N-[(1,1-二甲基乙氧基)羰基]-D-天冬氨酸4-(9H-芴-9-基甲基)酯 | 123417-19-6

• 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
• 中文名称: N-[(1,1-二甲基乙氧基)羰基]-D-天冬氨酸4-(9H-芴-9-基甲基)酯
• 英文名称: Boc-DAsp(β-OFm)
• 英文别名: Boc-D-Asp(OFm)-OH；(2R)-4-(9H-fluoren-9-ylmethoxy)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-4-oxobutanoic acid
• CAS: 123417-19-6
• 化学式: C₂₃H₂₅NO₆
• 分子量: 411.455
• InChiKey: NHLRMCFWGFPSLT-LJQANCHMSA-N

物化性质

• 熔点：
  137-138 °C
• 沸点：
  620.8±55.0 °C(Predicted)
• 密度：
  1.251±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  30
• 可旋转键数：
  9
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  102
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  N-[(1,1-二甲基乙氧基)羰基]-D-天冬氨酸4-(9H-芴-9-基甲基)酯 在 1-羟基苯并三唑一水物 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 、 N,N-二异丙基乙胺 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 144.0h， 生成 Boc-D-Asp-Ala-O-t-Bu
  参考文献：
  名称：

  专为肠肽转运蛋白设计的模型前药。一种将含羟基化合物偶联至二肽的合成方法。

  摘要：

  可以利用位于小肠中的人肽转运蛋白hPepT1，通过将它们附着于hPepT1识别的二肽上来增加药物或模型药物的吸收。已开发出用于此类模型前药的合成方案，其中通过可水解的酯键将含有羟基的模型药连接到酶稳定的二肽上。此外，将在苯环的4-位具有多个取代基的许多苄醇与D-Asp-Ala和D-Glu-Ala偶联。理想情况下，前药应在上小肠中稳定，并在转运进入血液循环期间或之后转化为母体药物。因此，我们研究了苯环4位上取代基的电负性对水溶液在pH 6.0和7.4（分别对应于空肠和血液的pH）中稳定性的影响。另外，检查了取代基的电负性对稳定性在储存时的影响。在存储时分解的苯环的4-位上含有供电子取代基的模型前药是稳定的，而在4-位上没有取代基或吸电子取代基的模型前药是稳定的。在水溶液（pH 6.0和7.4）中，在4位上的吸电子取代基会降低模型前药的半衰期。这些数据提供了有关这类模型前药在储存和水性条件下稳定性的重要信息。

  DOI：

  10.1016/s0928-0987(01)00137-3
• 作为产物：
  描述：

  1-O-benzyl 4-O-(9H-fluoren-9-ylmethyl) (2R)-2-[(2-methylpropan-2-yl)oxycarbonylamino]butanedioate 生成 N-[(1,1-二甲基乙氧基)羰基]-D-天冬氨酸4-(9H-芴-9-基甲基)酯
  参考文献：
  名称：

  BOLIN, D. R.;WANG, C. T.;FELIX, A. M., ORG. PREP. AND PROCED. INT., 21,(1989) N, C. 67-74

  摘要：

  DOI：

文献信息

• Design, Synthesis, and Biological Activities of Cyclic Lactam Peptide Analogues of Dynorphin A(1−11)-NH₂
  作者：Feng-Di T. Lung、Nathan Collins、Dagmar Stropova、Peg Davis、Henry I. Yamamura、Frank Porreca、Victor J. Hruby

  DOI：10.1021/jm950369c

  日期：1996.1.1

  selectivity for kappa opioid receptors. Positions 2-6, 3-7, and 5-9 were chosen as the sites for incorporating cyclic conformational constraints. Cyclization between D-Asp(2) and Lys(6) in c[D-Asp(2),Lys(6)]Dyn A(1-11)-NH2 led to an analogue with pronounced potency and selectivity enhancement for the mu opioid receptor, whereas cyclization between D-Asp(3) and Lys(7) in c[D-Asp(3),Lys(7)]Dyn A(1-11)-NH2 led to

