N⁴,N⁹-dioleoyl spermine

• 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: N⁴,N⁹-dioleoyl spermine
• 英文别名: (Z)-N-(3-aminopropyl)-N-[4-[3-aminopropyl-[(Z)-octadec-9-enoyl]amino]butyl]octadec-9-enamide
• 化学式: C₄₆H₉₀N₄O₂
• 分子量: 731.246
• InChiKey: HWUIVKGWQROBQJ-CLFAGFIQSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  13.7
• 重原子数：
  52
• 可旋转键数：
  41
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.87
• 拓扑面积：
  92.7
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  精胺 在 氨 、 1-羟基苯并三唑 、 N,N'-二环己基碳二亚胺 作用下， 以 甲醇 、 二氯甲烷 为溶剂， 反应 54.0h， 生成 N⁴,N⁹-dioleoyl spermine
  参考文献：
  名称：

  N4,N9-Dioleoyl Spermine Is a Novel Nonviral Lipopolyamine Vector for Plasmid DNA Formulation

  摘要：

  研究合成的 N4,N9-二油酰精胺对 DNA 凝聚的影响，然后测定其在细胞培养中的转染效率。脂多巴胺是由天然多胺精胺合成的。利用溴化乙锭荧光淬灭和光散射检测法研究了这种新型化合物凝结 DNA 的能力。研究了原代皮肤细胞（FEK4）和永生癌细胞系（HtTA）的转染效率，并与市售的转染制剂 Lipofectin 和 Lipofectamine 进行了比较。合成的 N4,N9-二油酰精胺配方能有效凝结小牛胸腺和环状质粒 DNA，并在电荷比（+/-铵/磷酸盐）为 2.5 的低水平上有效转染原代皮肤细胞和癌细胞系。N4,N9-二油酰精胺可凝结 DNA，并在培养细胞中达到较高的转染水平。

  DOI：

  10.1007/s11095-005-4592-1

文献信息

• 脂质修饰精胺衍生物及利用该衍生物制备的 脂质体
  申请人：苏州圣诺生物医药技术有限公司

  公开号：CN104876831B

  公开（公告）日：2017-05-17

  本发明提供了一种具有通式(1)的脂质修饰精胺衍生物以及利用该衍生物制备的脂质体。精胺衍生物通过直接使用，或与胆固醇、中性脂质和聚乙二醇修饰脂质中的一种或几种混合使用，可作为载体用于包载或吸附生物活性分子药物，并将其送入细胞达到调节、干预或治疗的用途。通式(1)中，X1为‑(CH2)n‑或羰基，其中n为1，2或3；X2选自‑(CH2)‑、酯基、酰胺基、氧或硫；R1和R2独立地选自C6‑C18烷基、含有烯键的C6‑C18烷基或亲脂性胆固醇类分子；
• N4,N9-Dioleoyl Spermine Is a Novel Nonviral Lipopolyamine Vector for Plasmid DNA Formulation
  作者：Osama A. A. Ahmed、Noppadon Adjimatera、Charareh Pourzand、Ian S. Blagbrough

  DOI：10.1007/s11095-005-4592-1

  日期：2005.6

  To study the effect of synthesized N4,N9-dioleoyl spermine on DNA condensation and then measure its transfection efficiency in cell culture. The lipopolyamine was synthesized from the naturally occurring polyamine spermine. The ability of this novel compound to condense DNA was studied using ethidium bromide fluorescence quenching and light scattering assays. Transfection efficiency was studied in primary skin cells (FEK4) and in an immortalized cancer cell line (HtTA), and compared with the commercially available transfection formulations Lipofectin and Lipofectamine. The synthesized N4,N9-dioleoyl spermine formula is efficient at condensing calf thymus and circular plasmid DNA and effectively transfects both primary skin cells and cancer cell lines at low charge ratios of (+/− ammonium/phosphate) 2.5. N4,N9-Dioleoyl spermine condenses DNA and achieves high transfection levels in cultured cells.

