ethyl 2-((1R,3R)-3-(tert-butoxycarbonylamino)-1-hydroxy-4-methylpentyl)thiazole-4-carboxylate | 944559-48-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: ethyl 2-((1R,3R)-3-(tert-butoxycarbonylamino)-1-hydroxy-4-methylpentyl)thiazole-4-carboxylate
• 英文别名: Ethyl 2-((1R,3R)-3-((tert-butoxycarbonyl)amino)-1-hydroxy-4-methylpentyl)thiazole-4-carboxylate；ethyl 2-[(1R,3R)-1-hydroxy-4-methyl-3-[(2-methylpropan-2-yl)oxycarbonylamino]pentyl]-1,3-thiazole-4-carboxylate
• CAS: 944559-48-2
• 化学式: C₁₇H₂₈N₂O₅S
• 分子量: 372.486
• InChiKey: GRYMFJTXVBVTGF-DGCLKSJQSA-N

物化性质

• 熔点：
  118-120 °C
• 沸点：
  500.6±50.0 °C(Predicted)
• 密度：
  1.166±0.06 g/cm3(Predicted)

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：

  ethyl 2-((1R,3R)-3-(tert-butoxycarbonylamino)-1-hydroxy-4-methylpentyl)thiazole-4-carboxylate 在 咪唑 、 三氟乙酸 作用下， 以 甲醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 15.17h， 生成
  参考文献：
  名称：

  The Multiple Multicomponent Approach to Natural Product Mimics: Tubugis, N-Substituted Anticancer Peptides with Picomolar Activity

  摘要：

  The synthesis of a new generation of highly cytotoxic tubulysin analogues (i.e., tubugis) is described. In the key step, the rare, unstable, and synthetically difficult to introduce tertiary amide-N,O-acetal moiety required for high potency in natural tubulysins is replaced by a dipeptoid element formed in an Ugi four-component reaction. Two of the four components required are themselves produced by other multicomponent reactions (MCRs). Thus, the tubugis represent the first examples of the synthesis of natural-product-inspired compounds using three intertwined isonitrile MCRs.

  DOI：

  10.1021/ja2022027
• 作为产物：
  描述：

  N-羟基氨基甲酸叔丁酯 在 dimethyl sulfide borane 、 sodium hydride 、 1,8-二氮杂双环[5.4.0]十一碳-7-烯 、 (S)-2-甲基-CBS-恶唑硼烷 、 molybdenum hexacarbonyl 作用下， 以 四氢呋喃 、 水 、 乙腈 、 mineral oil 为溶剂， 反应 24.33h， 生成 ethyl 2-((1R,3R)-3-(tert-butoxycarbonylamino)-1-hydroxy-4-methylpentyl)thiazole-4-carboxylate
  参考文献：
  名称：

  WO2020132658A5

  摘要：

  公开号：

  WO2020132658A5

文献信息

• 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。
• Tubulysin analogues
  申请人：Wessjohann Ludger A.

  公开号：US09371358B2

  公开（公告）日：2016-06-21

  The present invention relates to novel tubulysin compounds (tubulysin analogs) as well as pharmaceutical formulations thereof. The present invention further relates to the use of such compounds for medicinal, agricultural, biotool or cosmetic applications. In particular, the novel tubulysin analogs show a cytostatic effect and can therefore be used for the treatment of proliferative disorders. The tertiary amide moiety of the tubulysin analogs (so-called tubugis) according to the present invention is generated by an Ugi-type reaction.

  本发明涉及新型的管肽素化合物（管肽素类似物）以及其药物配方。本发明进一步涉及这些化合物在药用、农业、生物工具或化妆品应用中的使用。特别是，这些新型的管肽素类似物显示出细胞静止效应，因此可用于治疗增生性疾病。根据本发明，管肽素类似物（即所谓的管肽）的三级酰胺基团是通过Ugi型反应生成的。
• 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.
• 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
• [EN] TUBULYSINS AND PROTEIN-TUBULYSIN CONJUGATES<br/>[FR] TUBULYSINES ET CONJUGUÉS TUBULYSINES-PROTÉINES
  申请人：REGENERON PHARMA

  公开号：WO2021262910A3

  公开（公告）日：2022-04-21