(1S,3S)-2-(3-tert-butoxycarbonylamino-1-hydroxy-4-methylpentyl)thiazole-4-carboxylic acid ethyl ester | 944559-55-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: (1S,3S)-2-(3-tert-butoxycarbonylamino-1-hydroxy-4-methylpentyl)thiazole-4-carboxylic acid ethyl ester
• 英文别名: ethyl 2-((1S,3S)-3-(tert-butoxycarbonylamino)-1-hydroxy-4-methylpentyl)thiazole-4-carboxylate；ethyl 2-[(1S,3S)-1-hydroxy-4-methyl-3-[(2-methylpropan-2-yl)oxycarbonylamino]pentyl]-1,3-thiazole-4-carboxylate
• CAS: 944559-55-1
• 化学式: C₁₇H₂₈N₂O₅S
• 分子量: 372.486
• InChiKey: GRYMFJTXVBVTGF-AAEUAGOBSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  25
• 可旋转键数：
  10
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.71
• 拓扑面积：
  126
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  (1S,3S)-2-(3-tert-butoxycarbonylamino-1-hydroxy-4-methylpentyl)thiazole-4-carboxylic acid ethyl ester 在 N-羟基-7-氮杂苯并三氮唑 、 lithium hydroxide monohydrate 、 水 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 、 N,N-二异丙基乙胺 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 作用下， 以 四氢呋喃 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 16.0h， 生成 (2S,4R)-methyl 4-(2-((1S,3S)-1-hydroxy-4-methyl-3-((2S,3S)-3-methyl-2-((R)-1-methylpiperidine-2-carboxamido)pentanamido)pentyl)thiazole-4-carboxamido)-2-methyl-5-phenylpentanoate
  参考文献：
  名称：

  Synthesis and cytotoxicity evaluation of diastereoisomers and N-terminal analogues of tubulysin-U

  摘要：

  Tubulysins are potent anti-mitotic natural compounds and a scalable and efficient synthetic route for generation of its analogues has been developed and extended to the synthesis of diastereoisomers and N-terminal analogues of tubulysin-U. Structure-activity-relationship studies on these synthetic analogues reaffirmed the significance of native stereochemistry of tubulysins for optimal biological activity and cytotoxicity. However, while modification of Tup stereochemistry has only minor effect on the tubulysins cytotoxicity, Tuv stereochemistry is critically important and modification of either Tuv stereo-centre produced a dramatic drop in cytotoxicity. (C) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.tetlet.2013.09.010
• 作为产物：
  描述：

  乙基2-乙酰基-1,3-噻唑-4-羧酸酯 在 dimethyl sulfide borane 、 sodium hydride 、 (S)-2-甲基-CBS-恶唑硼烷 作用下， 以 四氢呋喃 、 mineral oil 为溶剂， 反应 5.75h， 生成 (1S,3S)-2-(3-tert-butoxycarbonylamino-1-hydroxy-4-methylpentyl)thiazole-4-carboxylic acid ethyl ester
  参考文献：
  名称：

  Synthesis and structure–activity relationship studies of novel tubulysin U analogues – effect on cytotoxicity of structural variations in the tubuvaline fragment

  摘要：

  Tubulysins是一种细胞毒性天然产物，具有有前景的抗癌特性，最初从粘细菌培养物中分离出来。在结构上，Tubulysins是四肽，包含三个不寻常的（Mep、Tuv和Tup）和一个蛋白质原生的氨基酸（Ile）。在这里，我们描述了新型Tubulysin U和V类似物的合成及其构效关系研究，这些类似物在中央Tuv片段上有所变化，该片段对于Tubulysins的效力和细胞毒性至关重要，但在先前的研究中很少被修改。具体而言，我们用其他结构相关的基团替代了天然的异丙基和乙酰氧基功能。总的来说，与天然Tubulysin U相比，新的类似物显示出较低的效力。然而，其中一个合成类似物（1f）具有MOM功能替代乙酰基，在HT-29细胞系上显示出22 nM的IC50，与Tubulysin U（3.8 nM）显示的IC50相当。此外，本文报道的合成方法被发现足够灵活，可以提供不同核心修饰的Tubulysin类似物，因此可以被视为产生新型Tubulysins类似物的可扩展和便捷策略。

