N-[芴甲氧羰基]-L-缬氨酰-L-脯氨酸 | 109425-49-2

• 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
• 中文名称: N-[芴甲氧羰基]-L-缬氨酰-L-脯氨酸
• 英文名称: Fmoc-Val-Pro-OH
• 英文别名: (2S)-1-[(2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-methylbutanoyl]pyrrolidine-2-carboxylic acid
• CAS: 109425-49-2
• 化学式: C₂₅H₂₈N₂O₅
• 分子量: 436.508
• InChiKey: PNFSGKNIZOXLKU-VXKWHMMOSA-N

物化性质

• 沸点：
  678.8±55.0 °C(Predicted)
• 密度：
  1.271±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.1
• 重原子数：
  32
• 可旋转键数：
  7
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  95.9
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  N-[芴甲氧羰基]-L-缬氨酰-L-脯氨酸 在 偶氮二甲酸二叔丁酯 、 (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate 、 三乙胺 、 三氟乙酸 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 162.0h， 生成 3-[2'-deoxy-5'-O-[N-(fluorenylmethoxycarbonyl)valylprolylalanyl]-β-D-ribofuranosyl]-6-(p-pentylphenyl)-2,3-dihydrofuro[2,3-d]pyrimidin-2-one
  参考文献：
  名称：

  高度亲脂性双环核苷类似物的二肽基肽酶IV依赖性水溶性前药

  摘要：

  我们提出基于二肽基肽酶IV（DPPIV / CD26）的前药方法在含羟基药物衍生物中的首次报道。特别是，我们将此策略应用于双环呋喃并嘧啶核苷类似物（BCNA）的高度亲脂性抗病毒药物家族，以改善其理化和药代动力学特性。我们的稳定性数据表明，通过纯化的DPPIV / CD26和存在于牛，鼠和人血清中的可溶性DPPIV / CD26的选择性转化，前药可有效释放母体BCNA药物。维达列汀，一种DPPIV / CD26的特异性抑制剂，在纯化的DPPIV / CD26人，鼠和牛血清的存在下能够完全阻断前药的水解。与难溶性母体药物相比，几种新颖的前药显示出水溶性的显着提高（最高超过3个数量级）。我们还证明了与小鼠母体药物相比，前药的口服生物利用度显着提高。

  DOI：

  10.1021/jm101624e
• 作为产物：
  描述：

  H-L-Arg(Cbz)₂-OH 在 cocktail R 作用下， 反应 3.0h， 生成 N-[芴甲氧羰基]-L-缬氨酰-L-脯氨酸
  参考文献：
  名称：

  Functional Identification and Structure Determination of Two Novel Prolidases from cog1228 in the Amidohydrolase Superfamily,

  摘要：

  Two uncharacterized enzymes from the amidohydrolase superfamily belonging to cog1228 were cloned, expressed, and purified to homogeneity. The two proteins, Sgx9260c (gi|44242006) and Sgx9260b (gi|44479596), were derived from environmental DNA samples originating from the Sargasso Sea. The catalytic function and substrate profiles for Sgx9260c and Sgx9260b were determined using a comprehensive library of dipeptides and N-acyl derivative of L-amino acids. Sgx9260c catalyzes the hydrolysis of Gly-L-Pro, L-Ala-L-Pro, and N-acyl derivatives of L-Pro. The best substrate identified to date is N-acetyl-L-Pro with a value of k(cat)/K-m of 3 x 10(5) M-1 s(-1). Sgx9260b catalyzes the hydrolysis of L-hydrophobic L-Pro dipeptides and N-acyl derivatives of L-Pro. The best substrate identified to date is N-propionyl-L-Pro with a value of k(cat)/K-m of 1 x 10(5) M-1 s(-1). Three-dimensional structures of both proteins were determined by X-ray diffraction methods (PDB codes 3MKV and 3FEQ). These proteins fold as distorted (beta/alpha)(8)-barrels with two divalent cations in the active site. The structure of Sgx9260c was also determined as a complex with the N-methylphosphonate derivative of L-Pro (PDB code 3N2C). In this structure the phosphonate moiety bridges the binuclear metal center, and one oxygen atom interacts with His-140. The a-carboxylate of the inhibitor interacts with Tyr-231. The proline side chain occupies a small substrate binding cavity formed by residues contributed from the loop that follows beta-strand 7 within the (beta/alpha)(8)-barrel. A total of 38 other proteins from cog1228 are predicted to have the same substrate profile based on conservation of the substrate binding residues. The structure of an evolutionarily related protein, Cc2672 from Caulobacter crecentus, was determined as a complex with the N-methylphosphonate derivative of L-arginine (PDB code 3MTW).

  DOI：

  10.1021/bi100897u

文献信息

• Aldehyde Capture Ligation for Synthesis of Native Peptide Bonds
  作者：Monika Raj、Huabin Wu、Sarah L. Blosser、Marc A. Vittoria、Paramjit S. Arora

  DOI：10.1021/jacs.5b03538

  日期：2015.6.3

  reactions for amide bond formation have transformed the ability to access synthetic proteins and other bioconjugates through ligation of fragments. In these ligations, amide bond formation is accelerated by transient enforcement of an intramolecular reaction between the carboxyl and the amine termini of two fragments. Building on this principle, we introduce an aldehyde capture ligation that parlays

  酰胺键形成的化学选择性反应改变了通过片段连接获得合成蛋白质和其他生物偶联物的能力。在这些连接中，两个片段的羧基和胺末端之间的分子内反应的瞬时增强加速了酰胺键的形成。基于这一原则，我们引入了一种醛捕获连接，它利用醛和胺的高化学选择性反应性来加强现有技术难以连接的氨基酸残基和肽之间的酰胺键形成。
• ALDEHYDE CAPTURE LIGATION TECHNOLOGY FOR SYNTHESIS OF AMIDE BONDS
  申请人：New York University

  公开号：US20170247324A1

  公开（公告）日：2017-08-31

  The present invention relates to ligation agents and their use in making an amide ligation product. Methods of making the ligation agents are also disclosed.

