2,3,5,6-F4Y | 157807-84-6

• 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: 2,3,5,6-F4Y
• 英文别名: (2S)-2-amino-3-(2,3,5,6-tetrafluoro-4-hydroxyphenyl)propanoic acid
• CAS: 157807-84-6
• 化学式: C₉H₇F₄NO₃
• 分子量: 253.153
• InChiKey: KFUSMUNGVKVABM-VKHMYHEASA-N

物化性质

• 沸点：
  337.0±42.0 °C(Predicted)
• 密度：
  1.657±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  -1.4
• 重原子数：
  17
• 可旋转键数：
  3
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.22
• 拓扑面积：
  83.6
• 氢给体数：
  3
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  2,3,5,6-F4Y 在 sodium 3-(N-morpholino)propanesulfonate 、 DL-dithiothreitol 、 phosphenolpyruvate 、 pyruvate kinase-lactate dehydrogenase 、 sodium carbonate 、 5’-三磷酸腺苷 、 manganese(ll) chloride 作用下， 以 1,4-二氧六环 、 水 为溶剂， 反应 48.0h， 生成
  参考文献：
  名称：

  蛋白质酪氨酸激酶反应过渡态的正向和反向动力学分析

  摘要：

  蛋白质酪氨酸激酶催化 γ-磷酰基从 ATP 转移到蛋白质中的酪氨酸残基，是细胞信号转导中的重要酶。我们通过分析一系列含氟酪氨酸的肽底物，研究了由 Csk 催化的蛋白质酪氨酸激酶反应的催化磷酰基转移过渡态。对于五种这样的含氟酪氨酸的肽底物已经确定，酪氨酸类似物苯酚 pKa 和负责 pH 速率曲线分析的基本分支的可电离基团之间存在良好的一致性。这表明底物酪氨酸苯酚必须是中性的才能具有酶活性。结合之前的数据表明一个小的 β 亲核系数（0-0.1），这些结果强烈支持磷酰基转移的解离过渡态。此外，β-离开基团系数是为反向蛋白酪氨酸激酶反应测量的，显示为-0.3。这个值很好...

  DOI：

  10.1021/ja9808393
• 作为产物：
  描述：

  2,3,5,6-四氟苯酚 、 sodium pyruvate 在 磷酸吡哆醛 乙酸铵 、 tyrosine phenol lyase 、 2-巯基乙醇 作用下， 生成 2,3,5,6-F4Y
  参考文献：
  名称：

  Mono-, Di-, Tri-, and Tetra-Substituted Fluorotyrosines:  New Probes for Enzymes That Use Tyrosyl Radicals in Catalysis

  摘要：

  A set of N-acylated, carboxyamide fluorotyrosine (FnY) analogues [Ac-3-FY-NH2, Ac-3,5-F2Y-NH2, Ac-2,3-F2Y-NH2, Ac-2,3,5-F3Y-NH2, Ac-2,3,6-F3Y-NH2 and Ac-2,3,5,6-F4Y-NH2] have been synthesized from their corresponding amino acids to interrogate the detailed reaction mechanism(s) accessible to FnY center dot S in small molecules and in proteins. These Ac-FnY-NH2 derivatives span a pK(a) range from 5.6 to 8.4 and a reduction potential range of 320 mV in the pH region accessible to most proteins (6-9). DFT electronic-structure calculations capture the observed trends for both the reduction potentials and pK(a)s. Dipeptides of the methyl ester of 4-benzoyl-L-phenylalanyl-F(n)Ys at pH 4 were examined with a nanosecond laser pulse and transient absorption spectroscopy to provide absorption spectra of FnY center dot S. The EPR spectrum of each FnY center dot has also been determined by UV photolysis of solutions at pH 11 and 77 K. The ability to vary systematically both pKa and radical reduction potential, together with the facility to monitor radical formation with distinct absorption and EPR features, establishes that F(n)Ys will be useful in the study of biological charge-transport mechanisms involving tyrosine. To demonstrate the efficacy of the fluorotyrosine method in unraveling charge transport in complex biological systems, we report the global substitution of tyrosine by 3-fluorotyrosine (3-FY) in the R2 subunit of ribonucleotide reductase (RNR) and present the EPR spectrum along with its simulation of 3-FY122 center dot. In the companion paper, we demonstrate the utility of FnYS in providing insight into the mechanism of tyrosine oxidation in biological systems by incorporating them site-specifically at position 356 in the R2 subunit of Escherichia coli RNR.

  DOI：

  10.1021/ja055926r

文献信息

• Integrin receptor inhibitors
  申请人：GENENTECH, INC.

  公开号：US20020035104A1

  公开（公告）日：2002-03-21

  Provided are compounds of formula (I) 1 wherein A, Q, W, X, Y, Z, R 1 to R 4 , m and n are as defined herein. Compounds of the invention bind to &agr; 4 integrin receptors and thereby inhibit binding of ligands for &agr; 4 integrins which is useful for prophylactic and/or therapeutic treatment of diseases and conditions associated with &agr; 4 integrins or their ligands.

  提供的是式(I)1的化合物，其中A、Q、W、X、Y、Z、R1至R4、m和n的定义如本文所述。本发明的化合物结合到α4整合素受体，从而抑制α4整合素的配体结合，这对于预防和/或治疗与α4整合素或其配体相关的疾病和症状是有用的。
• Diagnostic and therapeutic agents
  申请人：Taube Seija

  公开号：US20070258899A1

  公开（公告）日：2007-11-08

  Tumor targeting units are disclosed which have a peptide sequence C y —Y—G-F—X—W-G-Z-C yy (SEQ ID NO: 25), or a pharmaceutically or physiologically acceptable salt thereof. Tumor targeting agents are also disclosed having at least one targeting unit, directly or indirectly coupled to at least one effector unit. Diagnostic or pharmaceutical compositions having at least one targeting unit or at least one targeting agent, and targeting units or targeting agents for the preparation of a medicament for the treatment of cancer related diseases (including cancer), especially for the treatment of colon/colorectal cancer or its metastases are also disclosed.