  我们以前已经报道了使用分子力学能量最小化方法由地址序列诱导的强啡肽A（Dyn A）与中央κ阿片受体的四种可能的结合构象。发现最低的能量构象在环化的地址序列中表现出α-螺旋构象。有人提出，环化地址序列中的α-螺旋构象或由消息序列的构象特征诱导的螺旋构象对于结合力和κ阿片受体选择性可能是重要的。在i和i + 4位之间的侧链至侧链内酰胺桥已显示稳定α-螺旋构象。因此，设计了一系列强啡肽A（1-11）-NH2的环状内酰胺类似物，通过豚鼠脑（GPB）结合测定法和豚鼠回肠（GPI）生物测定法合成和评估，以评估构象分析预测，并进一步研究对κ阿片受体具有高效能和选择性的构象要求。选择位置2-6、3-7和5-9作为合并循环构象约束的位点。在c [D-Asp（2），Lys（6）] Dyn A（1-11）-NH2中D-Asp（2）和Lys（6）之间的环化导致类似物具有明显的效能和对mu的选择性增强阿片受体，而c
• Design of Monocyclic (1−3) and Dicyclic (1−3/4−10) Gonadotropin Releasing Hormone (GnRH) Antagonists
  作者：Jean E. Rivier、John Porter、Laura A. Cervini、Sabine L. Lahrichi、Dean A. Kirby、R. Scott Struthers、Steven C. Koerber、Catherine L. Rivier

  DOI：10.1021/jm9901172

  日期：2000.3.1

  DNal(6),DAla(10)]GnRH (21, K(i) = 0.17 nM), which inhibited ovulation significantly at doses equal to or lower than 25 microgram/rat. These results were particularly unexpected in view of the critical role(s) originally ascribed to the side chains of residues 1 and 3.(1) Other closely related analogues, such as those where the [DAsp(1)(betaAla), DOrn(3)] cycle of 21 was changed to [DOrn(1)(betaAla), DAsp(3)]

  仔细分析cyclo（4-10）[Ac-Delta（3）Pro（1），DFpa（2），DTrp（3），Asp（4），DNal（6），Dpr（10）的NMR结构GnRH，dicyclo（4-10 / 5-8）[Ac-DNal（1），DCpa（2），DTrp（3），Asp（4），Glu（5），DArg（6），Lys（8）， Dpr（10）] GnRH和dicyclo（4-10 / 5，5'-8）[Ac-DNal（1），DCpa（2），DPal（3），Asp（4），Glu（5）（Gly） ），DArg（6），Dbu（8），Dpr（10）] GnRH表明，在N末端三肽中，II型可能会围绕残基1和2发生β旋转，而DTrp（可能会围绕γ旋转） 3）/ DPal（3）。这表明通过引入cyclo（1-3）支架来约束N端的可能性。环尺寸和组成的优化导致发现了cyclo（1-3）[Ac-DAsp（1），DCpa
• Design of Potent Dicyclic (1−5/4−10) Gonadotropin Releasing Hormone (GnRH) Antagonists
  作者：Jean E. Rivier、Guangcheng Jiang、R. Scott Struthers、Steven C. Koerber、John Porter、Laura A. Cervini、Dean A. Kirby、A. Grey Craig、Catherine L. Rivier

