pentafluorophenyl 2-(R)-isobutyl-3-(N-tert-butoxycarbonyl-N-(tert-butyl-dimethylsilyloxy)carbamoyl)propionate | 886057-13-2

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯酚酯
• 英文名称: pentafluorophenyl 2-(R)-isobutyl-3-(N-tert-butoxycarbonyl-N-(tert-butyl-dimethylsilyloxy)carbamoyl)propionate
• 英文别名: (2,3,4,5,6-pentafluorophenyl) (2R)-2-[2-[[tert-butyl(dimethyl)silyl]oxy-[(2-methylpropan-2-yl)oxycarbonyl]amino]-2-oxoethyl]-4-methylpentanoate
• CAS: 886057-13-2
• 化学式: C₂₅H₃₆F₅NO₆Si
• 分子量: 569.641
• InChiKey: MIVWTBMTJKIDBL-CQSZACIVSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.04
• 重原子数：
  38
• 可旋转键数：
  12
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.64
• 拓扑面积：
  82.1
• 氢给体数：
  0
• 氢受体数：
  11

反应信息

• 作为反应物：
  描述：

  pentafluorophenyl 2-(R)-isobutyl-3-(N-tert-butoxycarbonyl-N-(tert-butyl-dimethylsilyloxy)carbamoyl)propionate 、 alkaline earth salt of/the/ methylsulfuric acid 在 哌啶 、 N,N-二异丙基乙胺 、 水 、 三氟乙酸 作用下， 以 N,N-二甲基甲酰胺 、 N-甲基吡咯烷酮 为溶剂， 反应 4.0h， 以8.5 mg的产率得到(2R)-N-[(2S)-1-[[(2S)-1,6-diamino-1-oxohexan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]-N'-hydroxy-2-(2-methylpropyl)butanediamide
  参考文献：
  名称：

  Solid-Phase Synthesis of Succinylhydroxamate Peptides:  Functionalized Matrix Metalloproteinase Inhibitors

  摘要：

  A novel solid-phase synthesis strategy toward succinylhydroxamate peptides, using an appropriately protected hydroxamate building block, is described. Rapid and efficient access is gained to amine-functionalized peptides, which can be decorated with, for instance, a fluorescent label. In addition, we demonstrate an on-resin synthesis of a biotinylated photoactivatable hydroxamate peptide, which can be used as an activity-based probe for matrix metalloproteinases and ADAMs.

  DOI：

  10.1021/ol060409e
• 作为产物：
  描述：

  4-甲基戊酸 在 4-二甲氨基吡啶 、 正丁基锂 、 氯化亚砜 、 草酰氯 、 palladium on activated charcoal 、 氢气 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 N,N-二甲基甲酰胺 、 三氟乙酸 、 lithium hexamethyldisilazane 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 乙腈 为溶剂， 生成 pentafluorophenyl 2-(R)-isobutyl-3-(N-tert-butoxycarbonyl-N-(tert-butyl-dimethylsilyloxy)carbamoyl)propionate
  参考文献：
  名称：

  A dual inhibitor of matrix metalloproteinases and a disintegrin and metalloproteinases, [18F]FB-ML5, as a molecular probe for non-invasive MMP/ADAM-targeted imaging