  本发明涉及连接剂及其在制备酰胺连接产物中的应用。还公开了制备连接剂的方法。
• COMPOSITIONS FOR THE TREATMENT OR PROPHYLAXIS OF VIRAL INFECTIONS
  申请人：Balzarini Jan

  公开号：US20100256087A1

  公开（公告）日：2010-10-07

  A compound of the general formula (III): wherein X is O, S, NH or CH 2 ; Y is O, S or NH; Z is O, S or CH 2 ; R 1 is C 1-8 alkyl, especially C 1-6 alkyl, preferably n-alkyl, e.g., n-pentyl or n-hexyl; at least one of R 2 and R 3 is H—[R 4 -R 5 ] n —R 6 —, in which: H—[R 4 -R 5 ] n — comprises an oligopeptide, R 4 being an amino acid and R 5 being an amino acid selected from proline, alanine, hydroxyproline, dihydroxyproline, thiazolidinecarboxylic acid (thioproline), dehydroproline, pipecolic acid (L-homoproline), azetidinecarboxylic acid, aziridinecarboxylic acid, glycine, serine, valine, leucine, isoleucine and threonine, R 6 is a neutral, non-polar amino acid moiety that is bonded to R 5 by a peptide bond, and n is 1, 2, 3, 4 or 5; and the other of R 3 and R 2 is H—[R 4 -R 5 ]n-R 6 — or H; or a pharmaceutically acceptable salt thereof.

  通式（III）的化合物：其中X为O、S、NH或CH2；Y为O、S或NH；Z为O、S或 ；R1为C1-8烷基，特别是C1-6烷基，最好是n-烷基，例如n-戊基或n-己基；R2和R3中至少一个为H—[R4-R5]n—R6—，其中：H—[R4-R5]n—包括寡肽，R4为氨基酸，R5为从脯氨酸、丙氨酸、羟脯氨酸、二羟脯氨酸、噻唑烷羧酸（硫代脯氨酸）、去氢脯氨酸、吡咯烷羧酸（L-异脯氨酸）、氮杂环丙氨酸、氮杂环丙氨酸、甘氨酸、丝氨酸、缬氨酸、亮氨酸、异亮氨酸和苏氨酸中选择的氨基酸，R6是通过肽键与R5结合的中性、非极性氨基酸基团，n为1、2、3、4或5；R3和R2中的另一个为H—[R4-R5]n-R6—或H；或其药学上可接受的盐。
• [EN] PRODRUGS CLEAVABLE BY CD26<br/>[FR] PROMEDICAMENTS POUVANT ETRE CLIVES A MOYEN DE CD26
  申请人：LEUVEN K U RES & DEV

  公开号：WO2004098644A1

  公开（公告）日：2004-11-18

  The present invention provides a new prodrug technology and new prodrugs in order to increase the solubility, to modulate plasma protein binding or to enhance the biovailability of a drug. In the present invention the prodrugs are conjugates of a therapeutic compound and a peptide (eg tetrapeptide or hexapeptide) wherein the conjugate is cleavable by dipeptidyl-peptidases, more preferably by CD26, also known as DPPIV (dipeptidyl aminodipeptidase IV). The present invention furthermore provides a method of producing said prodrugs, to enhance brain and lymphatic delivery of drugs and/or to extend drug half-lives in plasma.

  本发明提供了一种新的前药技术和新的前药，以增加药物的溶解度，调节血浆蛋白结合或增强药物的生物利用度。在本发明中，前药是治疗化合物和肽（例如四肽或六肽）的结合物，其中结合物可被二肽肽酶（更优选为CD26，也称为DPPIV，即二肽氨二肽酶IV）水解。本发明还提供了一种生产所述前药的方法，以增强药物在大脑和淋巴系统中的传递，并/或延长药物在血浆中的半衰期。
• Dipeptidyl Peptidase IV-Activated Prodrugs of Anti-Varicella Zoster Virus Bicyclic Nucleoside Analogues Containing Different Self-Cleavage Spacer Systems
  作者：Alberto Diez-Torrubia、Silvia Cabrera、Ingrid De Meester、María-José Camarasa、Jan Balzarini、Sonsoles Velázquez

  DOI：10.1002/cmdc.201200295

  日期：2012.9

  stable. Most prodrugs containing a dipeptidyl linker efficiently converted into the BCNA parent drug. In contrast, the Val‐Pro alkyldiamino prodrugs converted predominantly into their alkyldiamino prodrug intermediates in the presence of CD26 and human serum. A marked increase in water solubility was observed for all prodrugs. In contrast to the parent compound, a tetrapeptide prodrug containing the Val‐Val

  合成了一种新型的双环抗病毒双环核苷类似物（BCNA）双前药，该双环前药在Val-Pro二肽序列与母体化合物之间带有环化自切割间隔子，并通过DPPIV / CD26酶进行了活化评估以及它们在人和牛血清中的稳定性。在缓冲溶液中，发现氨基甲酸酯和酯前药是化学稳定的。大多数含有二肽基接头的前药可有效地转化为BCNA母体药物。相反，Val-Pro烷基二氨基前药在存在CD26和人血清的情况下主要转化为烷基二氨基前药中间体。观察到所有前药的水溶性均显着增加。与母体化合物相比，