L-N_α-(9-fluorenylmethoxycarbonyloxy)-4-[(di-tert-butyl)phosphonomethyl]phenylalanine | 166409-77-4

• 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: L-N_α-(9-fluorenylmethoxycarbonyloxy)-4-[(di-tert-butyl)phosphonomethyl]phenylalanine
• 英文别名: L-N^α-(9-fluorenylmethoxycarbonyl)-4-[(di-tert-butyl)phosphonomethyl]phenylalanine；Fmoc-[4-(O-di-tert-butyl)phosphonomethyl]-L-phenylalanine；Fmoc-L-Pmp(tBu)2-OH；(2S)-3-[4-[bis[(2-methylpropan-2-yl)oxy]phosphorylmethyl]phenyl]-2-(9H-fluoren-9-ylmethoxycarbonylamino)propanoic acid
• CAS: 166409-77-4
• 化学式: C₃₃H₄₀NO₇P
• 分子量: 593.657
• InChiKey: ORTJTEQKISNAEV-LJAQVGFWSA-N

物化性质

• 沸点：
  744.3±60.0 °C(Predicted)
• 密度：
  1.214±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  5.7
• 重原子数：
  42
• 可旋转键数：
  13
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.39
• 拓扑面积：
  111
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  L-N_α-(9-fluorenylmethoxycarbonyloxy)-4-[(di-tert-butyl)phosphonomethyl]phenylalanine 在 N,N′-二叔丁基碳二亚胺 、 1-羟基苯并三唑 、 N,N-二异丙基乙胺 作用下， 以 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 3.17h， 生成 tert-butyl 2-[[(2S)-1-[[1-[[(2S)-4-amino-1-[3-(5-methylindol-1-yl)propylamino]-1,4-dioxobutan-2-yl]carbamoyl]cyclohexyl]amino]-3-[4-[bis[(2-methylpropan-2-yl)oxy]phosphorylmethyl]phenyl]-1-oxopropan-2-yl]amino]-2-oxoacetate
  参考文献：
  名称：

  Inhibition of Grb2 SH2 Domain Binding by Non-Phosphate-Containing Ligands. 2. 4-(2-Malonyl)phenylalanine as a Potent Phosphotyrosyl Mimetic

  摘要：

  Nonhydrolyzable phosphotyrosyl (pTyr) mimetics serve as important components of many competitive Grb2 SH2 domain inhibitors. To date, the most potent of these inhibitors have relied on phosphonate-based structures to replace the 4-phosphoryl group of the parent pTyr residue. Reported herein is the design and evaluation of a new pTyr mimetic, p-malonylphenylalanine (Pmf), which does not contain phosphorus yet, in Grb2 SH2 domain binding systems, approaches the potency of phosphonate-based pTyr mimetics. When incorporated into high affinity Grb2 SH2 domain-directed platforms, Pmf is 15-20 times more potent than the closely related previously reported pTyr mimetic, O-malonyltyrosine (OMT). Pmf-containing inhibitors show inhibition constants as low as 8 nM in extracellular Grb2 binding assays and in whole cell systems, effective blockade of both endogenous Grb2 binding to cognate erbB-2, and downstream MAP kinase activation. Evidence is provided that use of an N-alpha-oxalyl auxiliary enhances effectiveness of Pmf and other inhibitors in both extracellular and intracellular contexts. As one of the most potent Grb2 SH2 domain-directed pTyr mimetics yet disclosed, Pmf may potentially have utility in the design of new chemotherapeutics for the treatment of various proliferative diseases, including breast cancer.

  DOI：

  10.1021/jm9904248
• 作为产物：
  描述：

  9-芴甲基-N-琥珀酰亚胺基碳酸酯 、 L-4-((di-tert-butyl)phosphonomethyl)phenylalanine 在 碳酸氢钠 作用下， 以 水 、 乙腈 为溶剂， 以91%的产率得到L-N_α-(9-fluorenylmethoxycarbonyloxy)-4-[(di-tert-butyl)phosphonomethyl]phenylalanine
  参考文献：
  名称：

  Concise and Enantioselective Synthesis of Fmoc-Pmp(Bu^t)₂-OH and Design of Potent Pmp-Containing Grb2-SH2 Domain Antagonists

  摘要：

  L-Phosphonomethylphenylalanine (L-Pmp) is an important phosphatase-resistant pTyr analogue. A most concise and stereoselective approach to the synthesis of the suitably protected Fmoc-Pmp(Bu-t)(2)-OH was developed in order to incorporate the functionally significant L-Pmp residue into peptides and peptidomimetics efficiently using standard Fmoc protocol. With this key building block, we are able to efficiently synthesize a series of potent Pmp-containing Grb2-SH2 domain antagonists, which can be used as chemotherapeutic leads for the treatment of erbB2-overexpressed breast cancer.