  DOI：10.1021/jm990116+

  日期：2000.3.1

  In three earlier papers, the structures and biological potencies of numerous mono- and dicyclic antagonists of GnRH were reported. Among these, two families, each containing two to four members were identified that had very high antagonist potencies in an antiovulatory assay (within a factor of 2 of those of the most potent linear analogues) and high affinities (K-i < 0.5 nM) for the rat GnRH receptor (rGnRHR). The most favored cycles bridged the side chains of residues (4-10),(1,2) (5-8),(2) (4-10/5-8),(2) (1-3),(3) and (1-3/4-10).(3) Our goal was to identify a consensus model of bioactive conformations of GnRH antagonists, yet these biocompatible constraints did not sufficiently restrain the spatial location of the N-terminal tripeptide with respect to the C-terminal heptapeptide, due largely to the rotational freedom about the bonds connecting these regions. Examination of models derived from NMR studies of cyclo(4-10) analogues suggested a large number of possible cyclic constraints such as cycle (0-8), (1-8), or (2-8). All analogues tested with these substitutions were inactive as antiovulatory agents at 1 mg/rat (5-9) and had low affinity for rGnRHR. On the other hand, bridging positions 3 and 8 with a [DAsp(3)] to [Dbu(8)] (12, K-i = 13 nM) or [Orn(8)] (13, K-i = 14 nM) in the parent compound cyclo(3-8)[Ac-DNal(1),DCpa(2),DXaa(3),Arg(5),DNal(6),Xbb(8),DAla(10)]GnRH yielded analogues that blocked ovulation at 250 mu g/rat. Analogue 14 (K-i = 2.3 nM), with a [DAsp(3), Lys(8)] bridge, was fully active at 50 mu g/rat. Loss of potency (> 20-fold) was observed with the substitution of [DAsp(3)] in 14 by [DGlu(3)] in 15 (K-i = 23 nM), Dicyclic analogues possessing the (4-10) cycle and selected (1-6), (2-6), and (2-8) cycles led to analogues that were inactive at doses of 500 mu g/rat or larger. Two analogues with (1-8/4-10) cycles (16, K-i = 1.1 nM) or (3-8/4-10) cycles (22, K-i = 17 nM) showed full antiovulatory potency at 250 mu g/rat. None of these substitutions yielded analogues potent enough (>80% inhibition of ovulation at 5 mu g/rat or less and K-i < 0.5 nM) to be candidates for structural analysis by NMR. On the other hand, four dicyclic (1,1'-5/4-10) analogues met this criterion: dicyclo(1,1'-5/4-10)[Ac-Asp(1)(Gly),DCpa(2),DTrp(3),Asp(4),Dbu(5), DNal(6),Dpr(10)]GnRH (32, K-i = 0.22 nM), dicyclo(1,1'-5/4-10)[Ac-Asp(1)(Gly),DCpa(2),DTrp(3),Asp(4),Dbu(5), DNal(6),Dpr(10)]GnRH (34, K-i = 0.38 nM), dicyclo(1,1'-5/4 - 10)[Ac-Asp(1)(beta Ala),DCpa(2), DTrp(3),Asp(4),Dbu(5),DNal(6),Dpr(10)]GnRH (40, K-i = 0.15 nM), and dicyclo(1,1'-5/4-10)[Ac-Glu(1)(Gly), DCpa(2),DTrp(3),Asp(4),Dbu(5),DNal(6),Dpr(10)]GnRH (41, K-i = 0.24 nM). Since they differed slightly in terms of the (1,1'-5) bridge length (21 and 22 atoms) and bridgehead configuration, we may hypothesize that they assume similar bioactive conformations that satisfy a very discriminating receptor, since many other closely related analogues were significantly less potent.
• Effect of 2′,6′-dimethyl-l-tyrosine (Dmt) on pharmacological activity of cyclic endomorphin-2 and morphiceptin analogs
  作者：Jakub Fichna、Renata Perlikowska、Anna Wyrębska、Katarzyna Gach、Justyna Piekielna、Jean Claude do-Rego、Geza Toth、Alicja Kluczyk、Tomasz Janecki、Anna Janecka

  DOI：10.1016/j.bmc.2011.10.040

  日期：2011.12

  This study reports the synthesis and biological evaluation of a series of new side-chain-to-side-chain cyclized endomorphin-2 (EM-2) and morphiceptin analogs of a general structure Tyr-c(Xaa-Phe-Phe-Yaa) NH(2) or Tyr-c(Xaa-Phe-D-Pro-Yaa)NH(2), respectively, where Xaa and Yaa were L/D Asp or L/D Lys. Further modification of these analogs was achieved by introduction of 2',6'-dimethyl-L-tyrosine (Dmt) instead of Tyr in position 1. Peptides were synthesized by solid phase method and cleaved from the resin by a microwave-assisted procedure.Dmt(1)-substituted analogs displayed high affinity at the mu-opioid receptors, remained intact after incubation with the rat brain homogenate and showed remarkable, long-lasting mu-opioid receptor-mediated antinociceptive activity after central, but not peripheral administration.Our results demonstrate that cyclization is a promising strategy in the development of new opioid analgesics, but further modifications are necessary to enhance the blood-brain barrier permeability. (C) 2011 Published by Elsevier Ltd.
• BOLIN, D. R.;WANG, C. T.;FELIX, A. M., ORG. PREP. AND PROCED. INT., 21,(1989) N, C. 67-74
  作者：BOLIN, D. R.、WANG, C. T.、FELIX, A. M.

  DOI：——

  日期：——