N-methyl leucyl leucine methyl ester | 100076-30-0

• 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: N-methyl leucyl leucine methyl ester
• 英文别名: methyl (2S)-4-methyl-2-[[(2S)-4-methyl-2-(methylamino)pentanoyl]amino]pentanoate
• CAS: 100076-30-0
• 化学式: C₁₄H₂₈N₂O₃
• 分子量: 272.388
• InChiKey: OXWUUKIXOPBUEZ-RYUDHWBXSA-N

物化性质

• 沸点：
  378.2±22.0 °C(Predicted)
• 密度：
  0.974±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  19
• 可旋转键数：
  9
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.86
• 拓扑面积：
  67.4
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  N-methyl leucyl leucine methyl ester 在 6-chloro-3-((dimethylamino)(dimethyliminio)methyl)-1H-benzo[d][1,2,3]triazol-3-ium-1-olatehexafluorophosphate(V) 、 lithium hydroxide monohydrate 、 5%-palladium/activated carbon 、 水 、 氢气 、 甲酸铵 、 N,N-二异丙基乙胺 、 三氟乙酸 作用下， 以 四氢呋喃 、 二氯甲烷 、 N,N-二甲基甲酰胺 、 叔丁醇 为溶剂， 反应 60.0h， 生成 (3R,6S,9S,12S,15R,18R,21S)-15-((R)-sec-butyl)-18-((R)-1-hydroxy-2-methylpropyl)-6,9-diisobutyl-1,3,4,10,12,13-hexamethyl-21-(4-(methylamino)butyl)-1,4,7,10,13,16,19-heptaazacyclohenicosane-2,5,8,11,14,17,20-heptaone
  参考文献：
  名称：

  Design, synthesis, and evaluation, derivatives of the fat-accumulation inhibitor ternatin: toward ternatin molecular probes

  摘要：

  Ternatin, a cyclic heptapeptide derived from mushroom, strongly inhibits fat accumulation in 3T3-L1 adipocytes. However, its mechanism of action remains unclear. In this Letter, we designed, synthesized, and evaluated its derivatives for use as molecular probes to isolate its target protein. Finally, we successfully established a pair of ternatin molecular probes. (C) 2014 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.tetlet.2014.06.036
• 作为产物：
  描述：

  Boc-N(Me)Leu-Leu-OMe 在 盐酸 作用下， 以 甲醇 为溶剂， 反应 2.0h， 生成 N-methyl leucyl leucine methyl ester
  参考文献：
  名称：

  Ternatin and improved synthetic variants kill cancer cells by targeting the elongation factor-1A ternary complex

  摘要：

  环肽天然产物的发展利用了多种蛋白质靶标，其中许多靶标控制着重要的细胞过程。受一系列结构已部分阐明的环肽的启发，我们设计出了具有细胞毒性和抗脂肪生成作用的天然产品 ternatin 的合成变体，而这种天然产品的分子作用模式尚不清楚。新的燕麦素变体对癌细胞具有细胞毒性，其效力比燕麦素本身高出 500 倍。利用特纳丁的光亲和探针，我们确定了翻译延伸因子-1A 三元复合物（eEF1A-GTP-氨基酰-tRNA）为特异性靶标，并证明了与之无关的天然产物--didemnin 和 cytotrienin 的竞争性结合。eEF1A 结构域 III 的突变阻止了 ternatin 的结合，并使其对细胞毒性效应产生抗性，这表明邻近的疏水表面是 eEF1A 调节的功能热点。我们的结论是，真核生物伸长因子-1A及其与 GTP 和氨基酰-tRNA 的三元复合物是细胞毒性天然产物进化的共同目标。

  DOI：

  10.7554/elife.10222

文献信息

• Convergent synthesis and in vivo inhibitory effect on fat accumulation of (−)-ternatin, a highly N-methylated cyclic peptide
  作者：Kenichiro Shimokawa、Kaoru Yamada、Masaki Kita、Daisuke Uemura

  DOI：10.1016/j.bmcl.2007.06.015

  日期：2007.8

  (-)-Ternatin (1), a highly N-methylated cyclic heptapeptide, is a potent inhibitor of fat accumulation against 3T3-LI murine adipocytes (EC50 = 0.14 mu g/mL) [Shimokawa, K.; Mashima, I.; Asai, A.; Yamada, K.; Kita, M.; Uemura, D. Tetrahedron Lett. 2006, 47, 4445]. Compound 1 was synthesized from Boc-protected amino acids in solution. Upon treatment with 1 at 5 mg/kg/day, increases in body weight and fat accumulation in high-fat-fied mice were both significantly suppressed. 0 2007 Elsevier Ltd. All rights reserved.

