Z-Phe-Lys(ε-Boc)CH₂Br | 114480-06-7

• 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: Z-Phe-Lys(ε-Boc)CH₂Br
• 英文别名: Cbz-Phe-Lys(Boc)-BMK；Cbz-Phe-Lys(Boc)-CH2Br；benzyl N-[(2S)-1-[[(3S)-1-bromo-7-[(2-methylpropan-2-yl)oxycarbonylamino]-2-oxoheptan-3-yl]amino]-1-oxo-3-phenylpropan-2-yl]carbamate
• CAS: 114480-06-7
• 化学式: C₂₉H₃₈BrN₃O₆
• 分子量: 604.541
• InChiKey: OLTFUEJINDSCMR-ZEQRLZLVSA-N

物化性质

• 沸点：
  793.0±60.0 °C(Predicted)
• 密度：
  1.280±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  5.1
• 重原子数：
  39
• 可旋转键数：
  17
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.45
• 拓扑面积：
  123
• 氢给体数：
  3
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  Z-Phe-Lys(ε-Boc)CH₂Br 在 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 反应 2.0h， 生成 Z-Phe-Lys-CH2-Br
  参考文献：
  名称：

  达到目标的时间延长：利用半胱氨酸组织蛋白酶抑制剂来增强受体靶向药物的肿瘤保留能力†

  摘要：

  我们报告了利用不可逆的半胱氨酸组织蛋白酶抑制剂作为捕获剂以增加受体靶向药物的肿瘤停留时间的策略。掺入这些半胱氨酸组织蛋白酶捕获剂的靶向构建体能够与细胞内半胱氨酸组织蛋白酶形成高分子量加合物，从而在肿瘤组织中实现优异的保留。

  DOI：

  10.1039/c8cc05982a
• 作为产物：
  描述：

  N-Boc-L-赖氨酸甲酯盐酸盐 在 N-甲基吗啉 、 sodium hydroxide 、 氯甲酸异丁酯 作用下， 以 四氢呋喃 、 氯仿 、 乙腈 为溶剂， 反应 8.97h， 生成 Z-Phe-Lys(ε-Boc)CH₂Br
  参考文献：
  名称：

  Synthesis and Evaluation of Radioiodinated Acyloxymethyl Ketones as Activity-Based Probes for Cathepsin B

  摘要：

  Dipeptidyl (acyloxy)methyl ketones (AOMKs) were functionalized with different iodine-containing prosthetic groups to generate a library of candidate cathepsin B probes. Compound 23a, (S)-20-[(S)-2-{[(benzyloxy)carbonyl]amino}-3-phenylpropanamido]-1-(4-iodophenyl)-1,14,21-trioxo-5,8,11-trioxa-2,15-diazadocosan-22-yl 2,4,6-trimethylbenzoate, was identified as a potential lead through in vitro screening, having a K-i = 181 +/- 9 nM and demonstrating the ability to effectively label active cathepsin B in vitro. Its less potent analogue 11a, (S)-3-[(S)-2-{[(benzyloxy)carbonyl]amino}-3-phenylpropanamido]-7-[6-(4-iodobenzamido)hexanamido]-2-oxoheptyl 2,4,6-trimethylbenzoate, was also tested as a comparison. Biodistribution studies of the iodine-125-labeled compounds in MDA-MB-231 mouse xenografts exhibited tumor uptake of 0.58% +/- 0.06% injected dose per gram (ID/g) for [I-125]11a and 1.12% +/- 0.08% ID/g for [I-125]23a at 30 min. The tumor-to-blood ratios reached 1.2 for [I-125]23a and 1.6 for [I-125]11a after 23 h. The more hydrophilic [I-125]23a showed an improved clearance profile with a superior tumor-to-muscle ratio of 7.0 compared to 3.4 for [I-125]11a at 23 h. Iodinated AOMK ligands are suitable in vitro probes for cathepsin B and hold promise as a platform to develop molecular imaging probes.