  DOI：

  10.1039/c3ob27111k

文献信息

• Total Synthesis of Tubulysins U and V
  作者：Monica Sani、Giacomo Fossati、Florent Huguenot、Matteo Zanda

  DOI：10.1002/anie.200604557

  日期：2007.5.4
• Synthesis and structure–activity relationship studies of novel tubulysin U analogues – effect on cytotoxicity of structural variations in the tubuvaline fragment
  作者：Sreejith P. Shankar、Monika Jagodzinska、Luciana Malpezzi、Paolo Lazzari、Ilaria Manca、Iain R. Greig、Monica Sani、Matteo Zanda

  DOI：10.1039/c3ob27111k

  日期：——

  Tubulysins are cytotoxic natural products with promising anti-cancer properties, originally isolated from myxobacterial cultures. Structurally, tubulysins are tetrapeptides, incorporating three unusual (Mep, Tuv and Tup) and one proteinogenic amino acid (Ile). Here we describe the synthesis and structure–activity relationship studies of novel tubulysin U and V analogues, with variations in the central Tuv fragment, which is known to be of paramount importance for tubulysins’ potency and hence cytotoxicity, but has seldom been modified in previous studies. Specifically, we replaced the natural iso-propyl and acetoxy functionalities with other structurally related groups. In general, the new analogues showed much lower potency relative to native tubulysin U. However, one of the synthetic analogues (1f) having a MOM function replacing the acetyl group exhibited a 22 nM IC50 on the HT-29 cell line which is comparable to the IC50 displayed by tubulysin U (3.8 nM). Furthermore, the synthetic methodology reported herein was found to be flexible enough to deliver different core-modified tubulysin analogues and hence may be regarded as a scalable and convenient strategy for the chemical generation of novel tubulysin analogues.

  Tubulysins是一种细胞毒性天然产物，具有有前景的抗癌特性，最初从粘细菌培养物中分离出来。在结构上，Tubulysins是四肽，包含三个不寻常的（Mep、Tuv和Tup）和一个蛋白质原生的氨基酸（Ile）。在这里，我们描述了新型Tubulysin U和V类似物的合成及其构效关系研究，这些类似物在中央Tuv片段上有所变化，该片段对于Tubulysins的效力和细胞毒性至关重要，但在先前的研究中很少被修改。具体而言，我们用其他结构相关的基团替代了天然的异丙基和乙酰氧基功能。总的来说，与天然Tubulysin U相比，新的类似物显示出较低的效力。然而，其中一个合成类似物（1f）具有MOM功能替代乙酰基，在HT-29细胞系上显示出22 nM的IC50，与Tubulysin U（3.8 nM）显示的IC50相当。此外，本文报道的合成方法被发现足够灵活，可以提供不同核心修饰的Tubulysin类似物，因此可以被视为产生新型Tubulysins类似物的可扩展和便捷策略。
• Synthesis and cytotoxicity evaluation of diastereoisomers and N-terminal analogues of tubulysin-U
  作者：P. Sreejith Shankar、Serena Bigotti、Paolo Lazzari、Ilaria Manca、Marco Spiga、Monica Sani、Matteo Zanda

  DOI：10.1016/j.tetlet.2013.09.010

  日期：2013.11

  Tubulysins are potent anti-mitotic natural compounds and a scalable and efficient synthetic route for generation of its analogues has been developed and extended to the synthesis of diastereoisomers and N-terminal analogues of tubulysin-U. Structure-activity-relationship studies on these synthetic analogues reaffirmed the significance of native stereochemistry of tubulysins for optimal biological activity and cytotoxicity. However, while modification of Tup stereochemistry has only minor effect on the tubulysins cytotoxicity, Tuv stereochemistry is critically important and modification of either Tuv stereo-centre produced a dramatic drop in cytotoxicity. (C) 2013 Elsevier Ltd. All rights reserved.