(2S,4s)-Fmoc-4-氟吡咯烷-2-羧酸 | 203866-19-7

• 物质功能分类: 生物化工 - 生化试剂 - 氨基酸
• 分子结构分类: 有机化合物 - 苯类化合物 - 芴
• 中文名称: (2S,4s)-Fmoc-4-氟吡咯烷-2-羧酸
• 中文别名: (2S,4S)-FMOC-4-氟吡咯烷-2-甲酸
• 英文名称: Fmoc-4S-Fl-Pro-OH
• 英文别名: (2S,4S)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-fluoropyrrolidine-2-carboxylic acid；Fmoc-cis-4-FPro；Fmoc-cis-4-fluoro-L-proline；Fmoc-L-Pro(cis-4-F)；N-(N-(9-fluorenyl)methoxycarbonyl)-cis-4-fluoro-L-proline；N-Fmoc-cis-4-fluoro-L-proline；(2S,4S)-1-(9H-fluoren-9-ylmethoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid
• CAS: 203866-19-7
• 化学式: C₂₀H₁₈FNO₄
• 分子量: 355.366
• InChiKey: CJEQUGHYFSTTQT-SGTLLEGYSA-N

物化性质

• 沸点：
  556.0±50.0 °C(Predicted)
• 密度：
  1.40±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  26
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  66.8
• 氢给体数：
  1
• 氢受体数：
  5

安全信息

• 危险等级：
  IRRITANT
• 海关编码：
  2933990090
• 危险性防范说明：
  P261,P305+P351+P338
• 危险性描述：
  H302,H315,H319,H335
• 储存条件：
  2-8°C，干燥密封保存。

反应信息

• 作为反应物：
  描述：

  (2S,4R)-4-fluoroprolylglycine benzyl ester hydrochloride 、 (2S,4s)-Fmoc-4-氟吡咯烷-2-羧酸 在 N,N-二异丙基乙胺 、 bromo-tris(1-pyrrolidinyl)phosphonium hexafluorophosphate 作用下， 以 二氯甲烷 为溶剂， 反应 1.58h， 以79%的产率得到N-9-fluorenylmethoxycarbonyl-(2S,4S)-4-fluoroprolyl-(2S,4R)-4-fluoroprolylglycine benzyl ester
  参考文献：
  名称：

  Stereoelectronic and Steric Effects in the Collagen Triple Helix:  Toward a Code for Strand Association

  摘要：

  Collagen is the most abundant protein in animals. The protein consists of a helix of three strands, each with sequence X-Y-Gly. Natural collagen is most stable when X is (2S)-proline (Pro) and Y is (2S,4R)-4-hydroxyproline (4R-Hyp). We had shown previously that triple helices in which X is (2S,4S)-4-fluoroproline (4S-Flp) or Y is (2S,4R)-4-fluoroproline (4R-Flp) display hyperstability. This hyperstability arises from stereoelectronic effects that preorganize the main-chain dihedral angles in the conformation found in the triple helix. Here, we report the synthesis of strands containing both 4S-Flp in the X-position and 4R-Flp in the Y-position. We find that these strands do not form a stable triple helix, presumably because of an unfavorable steric interaction between fluoro groups on adjacent strands. Density functional theory calculations indicate that (2S,3S)-3-fluoroproline (3S-Flp), like 4S-Flp, should preorganize the main chain properly for triple-helix formation but without a steric conflict. Synthetic strands containing 3S-Flp in the X-position and 4R-Flp in the Y-position do form a triple helix. This helix is, however, less stable than one with Pro in the X-position, presumably because of an unfavorable inductive effect that diminishes the strength of the interstrand 3S-FlpC=(OH)-H-...-NGly hydrogen bond. Thus, other forces can counter the benefits derived from the proper preorganization. Although (Pro-Pro-Gly)(7) and (4S-Flp-4R-Flp-Gly)(7) do not form stable homotrimeric helices, mixtures of these two peptides form stable heterotrimeric helices containing one (Pro-Pro-Gly)(7) strand and two (4S-Flp-4R-Flp-Gly)(7) strands. This stoichiometry can be understood by considering the cross sections of the two possible heterotrimeric helices. This unexpected finding portends the development of a "code" for the self-assembly of determinate triple helices from two or three strands.