  研究合成的 N4,N9-二油酰精胺对 DNA 凝聚的影响，然后测定其在细胞培养中的转染效率。脂多巴胺是由天然多胺精胺合成的。利用溴化乙锭荧光淬灭和光散射检测法研究了这种新型化合物凝结 DNA 的能力。研究了原代皮肤细胞（FEK4）和永生癌细胞系（HtTA）的转染效率，并与市售的转染制剂 Lipofectin 和 Lipofectamine 进行了比较。合成的 N4,N9-二油酰精胺配方能有效凝结小牛胸腺和环状质粒 DNA，并在电荷比（+/-铵/磷酸盐）为 2.5 的低水平上有效转染原代皮肤细胞和癌细胞系。N4,N9-二油酰精胺可凝结 DNA，并在培养细胞中达到较高的转染水平。
• N 1,N 12 -Diacyl Spermines: SAR Studies on Non-viral Lipopolyamine Vectors for Plasmid DNA and siRNA Formulation
  作者：Hassan M. Ghonaim、Shi Li、Ian S. Blagbrough

  DOI：10.1007/s11095-008-9764-3

  日期：2010.1

  To study the efficiency of novel synthetic N 1,N 12-diacyl spermines on DNA and siRNA binding, and to compare their transfection efficiency with viability in cell lines. Five long chain N 1,N 12-diacyl lipopolyamines: N 1,N 12-[didecanoyl, dimyristoyl, dimyristoleoyl, distearoyl and dioleoyl]-1,12-diamino-4,9-diazadodecane were synthesized from the naturally occurring polyamine spermine. Their abilities to condense DNA and to form nanoparticles were characterized. Transfection efficiencies were studied in FEK4 primary skin cells and in an immortalized cancer cell line (HtTA), and compared with N 4,N 9-regioisomers. Also, the abilities of these novel compounds to bind to siRNA-forming nanoparticles were studied using a RiboGreen intercalation assay, and their abilities to deliver fluorescein-tagged siRNA into cells were quantified and compared with TransIT-TKO. By incorporating two long aliphatic chains and varying their acylation position, length, and oxidation state in a stepwise manner, we show efficient p and siRNA formulation and delivery to primary skin and cancer cell lines. Although two C14 chains (both saturated or both mono-cis-unsaturated) were efficient transfecting agents, they were highly toxic. N 1,N 12-Dioleoyl spermine efficiently binds to and delivers pDNA and siRNA with high cell viability even in a primary skin cell line. It is a novel, efficient non-viral vector in the presence of serum.

  研究新型合成 N 1,N 12-二乙酰精胺与 DNA 和 siRNA 的结合效率，并比较它们的转染效率和细胞系的存活率。五种长链 N 1,N 12-二酰脂多胺：N 1,N 12-[二癸酰基、二肉豆蔻酰基、二肉豆蔻油酰基、二硬脂酰基和二油酰基]-1,12-二氨基-4,9-二氮杂十二烷是由天然多胺精胺合成的。对它们凝聚 DNA 和形成纳米颗粒的能力进行了表征。研究了 FEK4 原始皮肤细胞和永生癌细胞系（HtTA）的转染效率，并与 N 4,N 9-regioisomers 进行了比较。此外，还利用 RiboGreen 插层试验研究了这些新型化合物与 siRNA 形成的纳米颗粒结合的能力，并对它们向细胞递送荧光素标记 siRNA 的能力进行了量化，并与 TransIT-TKO 进行了比较。通过加入两条长脂肪族链，并逐步改变它们的酰化位置、长度和氧化态，我们展示了高效的 p 和 siRNA 制剂，并将其输送到原代皮肤细胞系和癌细胞系。虽然两种 C14 链（均为饱和或均为单顺式不饱和）都是高效的转染剂，但它们都有剧毒。N 1,N 12-二油酰精胺能有效地与 pDNA 和 siRNA 结合并传递它们，即使在原代皮肤细胞系中也有很高的细胞活力。在血清存在的情况下，它是一种新型、高效的非病毒载体。
• Varying the Unsaturation in N4,N9-Dioctadecanoyl Spermines: Nonviral Lipopolyamine Vectors for More Efficient Plasmid DNA Formulation
  作者：Osama A. A. Ahmed、Charareh Pourzand、Ian S. Blagbrough