  DOI：

  10.1021/jm501357r

文献信息

• Modulation of the inhibitor properties of dipeptidyl (acyloxy)methyl ketones toward the CaaX proteases
  作者：Anne-Marie R. Dechert、James P. MacNamara、Sarah R. Breevoort、Emily R. Hildebrandt、Ned W. Hembree、Adam C. Rea、Duncan E. McLain、Stephen B. Porter、Walter K. Schmidt、Timothy M. Dore

  DOI：10.1016/j.bmc.2010.07.041

  日期：2010.9

  Dipeptidyl (acyloxy) methyl ketones (AOMKs) have been identified as mechanism-based inhibitors of certain cysteine proteases. These compounds are also inhibitors of the integral membrane proteins Rce1p and Ste24p, which are proteases that independently mediate a cleavage step associated with the maturation of certain isoprenylated proteins. The enzymatic mechanism of Rce1p is ill-defined, whereas Ste24p is a zinc metalloprotease. Rce1p is required for the proper processing of the oncoprotein Ras and is viewed as a potential target for cancer therapy. In this study, we synthesized a small library of dipeptidyl AOMKs to investigate the structural elements that contribute to the inhibitor properties of this class of molecules toward Rce1p and Ste24p. The compounds were evaluated using a fluorescence-based in vitro proteolysis assay. The most potent dipeptidyl AOMKs contained an arginine residue and the identity of the benzoate group strongly influenced potency. A 'warhead' free AOMK inhibited Rce1p and Ste24p. The data suggest that the dipeptidyl AOMKs are not mechanism-based inhibitors of Rce1p and Ste24p and corroborate the hypothesis that Rce1p is not a cysteine protease. (C) 2010 Elsevier Ltd. All rights reserved.
• [EN] PHOTODYNAMIC QUENCHED ACTIVITY BASED PROBES AND USES THEREOF IN IMAGING AND TARGETED THERAPY<br/>[FR] SONDES BASÉES SUR L'ACTIVITÉ PHOTODYNAMIQUE ATTÉNUÉE ET LEURS UTILISATIONS EN IMAGERIE ET EN THÉRAPIE CIBLÉE
  申请人：BLUM GALIA

  公开号：WO2016157198A9

  公开（公告）日：2016-11-17
• WO2019/147338
  申请人：——

  公开号：——

  公开（公告）日：——
• Synthesis and Evaluation of Radioiodinated Acyloxymethyl Ketones as Activity-Based Probes for Cathepsin B
  作者：Patricia E. Edem、Shannon Czorny、John F. Valliant

  DOI：10.1021/jm501357r

  日期：2014.11.26

  Dipeptidyl (acyloxy)methyl ketones (AOMKs) were functionalized with different iodine-containing prosthetic groups to generate a library of candidate cathepsin B probes. Compound 23a, (S)-20-[(S)-2-[(benzyloxy)carbonyl]amino}-3-phenylpropanamido]-1-(4-iodophenyl)-1,14,21-trioxo-5,8,11-trioxa-2,15-diazadocosan-22-yl 2,4,6-trimethylbenzoate, was identified as a potential lead through in vitro screening, having a K-i = 181 +/- 9 nM and demonstrating the ability to effectively label active cathepsin B in vitro. Its less potent analogue 11a, (S)-3-[(S)-2-[(benzyloxy)carbonyl]amino}-3-phenylpropanamido]-7-[6-(4-iodobenzamido)hexanamido]-2-oxoheptyl 2,4,6-trimethylbenzoate, was also tested as a comparison. Biodistribution studies of the iodine-125-labeled compounds in MDA-MB-231 mouse xenografts exhibited tumor uptake of 0.58% +/- 0.06% injected dose per gram (ID/g) for [I-125]11a and 1.12% +/- 0.08% ID/g for [I-125]23a at 30 min. The tumor-to-blood ratios reached 1.2 for [I-125]23a and 1.6 for [I-125]11a after 23 h. The more hydrophilic [I-125]23a showed an improved clearance profile with a superior tumor-to-muscle ratio of 7.0 compared to 3.4 for [I-125]11a at 23 h. Iodinated AOMK ligands are suitable in vitro probes for cathepsin B and hold promise as a platform to develop molecular imaging probes.
• Increasing time on target: utilization of inhibitors of cysteine cathepsins to enhance the tumor retention of receptor-targeted agents
  作者：Wei Fan、Wenting Zhang、Sameer Alshehri、Jered C. Garrison

  DOI：10.1039/c8cc05982a

  日期：——

  report a strategy of utilizing irreversible cysteine cathepsin inhibitor as trapping agent to increase the tumor residence time of receptor-targeted agents. The targeted constructs incorporating these cysteine cathepsin trapping agents were able to form high molecular weight adducts with intracellular cysteine cathepsins, thus achieving superior retention in tumor tissues.

  我们报告了利用不可逆的半胱氨酸组织蛋白酶抑制剂作为捕获剂以增加受体靶向药物的肿瘤停留时间的策略。掺入这些半胱氨酸组织蛋白酶捕获剂的靶向构建体能够与细胞内半胱氨酸组织蛋白酶形成高分子量加合物，从而在肿瘤组织中实现优异的保留。