tert-butyl N-[(2S)-1-[[(2S)-6-[[(2S)-2,6-bis[(2-methylpropan-2-yl)oxycarbonylamino]hexanoyl]amino]-1-oxo-1-(prop-2-ynylamino)hexan-2-yl]amino]-6-[(2-methylpropan-2-yl)oxycarbonylamino]-1-oxohexan-2-yl]carbamate | 945749-39-3

• 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: tert-butyl N-[(2S)-1-[[(2S)-6-[[(2S)-2,6-bis[(2-methylpropan-2-yl)oxycarbonylamino]hexanoyl]amino]-1-oxo-1-(prop-2-ynylamino)hexan-2-yl]amino]-6-[(2-methylpropan-2-yl)oxycarbonylamino]-1-oxohexan-2-yl]carbamate
• CAS: 945749-39-3
• 化学式: C₄₁H₇₃N₇O₁₁
• 分子量: 840.071
• InChiKey: HOEBFBRJCAIODN-DTXPUJKBSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.5
• 重原子数：
  59
• 可旋转键数：
  30
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.78
• 拓扑面积：
  241
• 氢给体数：
  7
• 氢受体数：
  11

反应信息

• 作为反应物：
  描述：

  tert-butyl N-[(2S)-1-[[(2S)-6-[[(2S)-2,6-bis[(2-methylpropan-2-yl)oxycarbonylamino]hexanoyl]amino]-1-oxo-1-(prop-2-ynylamino)hexan-2-yl]amino]-6-[(2-methylpropan-2-yl)oxycarbonylamino]-1-oxohexan-2-yl]carbamate 在 四甲基乙二胺 、 copper(l) chloride 作用下， 以 二氯甲烷 为溶剂， 反应 27.0h， 以80%的产率得到
  参考文献：
  名称：

  Gelation and topochemical polymerization of peptide dendrimers

  摘要：

  本文介绍了一类新型肽基树枝和树枝状聚合物，它们显示出独特的囊泡驱动有机凝胶化作用。我们展示了二乙炔基树枝状聚合物在凝胶状态下的交联，从而产生了强荧光聚二乙炔。由多肽树枝状聚合物制成的交联凝胶可用于各种实际用途，包括组织工程中的支架材料和药物输送。

  DOI：

  10.1039/c0nj00544d
• 作为产物：
  描述：

  (S)-2,6-二叔丁氧羰基氨基己酸 在 三乙胺 、 N,N'-二环己基碳二亚胺 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 14.0h， 生成 tert-butyl N-[(2S)-1-[[(2S)-6-[[(2S)-2,6-bis[(2-methylpropan-2-yl)oxycarbonylamino]hexanoyl]amino]-1-oxo-1-(prop-2-ynylamino)hexan-2-yl]amino]-6-[(2-methylpropan-2-yl)oxycarbonylamino]-1-oxohexan-2-yl]carbamate
  参考文献：
  名称：

  One-Pot Orthogonal Copper-Catalyzed Synthesis and Self-Assembly of l-Lysine-Decorated Polymeric Dendrimers

  摘要：

  Synthetic peptides, including cyclic peptides and peptidomimetics, provide stability, protection, and long circulation times compared to free-circulating peptides. Dendritic structures with amino acids or peptides attached to the peripheral layer represent one form of peptidomimetics (i.e., a hybrid peptide/dendrimer construct) that has found use in biological applications. Constructing such dendritic structures from linear polymeric building blocks provides a further advantage of generating a highly ordered and defined structure in the nanoparticle size range. However, the rapid synthesis of such well-defined structures is still a challenge. In this work, we demonstrate that through modulating the copper activity concomitantly of the nitroxide radical coupling (NRC) and the azide-alkyne cycloaddition (CuAAC) reactions, polymeric dendrimers decorated with l-lysine on the periphery could be made rapidly in one pot at 25 degrees C. Three polymeric dendrimers were constructed with high purity (>94%) and with varying l-lysine density coated on the peripheral generation layer. The self-assembly of these dendrimers in water gave similar sizes to that found in organic solvents, suggesting that the aggregation number of dendritic structures in water was very low and possibly consisting of unimolecular micelles. The findings support the conclusion that the self-assembly of a dendritic architecture in water produces nanoparticles with predictable and well-controlled sizes. This synthetic methodology and the self-assembly properties represent an important step toward synthesizing peptide-decorated dendrimers targeted toward therapeutic applications.

