methyl 2-cyano-3-(2-naphthyl)-2-[(2-naphthyl)methyl]propionate | 1202778-96-8

• 分子结构分类: 有机化合物 - 苯类化合物 - 萘
• 英文名称: methyl 2-cyano-3-(2-naphthyl)-2-[(2-naphthyl)methyl]propionate
• 英文别名: cyano-di(2-methylene-naphthalene)acetic acid methyl ester；Methyl 2-cyano-3-naphthalen-2-yl-2-(naphthalen-2-ylmethyl)propanoate
• CAS: 1202778-96-8
• 化学式: C₂₆H₂₁NO₂
• 分子量: 379.458
• InChiKey: BPHFCRRSLITTSA-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.3
• 重原子数：
  29
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.15
• 拓扑面积：
  50.1
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  methyl 2-cyano-3-(2-naphthyl)-2-[(2-naphthyl)methyl]propionate 在 水 、 氢气 、 三乙胺 、 lithium hydroxide 作用下， 以 1,4-二氧六环 、 甲醇 、 水 为溶剂， 反应 156.0h， 生成 2-[[(2-Methylpropan-2-yl)oxycarbonylamino]methyl]-3-naphthalen-2-yl-2-(naphthalen-2-ylmethyl)propanoic acid
  参考文献：
  名称：

  Anticancer activity of small amphipathic β2,2-amino acid derivatives

  摘要：

  We report the anticancer activity from screening of a series of synthetic beta(2,2)-amino acid derivatives that were prepared to confirm the pharmacophore model of short cationic antimicrobial peptides with high anti-Staphylococcal activity. The most potent derivatives against human Burkitt's lymphoma (Ramos) cells displayed IC50 values below 8 mu M, and low toxicity against human red blood cells (EC50 > 200 mu M). A more than 5-fold preference for Ramos cancer cells compared to human lung fibroblasts (MRC-5 cells) was also obtained for the most promising beta(2.2)-amino acid derivative 3-amino-N-(2-aminoethyl)-2,2-bis(naphthalen-2-ylmethyl)propanamide (5c). Screening of 5c at the National Cancer Institute (NCI, USA) confirmed its anticancer potency and revealed a very broad range of anticancer activity with IC50 values of 0.32-3.89 mu M against 59 different cancer cell lines. Highest potency was obtained against the colon cancer cell lines, a non-small cell lung cancer, a melanoma, and three leukemia cell lines included in the NCI screening panel. The reported beta(2,2)-amino acid derivatives constitute a promising new class of anticancer agents based on their high anticancer potency, ease of synthesis, mode-of-action, and optimized pharmacokinetic properties compared to much larger antimicrobial peptides. (C) 2012 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2012.09.048
• 作为产物：
  描述：

  2-溴甲基萘 在 sodium methylate 作用下， 以 甲醇 为溶剂， 反应 0.66h， 生成 methyl 2-cyano-3-(2-naphthyl)-2-[(2-naphthyl)methyl]propionate
  参考文献：
  名称：

  Synthesis of Cationic Antimicrobial β^2,2-Amino Acid Derivatives with Potential for Oral Administration

  摘要：

  We have prepared a series of highly potent achiral cationic beta(2,2)-amino acid derivatives that fulfill the Lipinski's rule of five and that contain the basic structural requirements of short cationic antimicrobial peptides. Highest antimicrobial potency was observed for one of the smallest beta(2,2)-amino acid derivatives (M-w 423.6) exhibiting a MIC of 3.8 mu M against methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant Staphylococcus epidermidis (MRSE), and Staphylococcus aureus, and 7.7 mu M against Escherichia coli. The beta(2,2)-amino acid derivatives were shown to have similar absorption properties as several commercially available drugs, and the results implied a resembling membrane disrupting mechanism of action as reported for much larger cationic antimicrobial peptides. By their high potency, nontoxicity, absorption properties, and ease of synthesis, the beta(2,2)-amino acid derivatives demonstrate a way to modify a vastly investigated class of cationic antimicrobial peptides into small drug-like molecules with high commercial potential.

  DOI：

  10.1021/jm101327d

文献信息

• Efficient and scalable synthesis of α,α-disubstituted β-amino amides
  作者：Marianne Hagensen Paulsen、Magnus Engqvist、Dominik Ausbacher、Morten Bøhmer Strøm、Annette Bayer

  DOI：10.1039/c6ob01219a

  日期：——

  methodology for the preparation of 2-aminoethyl α,α-disubstituted β-amino amides in three steps from methyl cyanoacetate has been developed. The key step in the synthesis was the chemoselective reduction of the nitrile group in presence of an amide and aryl halide functionalities. Reduction with RANEY® Nickel catalyst, either with molecular hydrogen (8–10 bar) or under transfer hydrogenation conditions, necessitated

