product isolated from Streptomyces sp. A92-308110. SFA has a very strong affinity for cyclophilin A (IC50 = 6.9 +/- 0.9 nM) but is structurally different from cyclosporin A (CsA) and exerts its immunosuppressive activity via a novel mechanism. SFA has a complex molecular structure consisting of a 22-membered macrocycle, bearing in position 23 a nine-carbon tether terminated by a highly substituted spirobicyclic moiety. Selective oxidative cleavage of the C-26=C-27 exocyclic double bond affords the spirolactam containing fragment 1 and macrolide 2. The affinity of 2 for cyclophilin (IC50 = 29 +/- 2.1 nM) is essentially identical to SFA, which indicates that the interaction between SFA and cyclophilin A is mediated exclusively by the macrocyclic portion of the molecule. This observation was confirmed by the X-ray crystal structure resolved at 2.1 Angstrom of cyclophilin A complexed to macrolide 16, a close analogue of 2. The X-ray crystal structure showed that macrolide 16 binds to the same deep hydrophobic pocket of cyclophilin A as CsA. Additional valuable details of the structure-activity relationship were obtained by two different chemical approaches: (1) degradation work on macrolide 2 or (2) synthesis of a library of macrolide analogues using the ring-closing metathesis reaction as the key step. Altogether, it appears that the complex macrocyclic fragment of SFA is a highly optimized combination of multiple functionalities including an (E,E)-diene, a short polypropionate fragment, and an unusual tripeptide unit, which together provide an extremely strong affinity for cyclophilin A.

  DOI：

  10.1021/ja021327y

文献信息

• Macrolide Analogues of the Novel Immunosuppressant Sanglifehrin: New Application of the Ring-Closing Metathesis Reaction
  作者：Luisa M. Martin Cabrejas、Stefan Rohrbach、Dieter Wagner、Jörg Kallen、Gerhard Zenke、Jürgen Wagner

  DOI：10.1002/(sici)1521-3773(19990816)38:16<2443::aid-anie2443>3.0.co;2-b

  日期：1999.8.16

  Macrocycles containing a conjugated 1,3-diene moiety have been synthesized for the first time in good yields by the ring-closing metathesis reaction [Eq. (1)]. The new compounds represent cyclophilin-binding, simplified analogues of the macrocyclic core of sanglifehrin A, an immunosuppressant which binds with high affinity to cyclophilin.
• Synthesis of Macrolide Analogues of Sanglifehrin by RCM:  Unique Reactivity of a Ruthenium Carbene Complex Bearing an Imidazol-2-ylidene Ligand
  作者：Jürgen Wagner、Luisa M. Martin Cabrejas、Catharine E. Grossmith、Charles Papageorgiou、Francesco Senia、Dieter Wagner、Julien France、Steven P. Nolan

  DOI：10.1021/jo001296u

  日期：2000.12.1
• Sanglifehrin−Cyclophilin Interaction:  Degradation Work, Synthetic Macrocyclic Analogues, X-ray Crystal Structure, and Binding Data
  作者：Richard Sedrani、Jörg Kallen、Luisa M. Martin Cabrejas、Charles D. Papageorgiou、Francesco Senia、Stefan Rohrbach、Dieter Wagner、Binh Thai、Anne-Marie Jutzi Eme、Julien France、Lukas Oberer、Grety Rihs、Gerhard Zenke、Jürgen Wagner

  DOI：10.1021/ja021327y

  日期：2003.4.1

  Sanglifehrin A (SFA) is a novel immunosuppressive natural product isolated from Streptomyces sp. A92-308110. SFA has a very strong affinity for cyclophilin A (IC50 = 6.9 +/- 0.9 nM) but is structurally different from cyclosporin A (CsA) and exerts its immunosuppressive activity via a novel mechanism. SFA has a complex molecular structure consisting of a 22-membered macrocycle, bearing in position 23 a nine-carbon tether terminated by a highly substituted spirobicyclic moiety. Selective oxidative cleavage of the C-26=C-27 exocyclic double bond affords the spirolactam containing fragment 1 and macrolide 2. The affinity of 2 for cyclophilin (IC50 = 29 +/- 2.1 nM) is essentially identical to SFA, which indicates that the interaction between SFA and cyclophilin A is mediated exclusively by the macrocyclic portion of the molecule. This observation was confirmed by the X-ray crystal structure resolved at 2.1 Angstrom of cyclophilin A complexed to macrolide 16, a close analogue of 2. The X-ray crystal structure showed that macrolide 16 binds to the same deep hydrophobic pocket of cyclophilin A as CsA. Additional valuable details of the structure-activity relationship were obtained by two different chemical approaches: (1) degradation work on macrolide 2 or (2) synthesis of a library of macrolide analogues using the ring-closing metathesis reaction as the key step. Altogether, it appears that the complex macrocyclic fragment of SFA is a highly optimized combination of multiple functionalities including an (E,E)-diene, a short polypropionate fragment, and an unusual tripeptide unit, which together provide an extremely strong affinity for cyclophilin A.