  DOI：

  10.1021/ja054674r
• 作为产物：
  描述：

  N-Boc-反式-4-羟基-L-脯氨酸甲酯 在 lithium hydroxide 、 三乙胺 、 4,4'-二氨基二苯乙烯-2,2'-二磺酸 、 三氟乙酸 作用下， 以 甲醇 、 二氯甲烷 、 水 、 乙腈 为溶剂， 生成 (2S,4s)-Fmoc-4-氟吡咯烷-2-羧酸
  参考文献：
  名称：

  Practical synthesis of Boc and Fmoc protected 4-fluoro and 4-difluoroprolines from trans-4-hydroxyproline

  摘要：

  Boc-cis-4-fluoro-L-proline and 4-difluoro-L-proline, usable in classical peptide synthesis, were obtained in respectively 71% (3 steps) and 65% (4 steps) overall yields from the readily available trans-4-hydroxy-L-proline methyl ester. The corresponding fluorinated Irans-isomer was isolated in 24% yield (5 steps). Transformation of Boc-protected compounds to their Fmoc-equivalents was performed in high yields. (C) 1998 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0040-4039(97)10793-6

文献信息

• Electronic circular dichroism and nuclear magnetic resonance studies of peptides derived from the FKBP52‐interacting β‐turn of the hERα ligand‐binding domain
  作者：Cillian Byrne、Mathilde Belnou、Etienne‐Emile Baulieu、Olivier Lequin、Yves Jacquot

  DOI：10.1002/pep2.24113

  日期：2019.7

  modifications, cyclization, as well as from the replacement of both the proline and its preceding residue by various natural and non‐natural amino acids. All peptides are found to explore several conformational states in aqueous solution, differing by the conformation of the peptide bond preceding the proline residue of the central VPG segment. Trans isomers are characterized by a conformational equilibrium

  当位于蛋白质表面时，含有Pro-Gly（PG）基序的分子通常参与蛋白质/蛋白质相互作用，并且可能参与细胞内信号传导级联。因此，构象受限的短蛋白衍生的转肽为干扰蛋白间相互作用的候选药物的开发提供了有希望的前景。从人雌激素受体α配体结合结构域（hERα-LBD）的X射线晶体结构中，我们确定了一个短肽基序（残基363-367，序列：RVPGF），其采用II型β-转角，并且所述FK1肽基脯氨酰的基板顺-反式当与蛋白质独立合成时，亲免蛋白FKBP52的异构酶（PPIase或rotamase）催化位点。使用ECD和NMR光谱结合分子动力学模拟，我们着手研究了从该序列衍生的肽的构象研究，并且我们探索了N和C末端化学修饰，环化以及环己基用各种天然和非天然氨基酸替代脯氨酸及其之前的残基。发现所有肽都在水溶液中探索几种构象状态，不同之处在于中央VPG片段脯氨酸残基之前的肽键构象。反式异构体的特征是围绕PG的I
• Selection of DNA‐Encoded Dynamic Chemical Libraries for Direct Inhibitor Discovery
  作者：Yuqing Deng、Jianzhao Peng、Feng Xiong、Yinan Song、Yu Zhou、Jianfu Zhang、Fong Sang Lam、Chao Xie、Wenyin Shen、Yiran Huang、Ling Meng、Xiaoyu Li

  DOI：10.1002/anie.202005070

  日期：2020.8.24

  that can identify full ligand structures from large‐scale DEDLs. This method is also able to convert unbiased libraries into focused ones targeting specific protein classes. We demonstrated this method by selecting DEDLs against five proteins, and novel inhibitors were identified for all targets. Notably, several selective BD1/BD2 inhibitors were identified from the selections against bromodomain 4 (BRD4)

