N,N'',N'''-tri-Boc-L-arginine N-succinimidyl ester | 187032-31-1

• 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,N'',N'''-tri-Boc-L-arginine N-succinimidyl ester
• 英文别名: Boc-Arg(Boc)₂-OSu；(2,5-dioxopyrrolidin-1-yl) (2S)-5-[bis[(2-methylpropan-2-yl)oxycarbonylamino]methylideneamino]-2-[(2-methylpropan-2-yl)oxycarbonylamino]pentanoate
• CAS: 187032-31-1
• 化学式: C₂₅H₄₁N₅O₁₀
• 分子量: 571.628
• InChiKey: YEHUGLCKOIHDLM-HNNXBMFYSA-N

物化性质

• 熔点：
  56-58 °C(Solv: ethanol (64-17-5))
• 密度：
  1.26±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.67
• 重原子数：
  40.0
• 可旋转键数：
  7.0
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.72
• 拓扑面积：
  191.03
• 氢给体数：
  3.0
• 氢受体数：
  10.0

反应信息

• 作为反应物：
  描述：

  N,N'',N'''-tri-Boc-L-arginine N-succinimidyl ester 在 potassium hydrogencarbonate 作用下， 以 四氢呋喃 、 水 为溶剂， 反应 11.0h， 生成 di(hexadecyl) N-(arginyl)glutamate bis(trifluoroacetate)
  参考文献：
  名称：

  pH-sensitive cationic lipopeptides for the design of drug-delivery systems

  摘要：

  Lipopeptides on the basis of L-glutamic acid and glutamine di- and monoesters with aliphatic alcohols of various lengths that contain L-arginine, L-ornithine, and L-lysine were synthesized. The behavior of these amphiphiles in aqueous medium was shown to depend on their structure.

  DOI：

  10.1134/s1068162006050025
• 作为产物：
  描述：

  L-精氨酸 在 三乙胺 、 sodium hydroxide 作用下， 以 四氢呋喃 、 甲醇 、 水 为溶剂， 反应 8.5h， 生成 N,N'',N'''-tri-Boc-L-arginine N-succinimidyl ester
  参考文献：
  名称：

  COMPOSITIONS AND METHODS FOR THE TREATMENT OF METABOLIC DISEASES

  摘要：

  该发明涉及公式I、公式II和公式III的化合物或其药用可接受的盐，以及其多晶型、溶剂合物、对映体、立体异构体和水合物。包括公式I、公式II或公式III化合物的有效量的药物组合物；以及用于治疗或预防代谢性疾病的方法可以制备成口服、颊内、直肠、局部、经皮、经粘膜、静脉、肠道、糖浆或注射剂。这些组合物可用于治疗苯丙酮尿症、心血管疾病、自闭症、注意力缺陷多动障碍、高血压、内皮功能障碍和慢性肾脏疾病。

  公开号：

  US20150291590A1

文献信息

• Functional profiling of adenylation domains in nonribosomal peptide synthetases by competitive activity-based protein profiling
  作者：Shota Kasai、Sho Konno、Fumihiro Ishikawa、Hideaki Kakeya

  DOI：10.1039/c5cc04953a

  日期：——

  Using a library of sulfamoyloxy-linked aminoacyl-AMP analogs, we describe competitive activity-based protein profiling to facilitate directly the functional prediction and assessment of adenylation domains in nonribosomal peptide synthetases in proteomic environments.

  利用磺胺氧基连接的氨酰-AMP类似物库，我们描述了竞争性活性蛋白质分析技术，以直接促进在蛋白质组学环境中对非核糖体肽合成酶中腺苷化结构域的功能预测和评估。
• Quinone-Amino Acid Conjugates Targeting Leishmania Amino Acid Transporters
  作者：Federica Prati、Adele Goldman-Pinkovich、Federica Lizzi、Federica Belluti、Roni Koren、Dan Zilberstein、Maria Laura Bolognesi

  DOI：10.1371/journal.pone.0107994

  日期：——

  The aim of the present study was to investigate the feasibility of targeting Leishmania transporters via appropriately designed chemical probes. Leishmania donovani, the parasite that causes visceral leishmaniasis, is auxotrophic for arginine and lysine and has specific transporters (LdAAP3 and LdAAP7) to import these nutrients. Probes 1–15 were originated by conjugating cytotoxic quinone fragments (II and III) with amino acids (i.e. arginine and lysine) by means of an amide linkage. The toxicity of the synthesized conjugates against Leishmania extracellular (promastigotes) and intracellular (amastigotes) forms was investigated, as well their inhibition of the relevant amino acid transporters. We observed that some conjugates indeed displayed toxicity against the parasites; in particular, 7 was identified as the most potent derivative (at concentrations of 1 µg/mL and 2.5 µg/mL residual cell viability was reduced to 15% and 48% in promastigotes and amastigotes, respectively). Notably, 6, while retaining the cytotoxic activity of quinone II, displayed no toxicity against mammalian THP1 cells. Transport assays indicated that the novel conjugates inhibited transport activity of lysine, arginine and proline transporters. Furthermore, our analyses suggested that the toxic conjugates might be translocated by the transporters into the cells. The non-toxic probes that inhibited transport competed with the natural substrates for binding to the transporters without being translocated. Thus, it is likely that 6, by exploiting amino acid transporters, can selectively deliver its toxic effects to Leishmania cells. This work provides the first evidence that amino acid transporters of the human pathogen Leishmania might be modulated by small molecules, and warrants their further investigation from drug discovery and chemical biology perspectives.