  DOI：

  10.1021/ol035078+

文献信息

• Potent Inhibition of Grb2 SH2 Domain Binding by Non-Phosphate-Containing Ligands
  作者：Zhu-Jun Yao、C. Richter King、Tin Cao、James Kelley、George W. A. Milne、Johannes H. Voigt、Terrence R. Burke

  DOI：10.1021/jm980388x

  日期：1999.1.1

  Development of Grb2 Src homology 2 (SH2) domain binding inhibitors has important implications for treatment of a variety of diseases, including several cancers. In cellular studies, inhibitors of Grb2 SH2 domain binding have to date been large, highly charged peptides which relied on special transport devices for cell membrane penetration. Work presented in the current study examines a variety of pTyr mimetics in the context of a high-affinity Grb2 binding platform. Among the analogues studied are new norm-phosphorus-containing pTyr mimetics 23a and 23b which, when incorporated into tripeptide structures 18f and 20f, are able to inhibit Grb2 SH2 domain binding with affinities among the best yet reported for non-phosphorus-containing SH2 domain inhibitors (IC50 values of 6.7 and 1.3 mu M, respectively). The present study has also demonstrated the usefulness of the Na-oxalyl group as an auxiliary which enhances the binding potency of both phosphorus- and non-phosphorus-containing pTyr mimetics. When combined with the (phosphonomethyl)phenylalanine (Pmp) residue to give analogues such as L-20d, potent inhibition of Grb2 SH2 domain binding can be achieved both in extracellular assays using isolated Grb2 SH2 domain protein and in intracellular systems measuring the association of endogenous Grb2 with its cognate p185(erbB-2) ligand. These latter effects can be achieved at micromolar to submicromolar concentrations without prodrug derivatization. The oxalyl-containing pTyr mimetics presented in this study should be of general usefulness for the development of other Grb2 SH2 domain antagonists, independent of the beta-bend-mimicking platform utilized for their display.
• Enantioselective synthesis of N-fmoc protected di-tert-butyl 4-phosphonomethyl-L-phenylalanine : a hydrolytically stable analogue of O-phosphotyrosine
  作者：Wang-Qing Liu、Bernard P. Roques、Christiane Garbay-Jaureguiberry

  DOI：10.1016/0957-4166(95)00050-y

  日期：1995.3

  Fmoc-L-Pmp(tBu)(2)-OH was prepared with high enantiomeric purity by an asymmetric synthetic pathway, using a camphor sultam as chiral auxiliary.
• Discovery of Potent Antagonists of the Interaction between Human Double Minute 2 and Tumor Suppressor p53
  作者：Carlos García-Echeverría、Patrick Chène、Marcel J. J. Blommers、Pascal Furet

  DOI：10.1021/jm990966p

  日期：2000.8.1
• Preparation of l-Nα-Fmoc-4-[di-(tert-butyl)phosphonomethyl]phenylalanine from l-tyrosine
  作者：Zhu-Jun Yao、Yang Gao、Terrence R Burke

  DOI：10.1016/s0957-4166(99)00385-7

  日期：1999.9

  The unnatural amino acid analogue, 4-(phosphonomethyl)phenylalanine (Pmp, 2), has proven to be a valuable tool for studying protein-tyrosine kinase dependent signal transduction, where it is most often incorporated into peptides or peptide mimetics as a phosphatase-stable phosphotyrosyl mimetic. Although Pmp has been prepared previously bearing a number of protection strategies, the N-alpha-Fmoc 4- [di-(tert-butyl)phosphonomethyl] phenylalanine form [(N alpha-Fmoc-L-Pmp('Bu-2)-OH, 3] is particularly attractive since it can be cleanly introduced into peptides using standard Fmoc protocols. Synthesis of 3 was first reported as its (D/L)-racemate, and subsequently as its L-3 enantiomer, with the latter synthesis having relied on induction of chirality using a camphor sultam auxiliary. Reported herein is an alternate enantioselective synthesis of L-3 in high ensantiomeric purity by procedures which derive the stereochemistry of the final product directly from the starting amino acid, without the need for chiral induction. A key feature of the route is the racemization-free nucleophilic substitution of lithium di-tert-butyl phosphite onto protected 4-bromomethylphenylalanine (17). (C) 1999 Elsevier Science Ltd. All rights reserved.
• [EN] PHOSPHONOALKYL PHENYLALANINE COMPOUNDS SUITABLY PROTECTED FOR USE IN PEPTIDE SYNTHESIS<br/>[FR] COMPOSES DE PHOSPHONOALKYLE PHENYLALANINE PROTEGES DE MANIERE APPROPRIEE UTILISABLES DANS LA SYNTHESE PEPTIDIQUE
  申请人：THE GOVERNMENT OF THE UNITED STATES OF AMERICA as represented by THE DEPARTMENT OF HEALTH AND HUMAN SERVICES

  公开号：WO1993025561A1

  公开（公告）日：1993-12-23

  (EN) The disclosure is concerned with providing phosphonic acid-containing derivatives of phenylalanine and optically active isomers thereof, which are functionalized in a manner which makes them suitable for facile incorporation into peptides using standard solid-phase or solution-phase techniques.(FR) Dérivés contenant de l'acide phosphonique issus de la phénylalanine et de ses isomères optiquement actifs. Ces dérivés sont fonctionnalisés de manière à pouvoir être incorporés facilement dans des peptides à l'aide de techniques standard en phase solide ou en solution.