  揭示了具有肽序列Cy—Y—G-F—X—W-G-Z-Cyy（序列ID编号：25）或其药学或生理上可接受的盐的肿瘤靶向单元。还披露了具有至少一个靶向单元的肿瘤靶向剂，直接或间接地偶联至至少一个效应单元。还披露了具有至少一个靶向单元或至少一个靶向剂的诊断或药物组合物，以及用于制备治疗癌症相关疾病（包括癌症）的药物的靶向单元或靶向剂，特别是用于治疗结肠/结直肠癌或其转移的靶向单元或靶向剂。
• pH Rate Profiles of F<i>_n</i>Y₃₅₆−R2s (<i>n</i> = 2, 3, 4) in <i>Escherichia </i><i>c</i><i>oli</i> Ribonucleotide Reductase:  Evidence that Y₃₅₆ Is a Redox-Active Amino Acid along the Radical Propagation Pathway
  作者：Mohammad R. Seyedsayamdost、Cyril S. Yee、Steven Y. Reece、Daniel G. Nocera、JoAnne Stubbe

  DOI：10.1021/ja055927j

  日期：2006.2.1

  The Escherichia Coll ribonucleotide reductase (RNR), composed of two subunits (R1 and R2), catalyzes the conversion of nucleotides to deoxynucleotides. Substrate reduction requires that a tyrosyl radical (Y-122 center dot) in R2 generate a transient cysteinyl radical (C-439 center dot) in R1 through a pathway thought to involve amino acid radical intermediates [Y-122 center dot -> W-48 -> Y-356 within R2 to Y-731 -> Y-730 -> C-439 within R1]. To study this radical propagation process, we have synthesized R2 semisynthetically using intein technology and replaced Y-356 with a variety of fluorinated tyrosine analogues (2,3-F2Y, 3,5-F2Y, 2,3,5-F3Y, 2,3,6-F3Y, and F4Y) that have been described and characterized in the accompanying paper. These fluorinated tyrosine derivatives have potentials that vary from -50 to +270 mV relative to tyrosine over the accessible pH range for RNR and pK(a)S that range from 5.6 to 7.8. The pH rate profiles of deoxynucleotide production by these FnY356-R2s are reported. The results suggest that the rate-determining step can be changed from a physical step to the radical propagation step by altering the reduction potential Of Y-356 center dot using these analogues. As the difference in potential of the FnY center dot relative to Y center dot becomes > 80 mV, the activity of RNR becomes inhibited, and by 200 mV, RNR activity is no longer detectable. These studies support the model that Y356 is a redox-active amino acid on the radical-propagation pathway. On the basis of our previous studies with 3-NO2Y356-R2, we assume that 2,3,5-F3Y356, 2,3,6-F3Y356, and F4Y356-R2s are all deprotonated at pH > 7.5. We show that they all efficiently initiate nucleotide reduction. If this assumption is correct, then a hydrogen-bonding pathway between W-48 and Y-356 of R2 and Y-731 of R1 does not play a central role in triggering radical initiation nor is hydrogen-atom transfer between these residues obligatory for radical propagation.
• Incorporation of Fluorotyrosines into Ribonucleotide Reductase Using an Evolved, Polyspecific Aminoacyl-tRNA Synthetase
  作者：Ellen C. Minnihan、Douglas D. Young、Peter G. Schultz、JoAnne Stubbe

  DOI：10.1021/ja207719f

  日期：2011.10.12

  Tyrosyl radicals (Y center dot s) are prevalent in biological catalysis and are formed under physiological conditions by the coupled loss of both a proton and an electron. Fluorotyrosines (F(n)Ys, n = 1-4) are promising tools for studying the mechanism of Y center dot formation and reactivity, as their pK(a) values and peak potentials span four units and 300 mV, respectively, between pH 6 and 10. In this manuscript, we present the directed evolution of aminoacyl-tRNA synthetases (aaRSs) for 2,3,5-trifluorotyrosine (2,3,5-F3Y) and demonstrate their ability to charge an orthogonal tRNA with a series of F(n)Ys while maintaining high specificity over Y. An evolved aaRS is then used to incorporate F(n)Ys site-specifically into the two subunits (alpha 2 and beta 2) of Escherichia coli class Ia ribonucleotide reductase (RNR), an enzyme that employs stable and transient Y center dot s to mediate long-range, reversible radical hopping during catalysis. Each of four conserved Ys in RNR is replaced with FnY(s), and the resulting proteins are isolated in good yields. F(n)Ys incorporated at position 122 of beta 2, the site of a stable Y center dot in wild-type RNR, generate long-lived FnY center dot s that are characterized by electron paramagnetic resonance (EPR) spectroscopy. Furthermore, we demonstrate that the radical pathway in the mutant Y-122(2,3,5)F3Y-beta 2 is energetically and/or conformationally modulated in such a way that the enzyme retains its activity but a new on-pathway Y center dot can accumulate. The distinct EPR properties of the 2,3,5-F3Y center dot facilitate spectral subtractions that make detection and identification of new Y center dot s straightforward.
• Measurement of a Brønsted Nucleophile Coefficient and Insights into the Transition State for a Protein Tyrosine Kinase
  作者：Kyonghee Kim、Philip A. Cole

  DOI：10.1021/ja972110k

  日期：1997.11.1