4-(1-oxyl-2,2,6,6-tetramethylpiperidin-4-yloxy)-4-oxobutanoic acid

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 脂肪酰基
• 英文名称: 4-(1-oxyl-2,2,6,6-tetramethylpiperidin-4-yloxy)-4-oxobutanoic acid
• 化学式: C₁₃H₂₂NO₅
• 分子量: 272.321
• InChiKey: ZIWZPVIPOYZKJN-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -1.4
• 重原子数：
  19
• 可旋转键数：
  5
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.85
• 拓扑面积：
  67.8
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  拉帕替尼 、 4-(1-oxyl-2,2,6,6-tetramethylpiperidin-4-yloxy)-4-oxobutanoic acid 在 N,N-二异丙基乙胺 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 5.5h， 以78%的产率得到
  参考文献：
  名称：

  Heterotelechelic polymer prodrug nanoparticles: Adaptability to different drug combinations and influence of the dual functionalization on the cytotoxicity

  摘要：

  Well-defined, heterotelechelic polymer prodrugs for combination therapy were synthesized by using a combination of the "drug-initiated" nitroxide-mediated polymerization from a gemcitabine-alkoxyamine initiator and the nitroxide exchange reaction using TEMPO-bearing drugs to end-cap the drug-polymer chain-end by a second drug. This methodology was successfully applied to two different clinically relevant combinations, gemcitabine/doxorubicin (Gem/Dox) and gemcitabine/lapatinib (Gem/Lap), showing a certain degree of universality of the synthetic methodology. It also represented the first nanocarrier for the co-delivery of Gem and Lap ever reported. Well-controlled, low molar mass heterotelechelic polymers (M-n = 2100-4090 g.mol(-1), D = 1.18-1.38) with similar to 1:1 drug ratios and high overall drug loadings up to 40 wt% were obtained. They were formulated into nanoparticles by nanoprecipitation and exhibited average diameters in the 34-154 nm range, with narrow particle size distributions (PSD= 0.01-0.22) and excellent colloidal stability over time. Their biological evaluation in terms of drug release and cytotoxicity was performed and compared to that of different monofunctional polymer prodrug formulations. We showed that heterobifunctional polymer prodrugs induced cytotoxicity to MCF-7 cells, with IC50 values in the 120-300 nM range depending on the combination tested. Interestingly, whereas Gem/Dox combination did not lead to noticeable improvement over monofunctional therapies, co-nanoprecipitation of Gem/Lap prodrugs led to synergistic effect.

  DOI：

  10.1016/j.jconrel.2018.12.047
• 作为产物：
  描述：

  丁二酸酐 、 阻聚剂701 在 4-二甲氨基吡啶 作用下， 以 二氯甲烷 为溶剂， 以99%的产率得到4-(1-oxyl-2,2,6,6-tetramethylpiperidin-4-yloxy)-4-oxobutanoic acid
  参考文献：
  名称：

  使用可溶性聚合物负载的 TEMPO 与 Oxone 对醇进行轻度氧化：TEMPO 衍生物的基本基质的影响

  摘要：

  公开了使用新的可溶性聚合物负载的 TEMPO 衍生物与 Oxone 组合的高效和温和的醇氧化。两种类型的 PEG 负载的 TEMPO 衍生物很容易通过简单的酯化或点击化学合成。在 CH 2 Cl 2 或 BTF 中，伯醇与预催化剂 TBAB 和 Oxone 的氧化继续得到相应的氧化产物。由于在相同反应条件下使用几种 TEMPO 衍生物（包括非聚合物负载和不溶性聚合物负载的化合物）进行反应，合成的 PEG 负载 TEMPO 在 PEG 和 TEMPO 部分之间带有琥珀酸间隔物被选为最佳，因为其高反应性和产物选择性。该反应也适用于仲醇的氧化。在这个系统中，通过简单的过滤实现产物的分离。带有琥珀酸间隔物的 PEG 支持的 TEMPO 很容易回收并重复使用至少 10 次，无需纯化过程。

  DOI：

  10.3987/com-10-12027

文献信息

• Mild Oxidation of Alcohols Using Soluble Polymer-Supported TEMPO in Combination with Oxone: Effect of a Basic Matrix of TEMPO Derivatives
  作者：Kazutsugu Matsumoto、Toshiaki Iwata、Masahiro Suenaga、Masayuki Okudomi、Masaki Nogawa、Mariko Nakano、Ai Sugahara、Yuta Bannai、Kenji Baba

  DOI：10.3987/com-10-12027

  日期：——

  The highly efficient and mild oxidation of alcohols using new soluble polymer-supported TEMPO derivatives in combination with Oxone is disclosed. Two types of the PEG-supported TEMPO derivative were easily synthesized by a simple esterification or Click Chemistry. The oxidation of primary alcohols with the precatalysts, TBAB, and Oxone in CH 2 Cl 2 or BTF proceeded to afford the corresponding oxidized

  公开了使用新的可溶性聚合物负载的 TEMPO 衍生物与 Oxone 组合的高效和温和的醇氧化。两种类型的 PEG 负载的 TEMPO 衍生物很容易通过简单的酯化或点击化学合成。在 CH 2 Cl 2 或 BTF 中，伯醇与预催化剂 TBAB 和 Oxone 的氧化继续得到相应的氧化产物。由于在相同反应条件下使用几种 TEMPO 衍生物（包括非聚合物负载和不溶性聚合物负载的化合物）进行反应，合成的 PEG 负载 TEMPO 在 PEG 和 TEMPO 部分之间带有琥珀酸间隔物被选为最佳，因为其高反应性和产物选择性。该反应也适用于仲醇的氧化。在这个系统中，通过简单的过滤实现产物的分离。带有琥珀酸间隔物的 PEG 支持的 TEMPO 很容易回收并重复使用至少 10 次，无需纯化过程。
• A versatile approach for the preparation of end‐functional polymers and block copolymers by stable radical exchange reactions
  作者：Yonca Alkan Goksu、Gorkem Yilmaz、Yusuf Yagci

