methyl 2-cyano-3-[4-(trifluoromethyl)phenyl]-2-{[4-(trifluoromethyl)phenyl]methyl}propionate | 1202778-98-0

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 直链 1,3-二芳基丙烷
• 英文名称: methyl 2-cyano-3-[4-(trifluoromethyl)phenyl]-2-{[4-(trifluoromethyl)phenyl]methyl}propionate
• 英文别名: cyano-di(4-trifluoromethyl-benzyl)acetic acid methyl ester；Methyl 2-cyano-3-[4-(trifluoromethyl)phenyl]-2-[[4-(trifluoromethyl)phenyl]methyl]propanoate
• CAS: 1202778-98-0
• 化学式: C₂₀H₁₅F₆NO₂
• 分子量: 415.335
• InChiKey: MUFHVZUYKATDTA-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.5
• 重原子数：
  29
• 可旋转键数：
  6
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  50.1
• 氢给体数：
  0
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  methyl 2-cyano-3-[4-(trifluoromethyl)phenyl]-2-{[4-(trifluoromethyl)phenyl]methyl}propionate 在 水 、 氢气 、 溶剂黄146 、 三乙胺 、 lithium hydroxide 作用下， 以 1,4-二氧六环 、 甲醇 、 水 为溶剂， 20.0~100.0 ℃ 、100.0 kPa 条件下， 反应 156.0h， 生成 2-[[(2-Methylpropan-2-yl)oxycarbonylamino]methyl]-3-[4-(trifluoromethyl)phenyl]-2-[[4-(trifluoromethyl)phenyl]methyl]propanoic acid
  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
• 作为产物：
  描述：

  1-溴-三氟对二甲苯 在 sodium methylate 作用下， 以 甲醇 为溶剂， 反应 0.66h， 生成 methyl 2-cyano-3-[4-(trifluoromethyl)phenyl]-2-{[4-(trifluoromethyl)phenyl]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

• An amphipathic cyclic tetrapeptide scaffold containing halogenated β^2,2-amino acids with activity against multiresistant bacteria
  作者：Marianne H. Paulsen、Eskil André Karlsen、Dominik Ausbacher、Trude Anderssen、Annette Bayer、Philipp Ochtrop、Christian Hedberg、Tor Haug、Johanna U. Ericson Sollid、Morten B. Strøm

  DOI：10.1002/psc.3117

  日期：2018.10

  The present study describes the synthesis and biological studies of a small series of head‐to‐tail cyclic tetrapeptides of the general structure c(Lys‐β2,2‐Xaa‐Lys) containing one lipophilic β2,2‐amino acid and Lys, Gly, Ala, or Phe as the Xaa residue in the sequence. The peptides were investigated for antimicrobial activity against gram‐positive and gram‐negative reference strains and 30 multiresistant

  本研究中描述的一小系列的一般结构C的头-尾环四肽（赖氨酸-β的合成和生物学研究2,2-含有一种亲脂性β-Xaa-LYS）2,2--氨基酸，序列中的Xaa残基为Lys，Gly，Ala或Phe。研究了这些肽对革兰氏阳性和革兰氏阴性参考菌株以及30种多重耐药临床分离株的抗菌活性，这些菌株包括具有广谱β-内酰胺酶-卡巴内切酶（ESBL-CARBA）生产菌株。确定对人红细胞的毒性。最有效的肽表现出对革兰氏阳性临床分离株的高活性，最低抑制浓度为4–8μg/ mL，溶血活性低。高的抗微生物活性和低毒性显示含有亲脂性β这些环状四肽的组合2,2 α-氨基酸形成用于设计新的抗微生物剂的宝贵支架。
• Antimicrobial activity of amphipathic α,α-disubstituted β-amino amide derivatives against ESBL – CARBA producing multi-resistant bacteria; effect of halogenation, lipophilicity and cationic character
  作者：Marianne H. Paulsen、Dominik Ausbacher、Annette Bayer、Magnus Engqvist、Terkel Hansen、Tor Haug、Trude Anderssen、Jeanette H. Andersen、Johanna U. Ericson Sollid、Morten B. Strøm

  DOI：10.1016/j.ejmech.2019.111671

  日期：2019.12

  potency and minimize formation of Phase I metabolites. Net positive charge and cationic character of the derivatives had an important effect on toxicity against human cell lines. The most potent and selective derivative was the diguanidine derivative 4e with 3,5-di-brominated benzylic side-chains. Derivative 4e displayed minimum inhibitory concentrations (MIC) of 0.25-8 μg/mL against Gram-positive and Gram-negative

  多重耐药菌的迅速出现和传播已经迫切需要新的抗菌剂。我们在这里报告了一系列两亲性的α，α-二取代的β-氨基酰胺衍生物，具有针对30种革兰氏阳性和革兰氏阴性细菌多耐药临床分离株的活性，包括具有广谱β-内酰胺酶-碳青霉烯酶（ESBL-CARBA）的分离株） 生产。研究了各种卤代芳族侧链，以提高抗菌效力并最大程度减少I相代谢物的形成。衍生物的净正电荷和阳离子特性对其对人细胞系的毒性具有重要影响。最有效和选择性最大的衍生物是具有3，5-二溴苄基侧链的二胍衍生物4e。导数4e的最小抑制浓度（MIC）为0。对革兰氏阳性和革兰氏阴性参考菌株为25-8μg/ mL，对多重耐药的临床分离株为2-32μg/ mL。衍生物4e对人红细胞（EC50> 200μg/ mL），人肝癌细胞（HepG2：EC50> 64μg/ mL）和人肺成纤维细胞（MRC-5：EC50> 64μg/ mL）的毒性也很低毫升）。双胍基衍生
• 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.