  (−)-Ternatin (1) 是一种高度N-甲基化的环状七肽，是针对 3T3-LI 小鼠脂肪细胞的强效脂肪积累抑制剂（EC50 = 0.14 μg/mL）[Shimokawa, K.; Mashima, I.; Asai, A.; Yamada, K.; Kita, M.; Uemura, D. Tetrahedron Lett. 2006, 47, 4445]。化合物 1 通过 Boc 保护的氨基酸在溶液中合成。在高脂饮食小鼠中，每天给予 5 mg/kg 的化合物 1 处理后，体重增加和脂肪积累均显著受到抑制。2007 Elsevier 有限公司。版权所有。
• Whole Structure−Activity Relationships of the Fat-Accumulation Inhibitor (−)-Ternatin: Recognition of the Importance of Each Amino Acid Residue
  作者：Kenichiro Shimokawa、Yoshiaki Iwase、Ryoka Miwa、Kaoru Yamada、Daisuke Uemura

  DOI：10.1021/jm800741n

  日期：2008.10.9

  A series of Ala and Aoc analogues of (-)-ternatin were prepared, and their bioactivities were assessed by a fat-accumulation inhibition assay using 3T3-L1 adipocytes, which led to the discovery of key structure-activity relationships (SAR).
• Design, synthesis, and evaluation, derivatives of the fat-accumulation inhibitor ternatin: toward ternatin molecular probes
  作者：Yoshinori Kawazoe、Yoko Tanaka、Sachikazu Omura、Daisuke Uemura

  DOI：10.1016/j.tetlet.2014.06.036

  日期：2014.8

  Ternatin, a cyclic heptapeptide derived from mushroom, strongly inhibits fat accumulation in 3T3-L1 adipocytes. However, its mechanism of action remains unclear. In this Letter, we designed, synthesized, and evaluated its derivatives for use as molecular probes to isolate its target protein. Finally, we successfully established a pair of ternatin molecular probes. (C) 2014 Elsevier Ltd. All rights reserved.
• Ternatin and improved synthetic variants kill cancer cells by targeting the elongation factor-1A ternary complex
  作者：Jordan D Carelli、Steven G Sethofer、Geoffrey A Smith、Howard R Miller、Jillian L Simard、William C Merrick、Rishi K Jain、Nathan T Ross、Jack Taunton

  DOI：10.7554/elife.10222

  日期：——

  Cyclic peptide natural products have evolved to exploit diverse protein targets, many of which control essential cellular processes. Inspired by a series of cyclic peptides with partially elucidated structures, we designed synthetic variants of ternatin, a cytotoxic and anti-adipogenic natural product whose molecular mode of action was unknown. The new ternatin variants are cytotoxic toward cancer cells, with up to 500-fold greater potency than ternatin itself. Using a ternatin photo-affinity probe, we identify the translation elongation factor-1A ternary complex (eEF1A·GTP·aminoacyl-tRNA) as a specific target and demonstrate competitive binding by the unrelated natural products, didemnin and cytotrienin. Mutations in domain III of eEF1A prevent ternatin binding and confer resistance to its cytotoxic effects, implicating the adjacent hydrophobic surface as a functional hot spot for eEF1A modulation. We conclude that the eukaryotic elongation factor-1A and its ternary complex with GTP and aminoacyl-tRNA are common targets for the evolution of cytotoxic natural products.

  环肽天然产物的发展利用了多种蛋白质靶标，其中许多靶标控制着重要的细胞过程。受一系列结构已部分阐明的环肽的启发，我们设计出了具有细胞毒性和抗脂肪生成作用的天然产品 ternatin 的合成变体，而这种天然产品的分子作用模式尚不清楚。新的燕麦素变体对癌细胞具有细胞毒性，其效力比燕麦素本身高出 500 倍。利用特纳丁的光亲和探针，我们确定了翻译延伸因子-1A 三元复合物（eEF1A-GTP-氨基酰-tRNA）为特异性靶标，并证明了与之无关的天然产物--didemnin 和 cytotrienin 的竞争性结合。eEF1A 结构域 III 的突变阻止了 ternatin 的结合，并使其对细胞毒性效应产生抗性，这表明邻近的疏水表面是 eEF1A 调节的功能热点。我们的结论是，真核生物伸长因子-1A及其与 GTP 和氨基酰-tRNA 的三元复合物是细胞毒性天然产物进化的共同目标。