  DOI：

  10.1021/acs.macromol.5b00195

文献信息

• Design and synthesis of triazole-based peptide dendrimers
  作者：V. Haridas、Kashmiri Lal、Yogesh K. Sharma

  DOI：10.1016/j.tetlet.2007.05.023

  日期：2007.7

  A series of novel designer dendrimers (8, 9, 11, 13 and 16) was synthesized by employing click chemistry. The dendritic structures reported here include symmetrical, unsymmetrical and cationic dendrimers with a variety of cores such as triazole, cystine and Lys-Asp dipeptide.

  一系列新颖设计的树枝状聚合物（的8，9，11，13和16）通过采用点击化学合成。本文报道的树状结构包括具有各种核心的对称，不对称和阳离子树状聚合物，例如三唑，胱氨酸和Lys-Asp二肽。
• Multi-Tier Dendrimers with an Aromatic Core
  作者：V. Haridas、Yogesh K. Sharma、Sarala Naik

  DOI：10.1002/ejoc.200801150

  日期：2009.4

  report various multi-tier designer dendritic molecules that incorporate an aromatic core and heterocyclic and peptide units. The 5-(azidomethyl)benzene-1,3-dicarbonyl unit was chosen as the scaffold as this unit allows two identical units and a reactive end to be incorporated, thus generating a dendron suitable for dendrimer synthesis. The design and synthesis of dendrimers with multi-tier architectures

  我们报告了各种包含芳香核和杂环和肽单元的多层设计树突分子。选择 5-(叠氮甲基)苯-1,3-二羰基单元作为支架，因为该单元允许引入两个相同的单元和一个反应端，从而生成适合树枝状聚合物合成的树枝状结构。具有多层结构的树枝状聚合物的设计和合成将有助于生成具有各种功能的树枝状结构。（© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009）
• [EN] A FORMULATION FOR STABILIZING BIO-THERAPEUTICS<br/>[FR] FORMULATION POUR LA STABILISATION D'AGENTS BIOLOGIQUES THÉRAPEUTIQUES
  申请人：INDIAN INSTITUTE TECH DELHI

  公开号：WO2018096552A1

  公开（公告）日：2018-05-31

  The present disclosure relates to a formulation comprising: a) a dendron of Formula I; b) at least one bio-therapeutic; c) at least one buffer; and d) at least one salt, wherein the bio-therapeutic to dendron molar ratio is in the range of 1:0.5-1:3. The dendron stabilizes the bio-therapeutic in the formulation at a temperature of up to 55 °C.

  本公开涉及一种配方，包括：a) 公式I的树状分子；b) 至少一种生物治疗药物；c) 至少一种缓冲剂；和d) 至少一种盐，其中生物治疗药物与树状分子的摩尔比在1:0.5至1:3的范围内。树状分子可以在高达55°C的温度下稳定配方中的生物治疗药物。
• Tailoring the Supramolecular Structure of Guanidinylated Pullulan toward Enhanced Genetic Photodynamic Therapy
  作者：Jie Zhou、Aisha Roshan Mohamed Wali、Shengnan Ma、Yiyan He、Dong Yue、James Zhenggui Tang、Zhongwei Gu

  DOI：10.1021/acs.biomac.8b00273

  日期：2018.6.11

  In the progress of designing a gene carrier system, what is urgently needed is a balance of excellent safety and satisfactory efficiency. Herein, a straightforward and versatile synthesis of a cationic guanidine-decorated dendronized pullulan (OGG3P) for efficient genetic photodynamic therapy was proposed. OGG3P was able to block the mobility of DNA from a weight ratio of 2. However, G3P lacking guanidine residues could not block DNA migration until at a weight ratio of 15, revealing guanidination could facilitate DNA condensation via specific guanidinium-phosphate interactions. A zeta potential plateau (∼+23 mV) of OGG3P complexes indicated the nonionic hydrophilic hydroxyl groups in pullulan might neutralize the excessive detrimental cationic charges. There was no obvious cytotoxicity and hemolysis, but also enhancement of transfection efficiency with regard to OGG3P in comparison with that of native G3P in Hela and HEK293T cells. More importantly, we found that the uptake efficiency in Hela cells between OGG3P and G3P complexes was not markedly different. However, guanidination caused changes in uptake pathway and led to macropinocytosis pathway, which may be a crucial reason for improved transfection efficiency. After introducing a therapeutic pKillerRed-mem plasmid, OGG3P complexes achieved significantly enhanced KillerRed protein expression and ROS production under irradiation. ROS-induced cancer cells proliferation suppression was also confirmed. This study highlights the guanidine-decorated dendronized pullulan could emerge as a reliable nonviral gene carrier to specifically deliver therapeutic genes.

