Ac-Ile-Glu(tBu)-Thr(tBu)-Asp(tBu)-OH | 1007603-72-6

• 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: Ac-Ile-Glu(tBu)-Thr(tBu)-Asp(tBu)-OH
• 英文别名: Ac-IETD-OH；Ac-Ile-Glu(OtBu)(OtBu)-Thr(tBu)-Asp(OtBu)(OtBu)-OH；(2S)-2-[[(2S,3R)-2-[[(2S)-2-[[(2S,3S)-2-acetamido-3-methylpentanoyl]amino]-5-[(2-methylpropan-2-yl)oxy]-5-oxopentanoyl]amino]-3-[(2-methylpropan-2-yl)oxy]butanoyl]amino]-4-[(2-methylpropan-2-yl)oxy]-4-oxobutanoic acid
• CAS: 1007603-72-6
• 化学式: C₃₃H₅₈N₄O₁₁
• 分子量: 686.844
• InChiKey: DOMCHWIVKQOGOJ-GDROYEOXSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  48
• 可旋转键数：
  22
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.79
• 拓扑面积：
  216
• 氢给体数：
  5
• 氢受体数：
  11

反应信息

• 作为反应物：
  描述：

  Ac-Ile-Glu(tBu)-Thr(tBu)-Asp(tBu)-OH 、 香豆素 151 在 HATU 、 2,4,6-三叔丁基吡啶 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 120.0h， 生成
  参考文献：
  名称：

  荧光半胱天冬酶8四肽底物的合成，酶评价和对接研究。

  摘要：

  描述了对半胱天冬酶8具有选择性的新型荧光基四肽底物的合成，酶学评估和分子模型研究，该底物具有一般结构Ac-IETD-AXX。von Pechmann缩合反应合成了各种荧光报告基团（AXX），即3和4个取代的香豆素和quinolin-2（1 H ）-1 。随后在新开发的合成条件下将它们与caspase-8选择性四肽Ac-IETD-OH偶联，以高收率和高对映体纯度提供所需的底物。基于K M和V max值，新化合物被证明是重组人caspase 8的优良底物。相反， K M与人半胱天冬酶3的底物相同的化合物的值大约高10–20倍。基于人半胱氨酸蛋白酶3和8的X射线晶体结构的分子建模研究表明，两个活性位点中都有足够的空间容纳在荧光香豆素和喹啉3和4位中具有中等体积取代基的底物。 2（1小时）-那些。使用程序AutoDock 3将底物自动对接至人胱天蛋白酶3和8的活性位点，其结构类似于已公开的晶体学结

  DOI：

  10.1002/cmdc.200900356
• 作为产物：
  描述：

  Fmoc-O-叔丁基-L-谷氨酸 、 乙酸酐 、 Fmoc-L-异亮氨酸 、 Fmoc-O-叔丁基-L-苏氨酸 、 alkaline earth salt of/the/ methylsulfuric acid 生成 Ac-Ile-Glu(tBu)-Thr(tBu)-Asp(tBu)-OH
  参考文献：
  名称：

  Control of aspartate epimerization during the coupling of caspase specific tetrapeptides with aromatic amines by using N-[[(dimethylamino)-1H-1,2,3-triazolo[4,5-b]-pyridin-1-yl]methylene]-N-methylmethanaminium hexafluorophosphate N-oxide (HATU) as a coupling reagent

  摘要：

  During the synthesis of new caspase substrates, we have encountered extensive aspartate epimerization upon coupling of t-Bu-protected tetrapeptides Ac-IETD-OH or Ac-DMQD-OH with aromatic amines (aminocoumarins and aminoquinolines) by using aminium-based coupling reagent HATU in the presence of 2,4,6-trimethylpyridine (TMP). To study this reaction in more detail, an RP-HPLC method was developed that afforded the separation of the epimers. By carefully adjusting the reaction conditions, the epimerization could be reduced to very small levels (from 75% down to below 3%). A new, highly hindered base 2,4,6-tri-tert-butyl-pyridine (TBP), was found to be superior to the traditional TMP in the catalysis of this reaction. Moreover, the aspartate epimers were found to be interconvertable at elevated temperatures in an inert solvent, whereby the D-aspartate containing epimer was the thermodynamically controlled product. Over the Course of the study, new side products of HATU coupling reactions, the N,N-dimethylamides of the aspartic residue of above tetrapeptides, were also identified. (c) 2007 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.tetasy.2007.11.036

文献信息

• Tailored Zwitterionic Hemicyanine Reporters for Early Diagnosis and Prognostic Assessment of Acute Renal Failure
  作者：Ya Zhou、Lijuan Zhu、Biaoxiang Liu、Weiping Xu、Xingyue Yang、Yi Liu、Bankang Ruan、Shujuan Yi、Baoshuai Liang、Guoqi Dong、Jiaguo Huang

  DOI：10.1002/anie.202315457

  日期：2023.12.21

  Drug‐induced renal failure (DIRF) poses a serious medical complication with high mortality risk. However, early diagnosis or prognosis of DIRF remain challenging, as current methods rely on detecting late‐stage biomarkers. Herein we present a library of zwitterionic unimolecular hemicyanines (ZCs) available for constructing activatable reporters to detect DIRF since its initial stage. Zwitterionic properties of these probes are achieved through interspersedly integrating alkyl sulfonates and quaternary ammonium cations onto hemicyanine skeleton, which result in record low plasma protein binding (<5 %) and remarkable renal clearance efficiencies (≈96 %). An activatable reporter ZCRR is further developed by masking the optimal candidate ZC6 with a tetrapeptide specifically cleavable by caspase‐8, an initiating indicator of apoptosis. In living mice with cisplatin‐induced DIRF, systematically administered ZCRR efficiently accumulates in kidneys and responds to elevated caspase‐8 for near‐infrared fluorescence signals ‘turn‐on’, enabling sensitive detection of intrarenal apoptosis 60 h earlier than clinical methods, and precise evaluation of apoptosis remediation effects by different medications on DIRF mice. As it's urinary excretable, ZCRR also allows for remote detection of DIRF and predicting renoprotective efficacy through in vitro optical urinalysis. This study thus presents unimolecular renal clearable scaffolds that are applicable to developing versatile activatable reporters for renal diseases management.