  DOI：10.1007/s11095-005-8717-3

  日期：2006.1

  (dioctadecylamidoglycyl spermine), which also contains two saturated C18 lipid chains. RESULTS: N4,N9-Dilinoleoyl spermine (C18, di-cis-9,12) is efficient at circular plasmid DNA (pEGFP) condensation and gives the most effective transfection in a series of primary skin cells and cancer cell lines at low charge ratios of 5.5 (+/-ammonium/phosphate). CONCLUSIONS: The dienoic fatty acyl spermine conjugate N4,N9-dilinoleoyl

  目的：本研究的目的是分析改变合成的N4，N9-二十八碳酰精胺中不饱和度对DNA缩合的影响，然后比较它们在细胞培养中的转染效率。方法：由天然存在的多胺精胺合成N4，N9-di-C18饱和脂肪硬脂胺，硬脂酰基，C9-顺式（油酰基）和C9,12-二顺式（亚油酰基）。使用溴化乙锭荧光猝灭和纳米颗粒表征技术研究了这些新型化合物缩合DNA和形成纳米颗粒的能力。研究了几种原代皮肤细胞（FEK4，FCP4，FCP5，FCP7，和FCP8）和永生化癌细胞系（HtTA）中，并与市售的非脂质体转染制剂Transfectam（二十八碳酰胺基糖基精胺）进行比较，后者也包含两个饱和的C18脂质链。结果：N4，N9-二亚油酰精胺（C18，di-cis-9,12）在环状质粒DNA（pEGFP）缩合反应中非常有效，并且在低电荷比的一系列原代皮肤细胞和癌细胞系中可实现最有效的转染5.5（+/-铵/磷酸盐）。结论：二烯键式脂肪
• Efficient Silencing of EGFP Reporter Gene with siRNA Delivered by Asymmetrical <i>N</i>⁴,<i>N</i>⁹-Diacyl Spermines
  作者：Abdelkader A. Metwally、Olivier Reelfs、Charareh Pourzand、Ian S. Blagbrough

  DOI：10.1021/mp200429n

  日期：2012.7.2

  It is important to obtain structure-activity relationship (SAR) data across cationic lipids for the self-assembly and nonviral intracellular delivery of siRNA. The aims of this work are to carry out a SAR study on the efficiency of asymmetrical N-4,N-9-diacyl spermines in siRNA delivery and EGFP reporter gene silencing, with comparisons to selected mixtures composed of symmetrical N-4,N-9-diacyl spermines. Another important aim of these studies is to quantify the changes in cell viability, assayed with alamarBlue, as a function of lipid structure. Therefore, we have designed, synthesized, purified, and assayed novel cationic lipids that are asymmetrical lipopolyamines based on spermine. Flow cytometry and fluorescence microscopy in an EGFP stably transfected HeLa cell line, measuring both delivery of fluorescently tagged siRNAs and silencing the EGFP signal, allowed quantitation of the differences between asymmetrical cationic lipids, mixtures of their symmetrical counterparts, and comparison with commercial nonviral delivery agents. Intracellular delivery of siRNA and gene silencing by siRNA differ with different hydrophobic domains. In these asymmetrical N-4,N-9-diacyl spermines, lipids that enhance siRNA uptake do not necessarily enhance siRNA-induced inhibition of gene expression: C18 and longer saturated chains promote uptake, while more unsaturated C18 chains promote gene silencing. These properties are efficiently demonstrated in a new nontoxic cationic lipid siRNA vector, N-4-linoleoyl-N-9-oleoyl-1,12-diamino-4,9-diazadodecane (LinOS), which is also shown to be comparable with or superior to TransIT-TKO and Lipofectamine 2000.