  已经开发了一种从氰基乙酸甲酯分三步制备2-氨基乙基α，α-二取代的β-氨基酰胺的实用而有效的方法。合成的关键步骤是在酰胺和芳基卤化物官能团存在下腈选择性化学还原。用RANEY®镍催化剂还原，无论是用分子氢（8-10 bar）还是在转移氢化条件下，都需要用Boc 2 O原位保护所得的胺，而用ZnCl 2 / NaBH可以化学选择性地还原含芳基腈的腈。4无脱溴。所开发的方案仅涉及一个色谱纯化步骤，并且可以以克为单位进行。
• Improved anticancer potency by head-to-tail cyclization of short cationic anticancer peptides containing a lipophilic<i>β</i>^2,2-amino acid
  作者：Veronika Tørfoss、Johan Isaksson、Dominik Ausbacher、Bjørn-Olav Brandsdal、Gøril E. Flaten、Trude Anderssen、Cristiane de A. Cavalcanti-Jacobsen、Martina Havelkova、Leonard T. Nguyen、Hans J. Vogel、Morten B. Strøm

  DOI：10.1002/psc.2441

  日期：2012.10

  lipophilic β2,2‐amino acid that display low toxicity against non‐malignant cells and high proteolytic stability. In the present study, we have further investigated the effects of increasing the rigidity and amphipathicity of two of our lead heptapeptides by preparing a series of seven to five residue cyclic peptides containing the two most promising β2,2‐amino acid derivatives as part of the central lipophilic

  我们最近报道了一系列合成的抗癌七肽的（H-KKW β 2,2- WKK-NH 2）含有非手性中心和亲脂β 2,2 -氨基酸，对非恶性细胞和高的蛋白水解稳定性显示低毒性。在本研究中，我们进一步研究通过制备含有两个最有前途的一系列七比五残留环肽的提高我们的两个铅七肽的刚性和两亲性的影响β 2,2-氨基酸衍生物，是中央亲脂性核心的一部分。测试了这些肽对人伯基特氏淋巴瘤（Ramos细胞）的抗癌活性，对人红细胞（RBC）的溶血活性以及对健康人肺成纤维细胞（MRC-5）的细胞毒性。结果表明，从头到尾的肽环化后，抗癌效力大大提高，尤其是对于缺少色氨酸残基的最短衍生物。高分辨率NMR研究和分子动力学模拟，以及Annexin-V-FITC和碘化丙啶荧光测定法表明，该肽具有破坏细胞膜的作用方式，并且更有效的肽更深地渗透到脂质双层中。迫切需要具有新作用方式的新型抗癌药物，具有整体刚性和两亲性结构的短环抗癌肽的开
• Synthesis of anticancer heptapeptides containing a unique lipophilic β2,2-amino acid building block
  作者：Veronika Tørfoss、Dominik Ausbacher、Cristiane de A. Cavalcanti-Jacobsen、Terkel Hansen、Bjørn-Olav Brandsdal、Martina Havelkova、Morten B. Strøm

  DOI：10.1002/psc.1434

  日期：2012.3

  We report a series of synthetic anticancer heptapeptides (H‐KKWβ2,2WKK‐NH2) containing eight different central lipophilic β2,2‐amino acid building blocks, which have demonstrated high efficiency when used as scaffolds in small cationic antimicrobial peptides and peptidomimetics. The most potent peptides in the present study had IC50 values of 9–23 µm against human Burkitt's lymphoma and murine B‐cell

  我们报告了一系列合成的抗癌七肽的（H-KKW β 2,2- WKK-NH 2）包含八个不同的中心的亲脂性β 2,2- α-氨基酸结构单元，作为支架以小的阳离子抗微生物肽一起使用时，其已经证明高效率和拟肽。在本研究中最有效的肽具有IC 50个的9-23μ值米针对人伯基特氏淋巴瘤和鼠B细胞淋巴瘤和均nonhaemolytic（EC 50  > 200μ米）。最有前途的肽10e还显示出对人胚胎肺成纤维细胞和外周血单核细胞的低毒性以及出色的蛋白水解稳定性。版权所有©2012欧洲肽协会和John Wiley＆Sons，Ltd.
• Antimicrobial Activity of Small β-Peptidomimetics Based on the Pharmacophore Model of Short Cationic Antimicrobial Peptides
  作者：Terkel Hansen、Tore Alst、Martina Havelkova、Morten B. Strøm

  DOI：10.1021/jm901052r

  日期：2010.1.28

  We have synthesized a series of small beta-peptidomimetics (M-w < 650) that were based on the minimal pharmacophore model for anti-Staphylococcal activity of short cationic antimicrobial peptides. All beta-peptidomimetics had a net charge of +2 and formed an amphipathic scaffold consisting of an achiral lipophilic beta(2,2)-amino acid coupled to a C-terminal L-arginine amide residue. By varying the lipophilic side-chains of the beta(2,2)-amino acids, we obtained a series of highly potent beta-peptidomimetics with high enzymatic stability against alpha-chymotrypsin and a general low toxicity against human erythrocytes. The most potent beta-peptidomimetics displayed minimal inhibitory concentrations of 2.1-7.2 mu M against Staphylococcus aureus, methicillin resistant Staphylococcus aureus (MRSA), methicillin resistant Staphylococcus epidermidis (MRSE), and Escherichia coli, Small amphipathic beta-peptidomimetics may be a promising class of antimicrobial agents by means of having a similar range of potency and selectivity as larger cationic antimicrobial peptides in addition to improved enzymatic stability and lower costs of production.