tert-butyl ((S)-1-(((S)-6-(((allyloxy)carbonyl)amino)-1-((4-(hydroxymethyl)phenyl)amino)-1-oxohexan-2-yl)amino)-1-oxo-3-phenylpropan-2-yl)carbamate | 1160844-43-8

• 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 ((S)-1-(((S)-6-(((allyloxy)carbonyl)amino)-1-((4-(hydroxymethyl)phenyl)amino)-1-oxohexan-2-yl)amino)-1-oxo-3-phenylpropan-2-yl)carbamate
• CAS: 1160844-43-8
• 化学式: C₃₁H₄₂N₄O₇
• 分子量: 582.697
• InChiKey: OYRGEKVKTMEHTL-UIOOFZCWSA-N

物化性质

• 沸点：
  852.3±65.0 °C(Predicted)
• 密度：
  1.195±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.82
• 重原子数：
  42.0
• 可旋转键数：
  15.0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  155.09
• 氢给体数：
  5.0
• 氢受体数：
  7.0

反应信息

• 作为反应物：
  描述：

  tert-butyl ((S)-1-(((S)-6-(((allyloxy)carbonyl)amino)-1-((4-(hydroxymethyl)phenyl)amino)-1-oxohexan-2-yl)amino)-1-oxo-3-phenylpropan-2-yl)carbamate 在 盐酸 、 2-乙氧基-1-乙氧碳酰基-1,2-二氢喹啉 、 三乙胺 作用下， 以 乙醇 、 水 为溶剂， 反应 44.0h， 生成
  参考文献：
  名称：

  VEGFR 抑制剂舒尼替尼的组织蛋白酶 B 可裂解前药的合成、表征和体外研究

  摘要：

  几十年来，前药概念因其克服与化学疗法相关的常见问题的潜力而引起了人们对癌症研究的极大兴趣。然而，对于也会引起严重副作用的小分子酪氨酸激酶抑制剂，迄今为止几乎没有报道过任何产生前药以改善治疗效果的策略。在这里，我们介绍了 VEGFR 抑制剂舒尼替尼的组织蛋白酶 B 可裂解前药的合成和生物学研究。细胞活力测定和蛋白质印迹分析表明，与非组织蛋白酶 B 可切割的参考化合物相比，该前药在高表达组织蛋白酶 B 的细胞系 Caki-1 和 RU-MH 中显示出与原始药物舒尼替尼相当的活性. 此外，组织蛋白酶 B 裂解测定证实了所需的前药酶促活化。

  DOI：

  10.1002/cbdv.201800520
• 作为产物：
  描述：

  BOC-L-苯胺-4-硝基苯酯 在 N-甲基吗啉 、 三乙胺 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 反应 14.33h， 生成 tert-butyl ((S)-1-(((S)-6-(((allyloxy)carbonyl)amino)-1-((4-(hydroxymethyl)phenyl)amino)-1-oxohexan-2-yl)amino)-1-oxo-3-phenylpropan-2-yl)carbamate
  参考文献：
  名称：

  [EN] POLYMERIC SYSTEMS AND USES THEREOF IN THERANOSTIC APPLICATIONS
  [FR] SYSTÈMES POLYMÈRES ET LEURS UTILISATIONS DANS DES APPLICATIONS DE THÉRAGNOSTIQUE

  摘要：

  披露了用于治疗诊断应用的聚合物系统。这些聚合物系统包括荧光或荧光原基和治疗活性剂，每个都连接到相同或不同的聚合物基团上。这些聚合物系统设计成在化学事件发生时生成荧光信号，最好是在接触到在患病组织或器官中过度表达的分析物（例如酶）时。还披露了用于包含在这种聚合物系统中的探针，制备这种探针和聚合物系统的过程，以及在诊断和/或治疗诊断应用中的用途。

  公开号：

  WO2015136545A1

文献信息

• Conjugates of a Novel 7-Substituted Camptothecin with RGD-Peptides as α_vβ₃ Integrin Ligands: An Approach to Tumor-Targeted Therapy
  作者：Alma Dal Pozzo、Emiliano Esposito、Minghong Ni、Laura Muzi、Claudio Pisano、Federica Bucci、Loredana Vesci、Massimo Castorina、Sergio Penco

  DOI：10.1021/bc100097r

  日期：2010.11.17

  Eight conjugates of a novel camptothecin derivative (Namitecan, NMT) with RGD peptides have been synthesized and biologically evaluated. This study focused on factors that optimize the drug linkage to the transport vector. The different linkages investigated consist of heterofunctional glycol fragments and a lysosomally cleavable peptide. The linkage length and conformation were systematically modified

  已经合成了新型喜树碱衍生物（Namitecan，NMT）与RGD肽的八种结合物，并对其进行了生物学评估。这项研究集中于优化药物与转运载体的联系的因素。研究的不同键由异功能的乙二醇片段和溶酶体可裂解的肽组成。为了理解它们对相应结合物的受体亲和力，系统稳定性，细胞毒性和溶解度的影响，对连接长度和构象进行了系统地修饰。在制备的新缀合物中，C6和C7表现出高的受体亲和力和肿瘤细胞粘附性，鼠血中可接受的稳定性以及高的细胞毒性活性（IC 50= 8 nM）。将介绍其原理，合成策略和初步生物学结果。
• CONJUGATES OF A POLYMER, A BISPHOSPHONATE AND AN ANTI-ANGIOGENESIS AGENT AND USES THEREOF IN THE TREATMENT AND MONITORING OF BONE RELATED DISEASES
  申请人：RAMOT AT TEL-AVIV UNIVERSITY LTD.

