diphenyl α-N(benzyloxycarbonyl)amino-(4-(di-Bocguanidiniumphenyl))methanephosphonate | 695172-01-1

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: diphenyl α-N(benzyloxycarbonyl)amino-(4-(di-Bocguanidiniumphenyl))methanephosphonate
• 英文别名: benzyl ((diphenoxyphosphoryl)(4-(N',N''-di-Boc)guanidinophenyl)methyl)carbamate；di-tert-butyl (E)-3-{p-[(benzyloxycarbonylamino)(diphenoxyphosphoryl)methyl]phenyl}-1,2-guanidinedicarboxylate；benzyl N-[[4-[bis[(2-methylpropan-2-yl)oxycarbonylamino]methylideneamino]phenyl]-diphenoxyphosphorylmethyl]carbamate
• CAS: 695172-01-1
• 化学式: C₃₈H₄₃N₄O₉P
• 分子量: 730.755
• InChiKey: RXQODWKZYQXBGL-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  8.7
• 重原子数：
  52
• 可旋转键数：
  17
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.26
• 拓扑面积：
  163
• 氢给体数：
  3
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  diphenyl α-N(benzyloxycarbonyl)amino-(4-(di-Bocguanidiniumphenyl))methanephosphonate 在 palladium on activated charcoal TEA 、 氢气 、 O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate 作用下， 以 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 8.17h， 生成 diphenyl (N-benzyloxycarbonyl-L-alanyl)amino-(4-(N,N'-bis(tert-butyloxycarbonyl)guanyl)phenyl)methanephosphonate
  参考文献：
  名称：

  Development of Irreversible Diphenyl Phosphonate Inhibitors for Urokinase Plasminogen Activator

  摘要：

  In this letter we report the synthesis and biochemical evaluation of selective, irreversible diphenyl phosphonate inhibitors for urokinase plasminogen activator (uPA). A diphenyl phosphonate group was introduced on the substratelike peptide Z-D-Ser-Ala-Arg, and modification of the guanidine side chain was investigated. A guanylated benzyl group appeared the most promising side chain modification. A k(app) value in the 10(3) M-1 s(-1) range for uPA was obtained, together with a selectivity index higher than 240 toward other trypsin-like proteases such as tPA, thrombin, plasmin, and FXa.

  DOI：

  10.1021/jm0499209
• 作为产物：
  描述：

  对氨基苯甲醇 在 sodium hydroxide 、 TEA 、 copper(II) bis(trifluoromethanesulfonate) 、 戴斯-马丁氧化剂 、 三氟乙酸 作用下， 以 1,4-二氧六环 、 甲醇 、 二氯甲烷 、 乙腈 为溶剂， 反应 10.0h， 生成 diphenyl α-N(benzyloxycarbonyl)amino-(4-(di-Bocguanidiniumphenyl))methanephosphonate
  参考文献：
  名称：

  Development of Irreversible Diphenyl Phosphonate Inhibitors for Urokinase Plasminogen Activator

  摘要：

  In this letter we report the synthesis and biochemical evaluation of selective, irreversible diphenyl phosphonate inhibitors for urokinase plasminogen activator (uPA). A diphenyl phosphonate group was introduced on the substratelike peptide Z-D-Ser-Ala-Arg, and modification of the guanidine side chain was investigated. A guanylated benzyl group appeared the most promising side chain modification. A k(app) value in the 10(3) M-1 s(-1) range for uPA was obtained, together with a selectivity index higher than 240 toward other trypsin-like proteases such as tPA, thrombin, plasmin, and FXa.

  DOI：

  10.1021/jm0499209

文献信息

• [EN] NOVEL KLK4 INHIBITORS<br/>[FR] NOUVEAUX INHIBITEURS DE KLK4
  申请人：UNIV ANTWERPEN

  公开号：WO2015144933A1

  公开（公告）日：2015-10-01

  The present invention relates to novel compounds and probes which have a common chemical structure necessary to obtain potent inhibitory activity against KLK4 and/or may be used for the detection of KLK4 peptides and their activity. It further relates to the use of these compounds and methods for inhibiting and/or detecting KLK4 activity in vitro and in vivo by making use of said probes or inhibitors. The compounds of the invention differ from prior art compounds at least in the presence of phenyl guanidine (instead of e.g. benzyl guanidine) and/or the presence of a heteroatom in the tail group, their combined presence unexpectedly leading to potent and selective KLK4 inhibitory activity.