  本研究的目的是探讨通过适当设计的化学探针靶向利什曼原虫转运蛋白的可行性。导致脏器利什曼病的寄生虫利什曼原虫（Leishmania donovani）对精氨酸和赖氨酸呈营养依赖，具有特定的转运蛋白（LdAAP3和LdAAP7）来摄取这些营养物质。探针1-15是通过酰胺连接将细胞毒性醌片段（II和III）与氨基酸（即精氨酸和赖氨酸）结合而制得的。我们研究了合成的结合物对利什曼原虫的细胞外（前鞭毛体）和细胞内（无鞭毛体）形式的毒性，以及它们对相关氨基酸转运蛋白的抑制作用。我们观察到某些结合物确实显示出对寄生虫的毒性；特别是，7被确定为最有效的衍生物（在1 µg/mL和2.5 µg/mL的浓度下，前鞭毛体和无鞭毛体的残留细胞活力分别降至15%和48%）。值得注意的是，6在保留醌II细胞毒活性的同时，对哺乳动物THP1细胞显示无毒性。转运实验表明，新型结合物抑制了赖氨酸、精氨酸和脯氨酸转运蛋白的转运活性。此外，分析结果表明，这些毒性结合物可能通过转运蛋白转位进入细胞。无毒探针通过与天然底物竞争结合转运蛋白而抑制转运，但未被转运。因此，6可能通过利用氨基酸转运蛋白，选择性地将其毒性作用传递至利什曼原虫细胞。这项工作提供了第一个证据，表明人类病原体利什曼原虫的氨基酸转运蛋白可能受到小分子的调节，值得进一步从药物发现和化学生物学的角度进行研究。
• Novel orally bioavailable piperidine derivatives as extracellular arginase inhibitors developed by a ring expansion
  作者：Anna Gzik、Bartlomiej Borek、Jacek Chrzanowski、Karol Jedrzejczak、Marek Dziegielewski、Joanna Brzezinska、Julita Nowicka、Marcin M. Grzybowski、Tomasz Rejczak、Dorota Niedzialek、Grzegorz Wieczorek、Jacek Olczak、Adam Golebiowski、Zbigniew Zaslona、Roman Blaszczyk

  DOI：10.1016/j.ejmech.2023.116033

  日期：2024.1

  had limitations such as analysis and purification without chromophores, synthetically challenging space, and poor oral bioavailability. Herein, we present a novel class of boronic acid-based arginase inhibitors which are piperidine derivatives exhibiting a different pharmacological profile compared to our drug candidate in cancer immunotherapy –OATD-02 – dual ARG1/2 inhibitor with high intracellular

  精氨酸酶是一种多面酶，在健康和疾病中发挥着重要作用，被视为治疗恶性肿瘤、哮喘和心血管疾病等各种病理状态的治疗靶点。 1997 年基于硼酸的精氨酸酶抑制剂的发现彻底改变了专注于开发针对精氨酸酶的药物的药物化学尝试。不幸的是，这些极性很强的化合物具有局限性，例如在没有发色团的情况下进行分析和纯化、合成具有挑战性的空间以及口服生物利用度差。在此，我们提出了一类新型的基于硼酸的精氨酸酶抑制剂，它们是哌啶衍生物，与我们的癌症免疫治疗候选药物 – OATD-02 – 具有高细胞内活性的双 ARG1/2 抑制剂相比，表现出不同的药理学特征。该新系列的化合物显示出低细胞内活性，因此它们主要抑制细胞外精氨酸酶，与双重细胞内 ARG1/2 抑制剂相比，提供了不同的治疗空间。所公开的系列在体外显示出对精氨酸酶的良好抑制潜力（IC 50高达160 nM），在动物模型中具有有利的药代动力学，并且鼓励初步的体外和体内
• The Synthesis of a Lipophilic Derivative of RGD Peptide
  作者：E. G. Stepanenko、Yu. L. Sebyakin

  DOI：10.1023/b:rubi.0000023094.72361.c7

  日期：2004.3

  Bishexadecyl ester of RGD peptide was synthesized in solution by the conventional methods of peptide chemistry in a total yield of 48%.
• Selective Water-Soluble Gelatinase Inhibitor Prodrugs
  作者：Major Gooyit、Mijoon Lee、Valerie A. Schroeder、Masahiro Ikejiri、Mark A. Suckow、Shahriar Mobashery、Mayland Chang

  DOI：10.1021/jm200566e

  日期：2011.10.13

  SB-3CT (1), a selective and potent thiirane-based gelatinase inhibitor, is effective in animal models of cancer metastasis and stroke; however, it is limited by poor aqueous solubility and extensive metabolism. We addressed these issues by blocking the primary site of metabolism and capitalizing on a prodrug strategy to achieve >5000-fold increased solubility. The amide prodrugs were quantitatively hydrolyzed in human blood to a potent gelatinase inhibitor, ND-322 (3). The arginyl amide prodrug (ND-478, 5d) was metabolically stable in mouse, rat, and human liver microsomes. Both 5d and 3 were nonmutagenic in the Ames II mutagenicity assay. The prodrug 5d showed moderate clearance of 0.0582 L/min/kg, remained mostly in the extracellular fluid compartment (Vd = 0.0978 L/kg), and had a terminal half-life of >4 h. The prodrug 5d had superior pharmacokinetic properties than those of 3, making the thiirane class of selective gelatinase inhibitors suitable for intravenous administration in the treatment of acute gelatinase-dependent diseases.