  在设计基因载体系统的过程中，迫切需要兼顾出色的安全性和令人满意的效率。本文提出了一种用于高效基因光动力疗法的阳离子胍装饰树枝化拉鲁兰（OGG3P）的直接、多功能合成方法。然而，缺乏胍残基的 G3P 在重量比为 15 时才能阻止 DNA 迁移，这表明胍化可通过特定的胍-磷酸相互作用促进 DNA 凝聚。OGG3P 复合物的 zeta 电位高原（∼+23 mV）表明，拉普兰中的非离子亲水羟基可以中和过多的有害阳离子电荷。与原生 G3P 相比，OGG3P 在 Hela 和 HEK293T 细胞中没有明显的细胞毒性和溶血现象，而且还提高了转染效率。更重要的是，我们发现 OGG3P 和 G3P 复合物在 Hela 细胞中的吸收效率没有明显差异。然而，鸟苷酸化引起了摄取途径的改变，并导致了大吞噬途径，这可能是提高转染效率的关键原因。引入治疗性 pKillerRed-mem 质粒后，OGG3P 复合物在辐照条件下显著增强了 KillerRed 蛋白的表达和 ROS 的产生。ROS 诱导的癌细胞增殖抑制也得到了证实。这项研究表明，胍基装饰的树枝化拉鲁兰可以作为一种可靠的非病毒基因载体，特异性地传递治疗基因。
• Peptide Dendrons as Thermal-Stability Amplifiers for Immunoglobulin G1 Monoclonal Antibody Biotherapeutics
  作者：Rohit Bansal、Sameer Dhawan、Soumili Chattopadhyay、Govind P. Maurya、V. Haridas、Anurag S. Rathore

  DOI：10.1021/acs.bioconjchem.7b00389

  日期：2017.10.18

  Biotherapeutics such as monoclonal antibodies (mAbs) have a major share of the pharmaceutical industry for treatment of life-threatening chronic diseases such as cancer, skin ailments, and immune disorders. Instabilities such as aggregation, fragmentation, oxidation, and reduction have resulted in the practice of storing these products at low temperatures (−80 to −20 °C). However, reliable storage at these temperatures can be a challenge, particularly in developing and underdeveloped countries; hence, lately, there has been a renewed interest in creating formulations that would offer stability at higher temperatures (25 to 55 °C). Most therapeutic formulations contain excipients such as salts, sugars, amino acids, surfactants, and polymers to provide stability to the biotherapeutic, but their efficacy at high temperatures is limited. The current work proposes the use of peptide dendrons of different generations to create formulations that would be stable at high temperature. Among these dendrons, third-generation lysine dendron L6 has been identified to provide the highest stability to mAbs, as demonstrated by a host of analytical techniques such as size-exclusion chromatography (SEC), dynamic light scattering (DLS), Nanoparticle tracking Analysis (NTA), and circular dichroism (CD). The biocompatibility of these dendrons was confirmed by hemolytic activity tests. Non-interference of the dendrons with the activity of the mAb was confirmed using a surface plasmon resonance (SPR) based activity assay. We hope that this study will stimulate utilization of such higher-generation dendrons for enhancing the thermal stability of mAbs.

  生物治疗药物如单克隆抗体（mAbs）在制药行业中占据重要份额，主要用于治疗癌症、皮肤疾病和免疫系统疾病等危及生命的慢性疾病。聚集、断裂、氧化和还原等不稳定性导致这些产品通常需要在低温（-80至-20°C）下储存。然而，在这些温度下可靠存储面临挑战，尤其是在发展中国家和欠发达国家。因此，最近人们对开发能够在较高温度（25至55°C）下保持稳定的配方产生了新的兴趣。大多数治疗性配方中含有盐、糖、氨基酸、表面活性剂和聚合物等辅料，以提供生物治疗药物的稳定性，但它们在高温下的有效性有限。本研究提出使用不同代际的肽树突状体来创建高温稳定的配方。在这些树突状体中，第三代赖氨酸树突状体L6被确定为提供对mAbs最高稳定性的材料，相关的分析技术如尺寸排阻色谱（SEC）、动态光散射（DLS）、纳米颗粒追踪分析（NTA）和圆二色谱（CD）均进行了验证。通过溶血活性测试确认了这些树突状体的生物相容性。通过基于表面等离子共振（SPR）的活性测定确认了树突状体与mAb活性之间不存在干扰。我们希望这项研究能促使人们利用这种高代树突状体来增强mAbs的热稳定性。