  公开号：US20150328330A1

  公开（公告）日：2015-11-19

  Conjugates of polymers or copolymers having attached thereto an anti-angiogenesis agent and a bisphosphonate bone targeting agent, and processes of preparing same, are disclosed. Pharmaceutical compositions containing these conjugates and uses thereof in the treatment of bone related disorders are also disclosed.

  本发明公开了附着有抗血管生成剂和双磷酸盐骨靶向剂的聚合物或共聚物的共轭物以及其制备方法。还公开了包含这些共轭物的药物组合物以及它们在治疗与骨有关的疾病中的用途。
• Miller, Keren; Erez, Rotem; Segal, Ehud, Angewandte Chemie - International Edition, 2009, vol. 48, p. 2949 - 2954
  作者：Miller, Keren、Erez, Rotem、Segal, Ehud、Shabat, Doron、Satchi-Fainaro, Ronit

  DOI：——

  日期：——
• Integrin-targeted nano-sized polymeric systems for paclitaxel conjugation: a comparative study
  作者：Anat Eldar-Boock、Rachel Blau、Claudia Ryppa、Hemda Baabur-Cohen、Ariel Many、María Jesús Vicent、Felix Kratz、Joaquin Sanchis、Ronit Satchi-Fainaro

  DOI：10.1080/1061186x.2017.1358727

  日期：2017.11.26

  The generation of rationally designed polymer therapeutics via the conjugation of low molecular weight anti-cancer drugs to water-soluble polymeric nanocarriers aims to improve the therapeutic index. Here, we focus on applying polymer therapeutics to target two cell compartments simultaneously - tumour cells and angiogenic endothelial cells. Comparing different polymeric backbones carrying the same therapeutic agent and targeting moiety may shed light on any correlation between the choice of polymer and the anti-cancer activity of the conjugate. Here, we compared three paclitaxel (PTX)-bound conjugates with poly-l-glutamic acid (PGA, 4.9mol%), 2-hydroxypropylmethacrylamide (HPMA, 1.2mol%) copolymer, or polyethyleneglycol (PEG, 1:1 conjugate). PGA and HPMA copolymers are multivalent polymers that allow the conjugation of multiple compounds within the same polymer backbone, while PEG is a bivalent commercially available Food and Drug Administration (FDA)-approved polymer. We further conjugated PGA-PTX and PEG-PTX with the integrin alpha(v)beta(3)-targeting moiety RGD (5.5mol% and 1:1 conjugate, respectively). We based our selection on the overexpression of integrin alpha(v)beta(3) on angiogenic endothelial cells and several types of cancer cells. Our findings suggest that the polymer structure has major effect on the conjugate's activity on different tumour compartments. A multivalent PGA-PTX-E-[c(RGDfK)(2)] conjugate displayed a stronger inhibitory effect on the endothelial compartment, showing a 50% inhibition of the migration of human umbilical vein endothelial cell cells, while a PTX-PEG-E-[c(RGDfK)(2)] conjugate possessed enhanced anti-cancer activity on MDA-MB-231 tumour cells (IC50 = 20 nM versus IC50 300 nM for the PGA conjugate).
• Enhanced cytotoxicity of a polymer–drug conjugate with triple payload of paclitaxel
  作者：Rotem Erez、Ehud Segal、Keren Miller、Ronit Satchi-Fainaro、Doron Shabat

  DOI：10.1016/j.bmc.2009.05.028

  日期：2009.7

  The development of targeting approaches to selectively release chemotherapeutic drugs into malignant tissue is a major challenge in anticancer therapy. We have synthesized an N-(2-hydroxypropyl)-methacrylamide (HPMA) copolymer-drug conjugate with an AB(3) self-immolative dendritic linker. HPMA copolymers are known to accumulate selectively in tumors. The water-soluble polymer-drug conjugate was designed to release a triple payload of the hydrophobic drug paclitaxel as a result of cleavage by the endogenous enzyme cathepsin B. The polymer-drug conjugate exhibited enhanced cytotoxicity on murine prostate adenocarcinoma (TRAMP C2) cells in comparison to a classic monomeric drug-polymer conjugate. (C) 2009 Elsevier Ltd. All rights reserved.