1-[(9H-芴-9-基甲氧基)羰基]-4-{[(9H-芴-9-基甲氧基)羰基]氨基}-4-哌啶羧酸 | 252029-00-8

• 分子结构分类: 有机化合物 - 苯类化合物 - 芴
• 中文名称: 1-[(9H-芴-9-基甲氧基)羰基]-4-{[(9H-芴-9-基甲氧基)羰基]氨基}-4-哌啶羧酸
• 英文名称: 1-Fmoc-4-(Fmoc-amino)piperidine-4-carboxylic acid
• 英文别名: Fmoc-Pip(Fmoc)-OH；1-(((9H-Fluoren-9-yl)methoxy)carbonyl)-4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)piperidine-4-carboxylic acid；1-(9H-fluoren-9-ylmethoxycarbonyl)-4-(9H-fluoren-9-ylmethoxycarbonylamino)piperidine-4-carboxylic acid
• CAS: 252029-00-8
• 化学式: C₃₆H₃₂N₂O₆
• 分子量: 588.66
• InChiKey: YCGIGJPLYCPSOP-UHFFFAOYSA-N

物化性质

• 沸点：
  810.4±65.0 °C(Predicted)
• 密度：
  1.40±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  6
• 重原子数：
  44
• 可旋转键数：
  8
• 环数：
  7.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  105
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  1-[(9H-芴-9-基甲氧基)羰基]-4-{[(9H-芴-9-基甲氧基)羰基]氨基}-4-哌啶羧酸 在 氯化亚砜 作用下， 反应 2.33h， 生成 4-chlorocarbonyl-4-(9H-fluoren-9-ylmethoxycarbonylamino)-piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester
  参考文献：
  名称：

  WO2008/75109

  摘要：

  公开号：

文献信息

• Synthesis and in Vitro Screening of New Series of 2,6-Dipeptidyl-anthraquinones: Influence of Side Chain Length on HIV-1 Nucleocapsid Inhibitors
  作者：Francesco Frecentese、Alice Sosic、Irene Saccone、Elia Gamba、Kristina Link、Angelica Miola、Marta Cappellini、Massimiliano Gianni Cattelan、Beatrice Severino、Ferdinando Fiorino、Elisa Magli、Angela Corvino、Elisa Perissutti、Dan Fabris、Barbara Gatto、Giuseppe Caliendo、Vincenzo Santagada

  DOI：10.1021/acs.jmedchem.5b01494

  日期：2016.3.10

  2,6-Dipeptidyl-anthraquinones are a promising class of nucleic acid-binding compounds that act as NC inhibitors in vitro. We designed, synthesized, and tested new series of 2,6-disubstituted-anthraquinones, which are able to bind viral nucleic acid substrates of NC. We demonstrate here that these novel derivatives interact preferentially with noncanonical structures of TAR and cTAR, stabilize their

  2，6-二肽基蒽醌是一类有前途的核酸结合化合物，在体外可作为NC抑制剂。我们设计，合成和测试了新系列的2,6-二取代蒽醌，它们能够结合NC的病毒核酸底物。我们在这里证明，这些新型衍生物优先与TAR和cTAR的非规范结构相互作用，稳定其动力学，并干扰NC伴侣活性。
• Non-Natural Linker Configuration in 2,6-Dipeptidyl-Anthraquinones Enhances the Inhibition of TAR RNA Binding/Annealing Activities by HIV-1 NC and Tat Proteins
  作者：Alice Sosic、Irene Saccone、Caterina Carraro、Thomas Kenderdine、Elia Gamba、Giuseppe Caliendo、Angela Corvino、Paola Di Vaio、Ferdinando Fiorino、Elisa Magli、Elisa Perissutti、Vincenzo Santagada、Beatrice Severino、Valentina Spada、Dan Fabris、Francesco Frecentese、Barbara Gatto