  摘要药物诱发肾功能衰竭（DIRF）是一种严重的医疗并发症，死亡率很高。然而，DIRF 的早期诊断或预后仍然具有挑战性，因为目前的方法依赖于检测晚期生物标志物。在本文中，我们介绍了一个单分子半氰基齐聚物（ZCs）库，该库可用于构建可激活的报告物，以检测初期阶段的 DIRF。这些探针通过将烷基磺酸盐和季铵盐阳离子穿插整合到半氰胺骨架上实现了其具有的齐聚物特性，从而实现了创纪录的低血浆蛋白结合率（<5 %）和显著的肾清除率（≈96 %）。通过将最佳候选 ZC6 与一种可被细胞凋亡启动标志物--Caspase-8 特异性裂解的四肽进行掩蔽，进一步开发了一种可激活的报告基因 ZCRR。在顺铂诱导的DIRF活体小鼠中，系统给药的ZCRR会在肾脏中有效蓄积，并对升高的caspase-8做出反应，使近红外荧光信号 "开启"，从而比临床方法提前60小时灵敏地检测到肾脏内的细胞凋亡，并精确评估不同药物对DIRF小鼠的细胞凋亡补救效果。由于 ZCRR 可通过尿液排出，因此还可通过体外光学尿液分析法远程检测 DIRF 和预测肾脏保护效果。因此，本研究提出的单分子肾脏可清除支架适用于开发用于肾脏疾病管理的多功能可激活报告物。
• Synthesis, Enzymatic Evaluation, and Docking Studies of Fluorogenic Caspase 8 Tetrapeptide Substrates
  作者：Przemysław Reszka、Riad Schulz、Karen Methling、Michael Lalk、Patrick J. Bednarski

  DOI：10.1002/cmdc.200900356

  日期：2010.1.4

  give the desired substrates in good yields and in high enantiomeric purity. Based on KM and Vmax values, the new compounds proved to be excellent substrates for recombinant human caspase 8. In contrast, the KM values for the same compounds as substrates for human caspase 3 were approximately 10–20‐fold higher. Molecular modeling studies based on the X‐ray crystal structures of both human caspases 3 and

  描述了对半胱天冬酶8具有选择性的新型荧光基四肽底物的合成，酶学评估和分子模型研究，该底物具有一般结构Ac-IETD-AXX。von Pechmann缩合反应合成了各种荧光报告基团（AXX），即3和4个取代的香豆素和quinolin-2（1 H ）-1 。随后在新开发的合成条件下将它们与caspase-8选择性四肽Ac-IETD-OH偶联，以高收率和高对映体纯度提供所需的底物。基于K M和V max值，新化合物被证明是重组人caspase 8的优良底物。相反， K M与人半胱天冬酶3的底物相同的化合物的值大约高10–20倍。基于人半胱氨酸蛋白酶3和8的X射线晶体结构的分子建模研究表明，两个活性位点中都有足够的空间容纳在荧光香豆素和喹啉3和4位中具有中等体积取代基的底物。 2（1小时）-那些。使用程序AutoDock 3将底物自动对接至人胱天蛋白酶3和8的活性位点，其结构类似于已公开的晶体学结
• Control of aspartate epimerization during the coupling of caspase specific tetrapeptides with aromatic amines by using N-[[(dimethylamino)-1H-1,2,3-triazolo[4,5-b]-pyridin-1-yl]methylene]-N-methylmethanaminium hexafluorophosphate N-oxide (HATU) as a coupling reagent
  作者：Przemysław Reszka、Karen Methling、Michael Lalk、Zhou Xiao、Klaus Weisz、Patrick J. Bednarski

  DOI：10.1016/j.tetasy.2007.11.036

  日期：2008.1

  During the synthesis of new caspase substrates, we have encountered extensive aspartate epimerization upon coupling of t-Bu-protected tetrapeptides Ac-IETD-OH or Ac-DMQD-OH with aromatic amines (aminocoumarins and aminoquinolines) by using aminium-based coupling reagent HATU in the presence of 2,4,6-trimethylpyridine (TMP). To study this reaction in more detail, an RP-HPLC method was developed that afforded the separation of the epimers. By carefully adjusting the reaction conditions, the epimerization could be reduced to very small levels (from 75% down to below 3%). A new, highly hindered base 2,4,6-tri-tert-butyl-pyridine (TBP), was found to be superior to the traditional TMP in the catalysis of this reaction. Moreover, the aspartate epimers were found to be interconvertable at elevated temperatures in an inert solvent, whereby the D-aspartate containing epimer was the thermodynamically controlled product. Over the Course of the study, new side products of HATU coupling reactions, the N,N-dimethylamides of the aspartic residue of above tetrapeptides, were also identified. (c) 2007 Elsevier Ltd. All rights reserved.