  摘要：

  Background: Numerous clinical studies have shown a correlation between increased matrix metalloproteinase (MMP)/a disintegrin and metalloproteinase (ADAM) activity and poor outcome of cancer. Various MMP inhibitors (MMPIs) have been developed for therapeutic purposes in oncology. In addition, molecular imaging of MMP/ADAM levels in vivo would allow the diagnosis of tumors. We selected the dual inhibitor of MMPs and ADAMs, ML5, which is a hydroxamate-based inhibitor with affinities for many MMPs and ADAMs. ML5 was radiolabelled with F-18 and the newly obtained radiolabelled inhibitor was evaluated in vitro and in vivo.Materials and methods: ML5 was radiolabelled by direct acylation with N-succinimidyl-4-[F-18]fluorobenzoate ([F-18]SFB) for PET (positron emission tomography). The resulting radiotracer [F-18]FB-ML5 was evaluated in vitro in human bronchial epithelium 16HBE cells and breast cancer MCF-7 cells. The non-radioactive probe FB-ML5 and native ML5 were tested in a fluorogenic inhibition assay against MMP-2, -9, -12 and ADAM-17. The in vivo kinetics of [F-18]FB-ML5 were examined in a HT1080 tumor-bearing mouse model. Specificity of probe binding was examined by co-injection of 0 or 2.5 mg/kg ML5. Results: ML5 and FB-ML5 showed high affinity for MMP-2, -9, -12 and ADAM-17; indeed IC50 values were respectively 7.4 +/- 2.0, 19.5 +/- 2.8, 2.0 +/- 0.2 and 5.7 +/- 2.2 nM and 12.5 +/- 3.1, 31.5 +/- 13.7, 138.0 +/- 10.9 and 24.7 +/- 2.8 nM. Radiochemical yield of HPLC-purified [F-18]FB-ML5 was 13-16% (corrected for decay). Cellular binding of [F-18]FB-ML5 was reduced by 36.6% and 27.5% in MCF-7 and 16HBE cells, respectively, after co-incubation with 10 mu M of ML5. In microPET scans, HT1080 tumors exhibited a low and homogeneous uptake of the tracer. Tumors of mice injected with [F-18]FB-ML5 showed a SUVmean of 0.145 +/- 0.064 (n = 6) which decreased to 0.041 +/- 0.027 (n = 6) after target blocking (p < 0.05). Ex vivo biodistribution showed a rapid excretion through the kidneys and the liver. Metabolite assays indicated that the parent tracer represented 23.2 +/- 7.3% (n = 2) of total radioactivity in plasma, at 90 min post injection (p.i.).Conclusion: The nanomolar affinity MMP/ADAM inhibitor ML5 was successfully labelled with F-18. [F-18]FB-ML5 demonstrated rather low binding in ADAM-17 overexpressing cell lines. [F-18]FB-ML5 uptake showed significant reduction in the HT1080 tumor in vivo after co-injection of ML5. [F-18]FB-ML5 may be suitable for the visualization/quantification of diseases overexpressing simultaneously MMPs and ADAMs. (C) 2014 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2014.11.013

文献信息

• A peptide hydroxamate library for enrichment of metalloproteinases: towards an affinity-based metalloproteinase profiling protocol
  作者：Paul Geurink、Theo Klein、Michiel Leeuwenburgh、Gijs van der Marel、Henk Kauffman、Rainer Bischoff、Herman Overkleeft

  DOI：10.1039/b718352f

  日期：——

  A compound library of 96 enantiopure N-terminal succinyl hydroxamate functionalized peptides was synthesized on solid phase. All compounds were tested for their inhibitory potential towards MMP-9, MMP-12 and ADAM-17, which led to the identification of both broad spectrum inhibitors and metalloproteinase-selective ones. Eight potent and less potent inhibitors were immobilized on Sepharose beads and evaluated in solid-phase enrichment of active MMP-9, MMP-12 and ADAM-17. In addition, one of these inhibitors was used for solid-phase enrichment of endogenous ADAM-17 from a complex proteome (a lysate prepared from cultured A549 cells).

  在固相上合成了一个由 96 个对映体纯 N 端琥珀酰羟酰胺官能化肽组成的化合物库。测试了所有化合物对 MMP-9、MMP-12 和 ADAM-17 的抑制潜力，从而确定了广谱抑制剂和金属蛋白酶选择性抑制剂。在固相富集活性 MMP-9、MMP-12 和 ADAM-17 的过程中，对固定在 Sepharose 珠上的八种强效和弱效抑制剂进行了评估。此外，其中一种抑制剂还被用于固相富集复杂蛋白质组（由培养的 A549 细胞制备的裂解物）中的内源性 ADAM-17。
• A dual inhibitor of matrix metalloproteinases and a disintegrin and metalloproteinases, [18F]FB-ML5, as a molecular probe for non-invasive MMP/ADAM-targeted imaging
  作者：Nathalie Matusiak、Riccardo Castelli、Adriaan W. Tuin、Herman S. Overkleeft、Rosalina Wisastra、Frank J. Dekker、Laurette M. Prély、Rainer P.H. Bischoff、Aren van Waarde、Rudi A.J.O. Dierckx、Philip H. Elsinga