  DOI：10.1021/acs.bioconjchem.8b00104

  日期：2018.7.18

  The HIV-1 nucleocapsid (NC) protein represents an excellent molecular target for the development of anti-retrovirals by virtue of its well-characterized chaperone activities, which play pivotal roles in essential steps of the viral life cycle. Our ongoing search for candidates able to impair NC binding/annealing activities led to the identification of peptidyl-anthraquinones as a promising class of nucleic acid ligands. Seeking to elucidate the inhibition determinants and increase the potency of this class of compounds, we have now explored the effects of chirality in the linker connecting the planar nucleus to the basic side chains. We show here that the non-natural linker configuration imparted unexpected TAR RNA targeting properties to the 2,6-peptidyl-anthraquinones and significantly enhanced their potency. Even if the new compounds were able to interact directly with the NC protein, they manifested a consistently higher affinity for the TAR RNA substrate and their TAR-binding properties mirrored their ability to interfere with NC-TAR interactions. Based on these findings, we propose that the viral Tat protein, sharing the same RNA substrate but acting in distinct phases of the viral life cycle, constitutes an additional druggable target for this class of peptidyl-anthraquinones. The inhibition of Tat-TAR interaction for the test compounds correlated again with their TAR-binding properties, while simultaneously failing to demonstrate any direct Tat-binding capabilities. These considerations highlighted the importance of TAR RNA in the elucidation of their inhibition mechanism, rather than direct protein inhibition. We have therefore identified anti-TAR compounds with dual in vitro inhibitory activity on different viral proteins, demonstrating that it is possible to develop multitarget compounds capable of interfering with processes mediated by the interactions of this essential RNA domain of HIV-1 genome with NC and Tat proteins.

  HIV-1 核苷酸蛋白（NC）是开发抗逆转录病毒药物的绝佳分子靶标，因为它具有特性良好的伴侣活性，在病毒生命周期的关键步骤中发挥着举足轻重的作用。我们一直在寻找能够损害 NC 结合/退火活动的候选药物，结果发现肽基蒽醌是一类很有前景的核酸配体。为了阐明抑制决定因素并提高这类化合物的效力，我们现在探索了连接平面核与碱性侧链的连接体中手性的影响。我们在此表明，非天然连接体构型赋予了 2,6-肽基蒽醌类化合物意想不到的 TAR RNA 靶向特性，并显著增强了它们的效力。即使新化合物能够直接与 NC 蛋白相互作用，它们对 TAR RNA 底物的亲和力也一直较高，其 TAR 结合特性反映了它们干扰 NC-TAR 相互作用的能力。基于这些发现，我们认为病毒 Tat 蛋白具有相同的 RNA 底物，但在病毒生命周期的不同阶段起作用，是这类肽基蒽醌类药物的另一个可治疗靶点。测试化合物对 Tat-TAR 相互作用的抑制作用再次与它们的 TAR 结合特性相关，同时也未能证明它们具有任何直接结合 Tat 的能力。这些考虑突出了 TAR RNA 在阐明其抑制机制方面的重要性，而不是直接抑制蛋白质。因此，我们发现了对不同病毒蛋白具有双重体外抑制活性的抗 TAR 化合物，这表明我们有可能开发出能够干扰 HIV-1 基因组中这一重要 RNA 结构域与 NC 和 Tat 蛋白相互作用过程的多靶点化合物。
• Design, synthesis and biological evaluation of TAR and cTAR binders as HIV-1 nucleocapsid inhibitors
  作者：Alice Sosic、Francesco Frecentese、Elisa Perissutti、Laura Sinigaglia、Vincenzo Santagada、Giuseppe Caliendo、Elisa Magli、Antonio Ciano、Giuseppe Zagotto、Cristina Parolin、Barbara Gatto

  DOI：10.1039/c3md00212h

  日期：——

  We designed, synthesized and tested novel 2,6-disubstituted-anthraquinones able to bind dynamic secondary structures of nucleic acids, such as TAR RNA and its reverse transcript cTAR, leading to inhibition of the chaperone activities of the nucleocapsid NCp7, a highly conserved viral protein implied in crucial steps of HIV-1 replication.