  DOI：10.1002/pola.29400

  日期：2019.12.15

  TEMPO derivatives bearing hydroxyl, azide and carboxylic acid functionalities, and polymers such as poly(ethylene glycol) (TEMPO‐PEG) and poly(ε‐caprolactone) (TEMPO‐PCL). Due to the simultaneous radical generation and reversible termination of the polymer radical, TEMPO moiety on polystyrene is replaced to form the corresponding end‐functional polymers and block copolymers. The intermediates and final

  描述了通过自由基交换反应制备末端功能聚合物和嵌段共聚物的通用策略。为此，首先通过硝基氧介导的自由基聚合（NMRP）制备具有2,2,6,6-四甲基哌啶-1-氧基端基（PS-TEMPO）的聚苯乙烯。在随后的步骤中，将这些聚合物在独立制备的带有羟基，叠氮化物和羧酸官能团的TEMPO衍生物以及诸如聚乙二醇（TEMPO-PEG）和聚ε-己内酯等聚合物的存在下加热至130°C ）（TEMPO-PCL）。由于同时发生自由基和聚合物自由基的可逆终止，聚苯乙烯上的TEMPO部分被取代以形成相应的端官能聚合物和嵌段共聚物。中间体和最终聚合物的特征在于1 H NMR，UV，IR和GPC测量。©2019 Wiley Periodicals，Inc.J.Polym。科学，A部分：Polym。化学 2019，57，2387年至2395年
• Heterotelechelic polymer prodrug nanoparticles: Adaptability to different drug combinations and influence of the dual functionalization on the cytotoxicity
  作者：Daniele Vinciguerra、Merel Jacobs、Stéphanie Denis、Julie Mougin、Yohann Guillaneuf、Gianpiero Lazzari、Chen Zhu、Simona Mura、Patrick Couvreur、Julien Nicolas

  DOI：10.1016/j.jconrel.2018.12.047

  日期：2019.2

  Well-defined, heterotelechelic polymer prodrugs for combination therapy were synthesized by using a combination of the "drug-initiated" nitroxide-mediated polymerization from a gemcitabine-alkoxyamine initiator and the nitroxide exchange reaction using TEMPO-bearing drugs to end-cap the drug-polymer chain-end by a second drug. This methodology was successfully applied to two different clinically relevant combinations, gemcitabine/doxorubicin (Gem/Dox) and gemcitabine/lapatinib (Gem/Lap), showing a certain degree of universality of the synthetic methodology. It also represented the first nanocarrier for the co-delivery of Gem and Lap ever reported. Well-controlled, low molar mass heterotelechelic polymers (M-n = 2100-4090 g.mol(-1), D = 1.18-1.38) with similar to 1:1 drug ratios and high overall drug loadings up to 40 wt% were obtained. They were formulated into nanoparticles by nanoprecipitation and exhibited average diameters in the 34-154 nm range, with narrow particle size distributions (PSD= 0.01-0.22) and excellent colloidal stability over time. Their biological evaluation in terms of drug release and cytotoxicity was performed and compared to that of different monofunctional polymer prodrug formulations. We showed that heterobifunctional polymer prodrugs induced cytotoxicity to MCF-7 cells, with IC50 values in the 120-300 nM range depending on the combination tested. Interestingly, whereas Gem/Dox combination did not lead to noticeable improvement over monofunctional therapies, co-nanoprecipitation of Gem/Lap prodrugs led to synergistic effect.
• Synthetic ditempolphosphatidylcholine liposome-like nanoparticles for anti-oxidative therapy of atherosclerosis
  作者：Chunxiao Wang、Ruifu Zhao、Zhen Wang、Tingting Xu、Peng Huang

  DOI：10.1039/d3ra01822a

  日期：——

  Atherosclerosis (AS), a chronic inflammatory disease, is the leading cause of death worldwide. Anti-oxidative therapy has been developed for AS therapy in light of the critical role of ROS in pathogenesis of AS, but current anti-oxidants have exhibited limited outcomes in the clinic. Herein, new ROS-eliminating liposome-like NPs (Tempol-Lips) were assembled from synthetic lipids that covalently conjugated

  动脉粥样硬化 (AS) 是一种慢性炎症性疾病，是全世界死亡的主要原因。鉴于 ROS 在 AS 发病机制中的关键作用，已经开发了用于 AS 治疗的抗氧化疗法，但目前的抗氧化剂在临床上表现出有限的结果。在此，新的 ROS 消除脂质体样 NPs (Tempol-Lips) 由合成脂质组装而成，合成脂质通过酯化反应将两个 Tempol 分子与磷脂酰胆碱共价结合。获得的 Tempol-Lips 可以有效地内化到炎症巨噬细胞中，并通过清除细胞内过量产生的 ROS 来减轻炎症。静脉注射后，具有纳米级特征的 Tempol-Lips 积聚在 ApoE 的斑块中-/-与用对照药物治疗的小鼠相比，小鼠通过被动靶向显着抑制了 AS 的发病机制。Tempol-Lips 的治疗益处主要归因于减少局部和系统性氧化应激和炎症。体内初步研究进一步证明，长期静脉注射后 Tempol-Lips 是安全且具有生物相容性的。总而言之，Tempol-Lips