Gallinamide A | 1208232-55-6

• 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: Gallinamide A
• 英文别名: [(2S)-1-[[(2S)-1-[[(E,2S)-5-[(2S)-3-methoxy-2-methyl-5-oxo-2H-pyrrol-1-yl]-5-oxopent-3-en-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl] (2S,3S)-2-(dimethylamino)-3-methylpentanoate
• CAS: 1208232-55-6
• 化学式: C₃₁H₅₂N₄O₇
• 分子量: 592.776
• InChiKey: ASRBKZHDORPEHO-KYJIWOQOSA-N

物化性质

• 沸点：
  747.8±60.0 °C(Predicted)
• 密度：
  1.11±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.2
• 重原子数：
  42
• 可旋转键数：
  17
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.71
• 拓扑面积：
  134
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  Gallinamide A 在 1% Pd on activated carbon 、 氢气 作用下， 以 乙醇 为溶剂， 生成 (S)-1-(((S)-1-(((S)-5-((S)-3-methoxy-2-methyl-5-oxo-2,5-dihydro-1H-pyrrol-1-yl)-5-oxopentan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)amino)-4-methyl-1-oxopentan-2-yl dimethyl-L-isoleucinate
  参考文献：
  名称：

  Gallinamide A类似物设计为半胱氨酸蛋白酶抑制剂人组织蛋白酶L和锥虫锥Cruzain。

  摘要：

  最初分离出具有适度抗疟疾活性的Gallinamide A，随后被重新分离，并表征为人半胱氨酸蛋白酶组织蛋白酶L的强效，选择性和不可逆抑制剂。分子对接鉴定出潜在的修饰以改善结合，将其合成为一组类似物。结果，该当前研究产生了针对组织蛋白酶L进行测试的最有效的没食子酰胺类似物（10，Ki = 0.0937±0.01 nM和kinact / Ki = 8 730 000）。从蛋白质结构和底物偏爱的角度来看，克鲁萨因是一种必需的锥虫克鲁兹半胱氨酸蛋白酶，具有高度同源性。我们的研究表明，没食子酰胺及其类似物在细胞内的鞭毛虫阶段中有效抑制克鲁萨因并对克鲁维氏酵母具有极强的毒性。活性最高的化合物5的IC50 = 5.1±1。

  DOI：

  10.1021/acs.jmedchem.9b00294
• 作为产物：
  描述：

  (S)-2-羟基-4-甲基戊酸甲酯 在 4-二甲氨基吡啶 、 1-羟基苯并三唑 、 O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 、 N,N-二异丙基乙胺 、 N,N'-二环己基碳二亚胺 、 三氟乙酸 、 lithium hydroxide 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 生成 Gallinamide A
  参考文献：
  名称：

  The Antimalarial Natural Product Symplostatin 4 Is a Nanomolar Inhibitor of the Food Vacuole Falcipains

  摘要：

  The marine natural product symplostatin 4 (Sym4) has been recognized as a potent antimalarial agent. However, its mode of action and, in particular, direct targets have to date remained elusive. We report a chemical synthesis of Sym4 and show that Sym4-treatment of P. falciparum-infected red blood cells (RBCs) results in the generation of a swollen food vacuole phenotype and a reduction of parasitemia at nanomolar concentrations. We furthermore demonstrate that Sym4 is a nanomolar inhibitor of the P. falciparum falcipains in infected RBCs, suggesting inhibition of the hemoglobin degradation pathway as Sym4's mode of action. Finally, we reveal a critical influence of the unusual methyl-methoxypyrrolinone (mmp) group of Sym4 for potent inhibition, indicating that Sym4 derivatives with such a mmp moiety might represent viable lead structures for the development of antimalarial falcipain inhibitors.

  DOI：

  10.1016/j.chembiol.2012.09.020

文献信息

• A novel Anti-Cancer Stem Cells compound optimized from the natural symplostatin 4 scaffold inhibits Wnt/β-catenin signaling pathway
  作者：Shuangwei Liu、Xian Gao、Lisong Zhang、Shuanglin Qin、Mingming Wei、Ning Liu、Rui Zhao、Benlong Li、Ye Meng、Gang Lin、Cheng Lu、Xinhua Liu、Maodun Xie、Tongtong Liu、Honggang Zhou、Min Qi、Guang Yang、Cheng Yang

  DOI：10.1016/j.ejmech.2018.06.046

  日期：2018.8

  Cancer stem cells (CSCs) are responsible for carcinogenesis, cancer progression, relapse, metastasis and drug resistance. Therefore, the development of drug molecules targeting CSCs plays a vital role in medicinal researching field. However, there are extremely rare molecules that selectively ablate CSCs. The research and development of drugs targeting CSCs is limited due to a lack of anti-CSCs lead

  癌症干细胞（CSC）负责癌变，癌症进展，复发，转移和耐药性。因此，靶向CSCs的药物分子的开发在医学研究领域中起着至关重要的作用。但是，有极少数的分子可以选择性地消融CSC。由于缺乏抗CSC的先导化合物，针对CSC的药物的研究和开发受到限制。在这项研究中，发现了一种抗CSCs铅化合物35b，该化合物衍生自Symplostatin 4的天然化学支架。该化合物在体外和体内均表现出对肿瘤生长的显着抑制作用。此外，35b可以显着减少黑色素瘤肿瘤球的数量，并降低ALDH +黑色素瘤细胞的百分比。进一步的机制研究表明，化合物35b可通过有效阻断Wnt /β-catenin信号传导途径消除黑色素瘤CSC。总的来说，我们的发现将为开发抗CSCs药物提供新颖的化学支架和分子设计的替代思路。
• Total Synthesis and Antimalarial Activity of Symplostatin 4
  作者：Trent Conroy、Jin T. Guo、Nicholas H. Hunt、Richard J. Payne

