grassypeptolide A | 1010433-25-6

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 肽模拟物
• 英文名称: grassypeptolide A
• 英文别名: grassypeptolide；(2R,5R,9R,12S,18S,21S,24R,25R,28R,31R,34R)-9,21-dibenzyl-2-ethyl-28-[(1R)-1-hydroxyethyl]-10,19,24,25,32-pentamethyl-31-(2-methylpropyl)-18-propan-2-yl-22-oxa-7,36-dithia-3,10,16,19,26,29,32,37,38-nonazatetracyclo[32.2.1.15,8.012,16]octatriaconta-1(37),8(38)-diene-4,11,17,20,23,27,30,33-octone
• CAS: 1010433-25-6
• 化学式: C₅₆H₇₉N₉O₁₀S₂
• 分子量: 1102.43
• InChiKey: KUUZFDUZAFJFSJ-IHTUVIFUSA-N

物化性质

• 沸点：
  1266.6±65.0 °C(Predicted)
• 密度：
  1.33±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  6.5
• 重原子数：
  77
• 可旋转键数：
  9
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.61
• 拓扑面积：
  290
• 氢给体数：
  4
• 氢受体数：
  14

反应信息

• 作为反应物：
  描述：

  grassypeptolide A 在 ruthenium trichloride 、 sodium periodate 、 盐酸 作用下， 以 四氯化碳 、 水 、 乙腈 为溶剂， 反应 17.0h， 生成 N-甲基-L-苯丙氨酸 、 N-甲基-D-苯丙氨酸
  参考文献：
  名称：

  Grassypeptolides A−C, Cytotoxic Bis-thiazoline Containing Marine Cyclodepsipeptides

  摘要：

  Grassypeptolides A-C (1-3), a group of closely related bis-thiazoline containing cyclic depsipeptides, have been isolated from extracts of the marine cyanobacterium Lyngbya confervoides. Although structural differences between the analogues are minimal, comparison of the in vitro cytotoxicity of the series revealed a structure-activity relationship. When the ethyl substituent of 1 is changed to a methyl substituent in 2, activity is only slightly reduced (3-4-fold), whereas inversion of the Phe unit flanking the bis-thiazoline moiety results in 16-23-fold greater potency. We show that both 1 and 3 cause G1 phase cell cycle arrest at lower concentrations, followed at higher concentrations by G2/M phase arrest, and that these compounds bind Cu2+. and Zn2+. The three-dimensional structure of 2 was determined by MS, NMR, and X-ray crystallography, and the structure of 3 was established by MS, NMR, and chemical degradation. The structure of 3 was explored by in silico molecular modeling, revealing subtle differences in overall conformation between 1 and 3. Attempts to interconvert 1 and 3 with base were unsuccessful, but enzymatic conversion may be possible and could be a novel form of activation for chemical defense.

  DOI：

  10.1021/jo1013564
• 作为产物：
  描述：

  在 ammonium acetate 、 锌 作用下， 以 四氢呋喃 为溶剂， 反应 1.0h， 以6.8 mg的产率得到grassypeptolide A
  参考文献：
  名称：

  草pe内酯A的全合成及生物评价

  摘要：

  在本文中，我们全面描述了草皮肽A（1）分17线性步长，总收率为11.3％。特别是，这项工作的特点是后期引​​入了敏感的双（噻唑啉）杂环和在空间拥挤的仲酰胺位点进行了出色的转化（72％收率）的31元大环化。生物学评估表明，草肽内酯A以剂量依赖的方式显着抑制癌细胞的增殖。它诱导癌细胞凋亡，这与聚（ADP-核糖）聚合酶（PARP）的切割增加和bcl-2和bcl-xL的表达降低有关。此外，草肽A还通过增加G1期的细胞和减少S期和G2期的细胞而引起细胞周期的重新分布。另外，细胞周期停滞与细胞周期蛋白D的下调以及p27和p21的上调相关。

  DOI：

  10.1002/chem.201203667

文献信息

• Total Synthesis and Biological Evaluation of Grassypeptolide A
  作者：Hui Liu、Yuqing Liu、Zhuo Wang、Xiangyou Xing、Anita R. Maguire、Hendrik Luesch、Hui Zhang、Zhengshuang Xu、Tao Ye

  DOI：10.1002/chem.201203667

  日期：2013.5.17

  investigations into the synthesis of grassypeptolide A (1) in 17 linear steps with an overall yield of 11.3 %. In particular, this work features the late‐stage introduction of sensitive bis(thiazoline) heterocycles and 31‐membered macrocyclization conducted at the sterically congested secondary amide site in superb conversion (72 % yield). Biological evaluation indicated that grassypeptolide A significantly

  在本文中，我们全面描述了草皮肽A（1）分17线性步长，总收率为11.3％。特别是，这项工作的特点是后期引​​入了敏感的双（噻唑啉）杂环和在空间拥挤的仲酰胺位点进行了出色的转化（72％收率）的31元大环化。生物学评估表明，草肽内酯A以剂量依赖的方式显着抑制癌细胞的增殖。它诱导癌细胞凋亡，这与聚（ADP-核糖）聚合酶（PARP）的切割增加和bcl-2和bcl-xL的表达降低有关。此外，草肽A还通过增加G1期的细胞和减少S期和G2期的细胞而引起细胞周期的重新分布。另外，细胞周期停滞与细胞周期蛋白D的下调以及p27和p21的上调相关。
• Grassypeptolides A−C, Cytotoxic Bis-thiazoline Containing Marine Cyclodepsipeptides
  作者：Jason C. Kwan、Ranjala Ratnayake、Khalil A. Abboud、Valerie J. Paul、Hendrik Luesch

  DOI：10.1021/jo1013564

  日期：2010.12.3

  Grassypeptolides A-C (1-3), a group of closely related bis-thiazoline containing cyclic depsipeptides, have been isolated from extracts of the marine cyanobacterium Lyngbya confervoides. Although structural differences between the analogues are minimal, comparison of the in vitro cytotoxicity of the series revealed a structure-activity relationship. When the ethyl substituent of 1 is changed to a methyl substituent in 2, activity is only slightly reduced (3-4-fold), whereas inversion of the Phe unit flanking the bis-thiazoline moiety results in 16-23-fold greater potency. We show that both 1 and 3 cause G1 phase cell cycle arrest at lower concentrations, followed at higher concentrations by G2/M phase arrest, and that these compounds bind Cu2+. and Zn2+. The three-dimensional structure of 2 was determined by MS, NMR, and X-ray crystallography, and the structure of 3 was established by MS, NMR, and chemical degradation. The structure of 3 was explored by in silico molecular modeling, revealing subtle differences in overall conformation between 1 and 3. Attempts to interconvert 1 and 3 with base were unsuccessful, but enzymatic conversion may be possible and could be a novel form of activation for chemical defense.