  动态组合库（DCL）是生物医学研究中配体发现的强大工具。但是，DCL的低多样性阻碍了它们的应用。最近，DCL中已经采用了DNA编码的概念来创建DNA编码的动态库（DEDL）。但是，当前所有的DEDL都仅限于片段识别，并且在选择后需要一个具有挑战性的片段链接过程。我们报告了一种锚定的DEDL方法，该方法可以从大规模DEDL中识别出完整的配体结构。这种方法还能够将无偏文库转换为针对特定蛋白质类别的集中文库。我们通过选择针对五种蛋白质的DEDLs证明了这种方法，并为所有靶标确定了新型抑制剂。值得注意的是 从针对重要的抗癌药物靶标bromodomain 4（BRD4）的选择中鉴定出了几种选择性的BD1 / BD2抑制剂。这项工作可以为抑制剂发现提供广泛适用的方法。
• Optimization of linear and cyclic peptide inhibitors of KEAP1-NRF2 protein-protein interaction
  作者：Stefania Colarusso、Daniele De Simone、Tommaso Frattarelli、Matteo Andreini、Mauro Cerretani、Antonino Missineo、Daniele Moretti、Sara Tambone、Georg Kempf、Martin Augustin、Stefan Steinbacher、Ignacio Munoz-Sanjuan、Larry Park、Vincenzo Summa、Licia Tomei、Alberto Bresciani、Celia Dominguez、Leticia Toledo-Sherman、Elisabetta Bianchi

  DOI：10.1016/j.bmc.2020.115738

  日期：2020.11

  Inhibition of KEAP1-NRF2 protein-protein interaction is considered a promising strategy to selectively and effectively activate NRF2, a transcription factor which is involved in several pathologies such as Huntington’s disease (HD). A library of linear peptides based on the NRF2-binding motifs was generated on the nonapeptide lead Ac-LDEETGEFL-NH2 spanning residues 76–84 of the Neh2 domain of NRF2

  抑制KEAP1-NRF2蛋白质-蛋白质相互作用被认为是有选择地和有效地激活NRF2的一种有前途的策略，NRF2是一种转录因子，涉及多种病理学，例如亨廷顿舞蹈病（HD）。在非肽铅Ac-LDEETGEFL-NH 2上生成了基于NRF2结合基序的线性肽库跨越NRF2 Neh2域的76-84位残基，目的是用非酸性氨基酸取代E78，E79和E82。基于结构的设计还旨在更深入地了解T80副口袋的功能和可及性。研究了使用不同种类的环肽以及与细胞穿透肽结合的提高细胞通透性的方法。这一见识将指导大环化合物，肽模拟物以及最重要的是中性小脑穿透分子的未来设计，以评估NRF2激活剂是否可用于HD。
• Effect of γ-Substituted Proline Derivatives on the Performance of the Peptidic Catalyst H-dPro-Pro-Glu-NH2
  作者：Helma Wennemers、Tobias Schnitzer

  DOI：10.1055/s-0037-1609547

  日期：2018.11

  Substituents at Cγ of proline are valuable probes to tune the trans/cis ratio of Xaa–Pro bonds. We investigated the effect of Cγ-substituents on the reactivity and stereoselectivity of the peptidic catalyst H-dPro-Pro-Glu-NH2. Derivatives that bear electron-withdrawing and -donating substituents (OH, F, N3, and SMe) at Cγ of the middle Pro-residue were examined. The results show that substituents at a 4R-configured Cγ hardly affect the stereoselectivity of the peptidic catalyst whereas substituents at a 4S-configured Cγ can be used to tune and improve the catalytic performance.

  脯氨酸Cγ位置的取代基是调节Xaa-Pro键的反式/顺式比例的有价值的探针。我们研究了Cγ取代基对肽催化剂H-dPro-Pro-Glu-NH2的反应性和立体选择性的影响。我们检查了在中间脯氨酸残基的Cγ位置带有电子吸引和给予取代基（OH，F，N3和SMe）的衍生物。结果表明，4R构型的Cγ位置的取代基几乎不影响肽催化剂的立体选择性，而4S构型的Cγ位置的取代基可以用来调节和改善催化性能。
• PEPTIDES AS OXYTOCIN AGONISTS
  申请人：Hoffmann-La Roche Inc.

  公开号：US20170081368A1

  公开（公告）日：2017-03-23

  The present compounds are oxytocin receptor agonists for the treatment of autism, stress, including post-traumatic stress disorder, anxiety, including anxiety disorders and depression, schizophrenia, psychiatric disorders and memory loss, alcohol withdrawal, drug addiction and for the treatment of Prader-Willi Syndrome.

  目前的化合物是催产素受体激动剂，用于治疗自闭症、压力（包括创伤后应激障碍）、焦虑（包括焦虑症和抑郁症）、精神分裂症、精神障碍和记忆丧失、酒精戒断、药物成瘾以及普拉德-威利综合征。