  DOI：10.1021/ol1024663

  日期：2010.12.3

  The first total synthesis of symplostatin 4, a marine cyanobacterium-derived natural product, is described. Notable features of the route include the efficient preparation of three key fragments and final assembly to the natural product via sequential imide and amide couplings. Symplostatin 4 was also demonstrated to possess significant antimalarial activity (ED50 of 74 nM against Plasmodium falciparum

  描述了Symplostatin 4（海洋蓝细菌衍生的天然产物）的第一个全合成。该路线的显着特征包括有效制备三个关键片段，并通过顺序的酰亚胺和酰胺偶联最终组装成天然产物。还证明了Symplostatin 4具有显着的抗疟活性（抗恶性疟原虫菌株3D7的ED 50为74 nM ）。
• Total Synthesis, Stereochemical Assignment, and Antimalarial Activity of Gallinamide A
  作者：Trent Conroy、Jin T. Guo、Roger G. Linington、Nicholas H. Hunt、Richard J. Payne

  DOI：10.1002/chem.201102538

  日期：2011.11.25

  The total synthesis and stereochemical assignment of gallinamide A, an antimalarial depsipeptide of cyanobacterial origin, is described. Synthesis of the four possible N‐terminal diastereoisomers of gallinamide A (including the natural product symplostatin 4) was achieved using a divergent strategy from a common imide fragment. The natural product and corresponding diastereoisomers were synthesized

  描述了没食子酰胺A（蓝细菌来源的抗疟疾十肽）的总合成和立体化学分配。胆碱酰胺A的四种可能的N端非对映异构体（包括天然产物symplostatin 4）的合成是通过从共同的酰亚胺片段中分离出来的策略实现的。天然产物和相应的非对映异构体以最长的线性步骤（共8步）合成，总收率为30-33％。四种合成的非对映异构体与分离的天然产物的比较NMR光谱研究表明，没食子酰胺A具有二甲基化的LN末端的异亮氨酰残基。因此，我们证明了没食子酰胺A在结构和立体化学上均与Symplostatin 4相同。还显示出没食子酰胺A及其N端非对映异构体对恶性疟原虫的3D7菌株具有显着的抗疟活性，其IC 50值在纳摩尔范围内。
• Design of Gallinamide A Analogs as Potent Inhibitors of the Cysteine Proteases Human Cathepsin L and <i>Trypanosoma cruzi</i> Cruzain
  作者：Paul D. Boudreau、Bailey W. Miller、Laura-Isobel McCall、Jehad Almaliti、Raphael Reher、Ken Hirata、Thu Le、Jair L. Siqueira-Neto、Vivian Hook、William H. Gerwick

  DOI：10.1021/acs.jmedchem.9b00294

  日期：2019.10.24

  reisolated and characterized as a potent, selective, and irreversible inhibitor of the human cysteine protease cathepsin L. Molecular docking identified potential modifications to improve binding, which were synthesized as a suite of analogs. Resultingly, this current study produced the most potent gallinamide analog yet tested against cathepsin L (10, Ki = 0.0937 ± 0.01 nM and kinact/Ki = 8 730 000). From a

  最初分离出具有适度抗疟疾活性的Gallinamide A，随后被重新分离，并表征为人半胱氨酸蛋白酶组织蛋白酶L的强效，选择性和不可逆抑制剂。分子对接鉴定出潜在的修饰以改善结合，将其合成为一组类似物。结果，该当前研究产生了针对组织蛋白酶L进行测试的最有效的没食子酰胺类似物（10，Ki = 0.0937±0.01 nM和kinact / Ki = 8 730 000）。从蛋白质结构和底物偏爱的角度来看，克鲁萨因是一种必需的锥虫克鲁兹半胱氨酸蛋白酶，具有高度同源性。我们的研究表明，没食子酰胺及其类似物在细胞内的鞭毛虫阶段中有效抑制克鲁萨因并对克鲁维氏酵母具有极强的毒性。活性最高的化合物5的IC50 = 5.1±1。
• The Antimalarial Natural Product Symplostatin 4 Is a Nanomolar Inhibitor of the Food Vacuole Falcipains
  作者：Sara Christina Stolze、Edgar Deu、Farnusch Kaschani、Nan Li、Bogdan I. Florea、Kerstin H. Richau、Tom Colby、Renier A.L. van der Hoorn、Hermen S. Overkleeft、Matthew Bogyo、Markus Kaiser

  DOI：10.1016/j.chembiol.2012.09.020

  日期：2012.12

  The marine natural product symplostatin 4 (Sym4) has been recognized as a potent antimalarial agent. However, its mode of action and, in particular, direct targets have to date remained elusive. We report a chemical synthesis of Sym4 and show that Sym4-treatment of P. falciparum-infected red blood cells (RBCs) results in the generation of a swollen food vacuole phenotype and a reduction of parasitemia at nanomolar concentrations. We furthermore demonstrate that Sym4 is a nanomolar inhibitor of the P. falciparum falcipains in infected RBCs, suggesting inhibition of the hemoglobin degradation pathway as Sym4's mode of action. Finally, we reveal a critical influence of the unusual methyl-methoxypyrrolinone (mmp) group of Sym4 for potent inhibition, indicating that Sym4 derivatives with such a mmp moiety might represent viable lead structures for the development of antimalarial falcipain inhibitors.