  我们设计，合成和测试了能够结合核酸的动态二级结构（例如TAR RNA及其逆转录cTAR）的新型2,6-二取代蒽醌，从而抑制了高度保守的病毒核衣壳NCp7的伴侣活性。蛋白暗示HIV-1复制的关键步骤。
• SUBSTITUTED PIPERIDINES HAVING PROTEIN KINASE INHIBITING ACTIVITY
  申请人：Woodhead Steven John

  公开号：US20100093748A1

  公开（公告）日：2010-04-15

  The invention provides PKA and PKB kinase-inhibiting compounds of the formula (I): or salts, solvates, tautomers or N-oxides thereof, wherein E is a five membered heteroaryl ring containing 1, 2, 3 or 4 heteroatoms selected from O, N and S provided that no more than 1 heteroatom may be other than N; q and r are each is 0 or 1; provided that q+r is 1 or 2; T is N or a group CR 5 ; J 1 -J 2 is N═C(R 6 ), (R 7 )C═N, (R 8 )N—C(O), (R 8 ) 2 C—C(O), N═N or (R 7 )C═C(R 6 ); Q 3 is a bond or a saturated C 1-3 hydrocarbon linker group optionally substituted by fluorine and hydroxy; G is NR 2 R 3 , CN or OH; m and n are each 0 or 1, provided that m+n is 1 or 2, and provided also that m or n are each 0 when the adjacent ring member of ring E is S or O; R 1a and R 1b are the same or different and each is hydrogen or a substituent R 10 ; or R 1a and R 1b together with the carbon atoms or heteroatoms to which they are attached form a 5 or 6-membered aryl or heteroaryl ring, wherein the aryl or heteroaryl rings are optionally substituted by one or more substituents R 10 ; and R 2 , R 3 , R 4 , R 5 , R 7 , R 6 , R 8 , and R 10 are as defined in the claims.

  本发明提供了式(I)的PKA和PKB激酶抑制化合物，或其盐、溶剂化物、互变异构体或N-氧化物，其中E是一个五元杂环芳基环，包含1、2、3或4个从O、N和S中选择的杂原子，但不得多于1个杂原子不是N；q和r各自为0或1；前提是q+r为1或2；T为N或CR5基团；J1-J2为N═C(R6)、(R7)C═N、(R8)N—C(O)、(R8)2C—C(O)、N═N或(R7)C═C(R6)；Q3为键或饱和的C1-3烃基连接基团，可选地被氟和羟基取代；G为NR2R3、CN或OH；m和n各自为0或1，前提是m+n为1或2，且当环E的相邻环成员为S或O时，m或n各自为0；R1a和R1b相同或不同，各自为氢或取代基R10；或R1a和R1b与它们所连接的碳原子或杂原子一起形成一个5或6元芳基或杂芳基环，其中芳基或杂芳基环可选地被一个或多个取代基R10取代；R2、R3、R4、R5、R7、R6、R8和R10如权利要求所定义。
• SUBSTITUTED PIPERIDINES CONTAINING A HETEROARYLAMIDE OR HETEROARYLPHENYL MOIETY
  申请人：Woodhead Steven John

  公开号：US20100120798A1

  公开（公告）日：2010-05-13

  The invention provides compounds of the formula (I) having PKA and PKB kinase inhibiting compounds of the formula (I): GP 1 J T 2 J N 4 R N H (I) or salts, solvates, tautomers or N-oxides thereof, wherein (1) GP is a group GP1: HET 2a a Q G (HNCO)f 7 (R)x N * (GP1) (2) GP is a group GP2: 10 (R)r O 2a a QG (CH2)w N V H N * (GP2) wherein HET is a monocyclic or bicyclic heterocyclic group containing up to 4 heteroatom ring members; the ring V is a monocyclic or bicyclic heteroaryl group of 5 to 10 ring members; and J1, J2, R4, R7, R10, Q2a, Ga, x, w and f are as defined in the claims

  本发明提供了公式（I）的化合物，它们具有PKA和PKB激酶抑制化合物的公式（I）：GP 1 J T 2 J N 4 R N H（I）或其盐，溶剂化物，互变异构体或N-氧化物，其中（1）GP是一个GP1组：HET 2a a Q G（HNCO）f 7（R）x N *（GP1）（2）GP是一个GP2组：10（R）r O 2a a QG（CH2）w N V H N *（GP2），其中HET是一个含有最多4个杂环环成员的单环或双环杂环基团；环V是5到10个环成员的单环或双环杂芳基基团；而J1，J2，R4，R7，R10，Q2a，Ga，x，w和f如权利要求所定义。