  本发明涉及具有共同化学结构的新化合物和探针，这种结构对于获得强大的对KLK4的抑制活性是必要的，或者可用于检测KLK4肽及其活性。它进一步涉及利用这些化合物和方法通过利用所述的探针或抑制剂来抑制和/或检测体外和体内的KLK4活性。本发明的化合物与先前的化合物不同，至少在于存在苯基胍（而不是苄基胍等）和/或尾基中存在杂原子，它们的共同存在意外地导致强大和选择性的KLK4抑制活性。
• The first potent diphenyl phosphonate KLK4 inhibitors with unexpected binding kinetics
  作者：Jeroen van Soom、Giuliana Cuzzucoli Crucitti、Rafaela Gladysz、Pieter van der Veken、Roberto Di Santo、Ingmar Stuyver、Victoria Buck、Anne-Marie Lambeir、Viktor Magdolen、Jurgen Joossens、Koen Augustyns

  DOI：10.1039/c5md00288e

  日期：——

  We report the first highly potent and selective small-molecule KLK4 inhibitors, showing surprising reversible binding kinetics.

  我们报告了第一批高效、选择性的小分子KLK4抑制剂，显示出令人惊讶的可逆结合动力学。
• Tuning activity-based probe selectivity for serine proteases by on-resin ‘click’ construction of peptide diphenyl phosphonates
  作者：Sevnur Serim、Susanne V. Mayer、Steven H. L. Verhelst

  DOI：10.1039/c3ob40907d

  日期：——

  Activity-based probes (ABPs) are powerful tools for functional proteomics studies. Their selectivity can be influenced by modification of a recognition element that interacts with pockets near the active site. For serine proteases there are a limited number of simple and efficient synthetic procedures for the development of selective probes. Here we describe a new synthetic route combining solid and solution phase chemistries to generate a small library of diphenyl phosphonate probes. Building blocks carrying a P1 recognition element and an electrophilic phosphonate warhead were prepared in solution and ‘clicked’ on-resin onto a tripeptide. We show the ability to modulate the activity and selectivity of diphenyl phosphonate ABPs and demonstrate activity-dependent labeling of endogenous proteases within a tissue proteome. The herein described synthetic approach therefore serves as a valuable method for rapid diversification of serine protease ABPs.

  基于活性的探针（ABPs）是功能蛋白质组学研究的强大工具。对与活性位点附近口袋相互作用的识别元件进行修饰可影响探针的选择性。对于丝氨酸蛋白酶来说，用于开发选择性探针的简单而高效的合成程序数量有限。在这里，我们介绍了一种结合固相和溶相化学的新合成路线，以生成一个小型的二苯基膦酸盐探针库。我们在溶液中制备了携带 P1 识别元件和亲电性膦酸盐弹头的构建模块，并通过树脂将其粘附到三肽上。我们展示了调节二苯基膦酸盐 ABPs 活性和选择性的能力，并展示了组织蛋白质组中内源性蛋白酶的活性依赖性标记。因此，本文所述的合成方法是快速实现丝氨酸蛋白酶 ABPs 多样化的重要方法。
• Furin-targeting activity-based probes with phosphonate and phosphinate esters as warheads
  作者：Shanping Ji、Steven H. L. Verhelst

  DOI：10.1039/d3ob00948c

  日期：——

  Activity-based probes (ABPs) are covalent chemical tools that are widely used to target proteases in chemical biology. Here, we report a series of novel ABPs for the serine protease furin with phosphonate and phosphinate esters as reactive electrophiles. We show that these probes covalently label furin and have nanomolar potencies, because of proposed interactions with the different recognition pockets around

  基于活性的探针 (ABP) 是共价化学工具，广泛用于化学生物学中的靶向蛋白酶。在这里，我们报道了一系列以膦酸酯和次膦酸酯作为反应性亲电子试剂的丝氨酸蛋白酶弗林蛋白酶的新型 ABP。我们表明，这些探针共价标记弗林蛋白酶并具有纳摩尔效力，因为所提出的与弗林蛋白酶活性位点周围不同识别袋的相互作用。
• KLK4 inhibitors
  申请人：Universiteit Antwerpen

  公开号：US10017527B2

  公开（公告）日：2018-07-10

  The present invention relates to novel compounds and probes which have a common chemical structure necessary to obtain potent inhibitory activity against KLK4 and/or may be used for the detection of KLK4 peptides and their activity. It further relates to the use of these compounds and methods for inhibiting and/or detecting KLK4 activity in vitro and in vivo by making use of said probes or inhibitors. The compounds of the invention differ from prior art compounds at least in the presence of phenyl guanidine (instead of e.g. benzyl guanidine) and/or the presence of a heteroatom in the tail group, their combined presence unexpectedly leading to potent and selective KLK4 inhibitory activity.

  本发明涉及新型化合物和探针，它们具有获得对 KLK4 的强效抑制活性所需的共同化学结构和/或可用于检测 KLK4 肽及其活性。本发明还涉及这些化合物的用途，以及利用所述探针或抑制剂抑制和/或检测体外和体内 KLK4 活性的方法。本发明化合物与现有技术化合物的不同之处至少在于苯基胍（而不是苄基胍）的存在和/或尾部基团中杂原子的存在，它们的联合存在意外地导致了强效和选择性的 KLK4 抑制活性。