  DOI：10.1016/j.bmc.2014.11.013

  日期：2015.1

  Background: Numerous clinical studies have shown a correlation between increased matrix metalloproteinase (MMP)/a disintegrin and metalloproteinase (ADAM) activity and poor outcome of cancer. Various MMP inhibitors (MMPIs) have been developed for therapeutic purposes in oncology. In addition, molecular imaging of MMP/ADAM levels in vivo would allow the diagnosis of tumors. We selected the dual inhibitor of MMPs and ADAMs, ML5, which is a hydroxamate-based inhibitor with affinities for many MMPs and ADAMs. ML5 was radiolabelled with F-18 and the newly obtained radiolabelled inhibitor was evaluated in vitro and in vivo.Materials and methods: ML5 was radiolabelled by direct acylation with N-succinimidyl-4-[F-18]fluorobenzoate ([F-18]SFB) for PET (positron emission tomography). The resulting radiotracer [F-18]FB-ML5 was evaluated in vitro in human bronchial epithelium 16HBE cells and breast cancer MCF-7 cells. The non-radioactive probe FB-ML5 and native ML5 were tested in a fluorogenic inhibition assay against MMP-2, -9, -12 and ADAM-17. The in vivo kinetics of [F-18]FB-ML5 were examined in a HT1080 tumor-bearing mouse model. Specificity of probe binding was examined by co-injection of 0 or 2.5 mg/kg ML5. Results: ML5 and FB-ML5 showed high affinity for MMP-2, -9, -12 and ADAM-17; indeed IC50 values were respectively 7.4 +/- 2.0, 19.5 +/- 2.8, 2.0 +/- 0.2 and 5.7 +/- 2.2 nM and 12.5 +/- 3.1, 31.5 +/- 13.7, 138.0 +/- 10.9 and 24.7 +/- 2.8 nM. Radiochemical yield of HPLC-purified [F-18]FB-ML5 was 13-16% (corrected for decay). Cellular binding of [F-18]FB-ML5 was reduced by 36.6% and 27.5% in MCF-7 and 16HBE cells, respectively, after co-incubation with 10 mu M of ML5. In microPET scans, HT1080 tumors exhibited a low and homogeneous uptake of the tracer. Tumors of mice injected with [F-18]FB-ML5 showed a SUVmean of 0.145 +/- 0.064 (n = 6) which decreased to 0.041 +/- 0.027 (n = 6) after target blocking (p < 0.05). Ex vivo biodistribution showed a rapid excretion through the kidneys and the liver. Metabolite assays indicated that the parent tracer represented 23.2 +/- 7.3% (n = 2) of total radioactivity in plasma, at 90 min post injection (p.i.).Conclusion: The nanomolar affinity MMP/ADAM inhibitor ML5 was successfully labelled with F-18. [F-18]FB-ML5 demonstrated rather low binding in ADAM-17 overexpressing cell lines. [F-18]FB-ML5 uptake showed significant reduction in the HT1080 tumor in vivo after co-injection of ML5. [F-18]FB-ML5 may be suitable for the visualization/quantification of diseases overexpressing simultaneously MMPs and ADAMs. (C) 2014 Elsevier Ltd. All rights reserved.
• Solid-Phase Synthesis of Succinylhydroxamate Peptides:  Functionalized Matrix Metalloproteinase Inhibitors
  作者：Michiel A. Leeuwenburgh、Paul P. Geurink、Theo Klein、Henk F. Kauffman、Gijs A. van der Marel、Rainer Bischoff、Herman S. Overkleeft

  DOI：10.1021/ol060409e

  日期：2006.4.1

  A novel solid-phase synthesis strategy toward succinylhydroxamate peptides, using an appropriately protected hydroxamate building block, is described. Rapid and efficient access is gained to amine-functionalized peptides, which can be decorated with, for instance, a fluorescent label. In addition, we demonstrate an on-resin synthesis of a biotinylated photoactivatable hydroxamate peptide, which can be used as an activity-based probe for matrix metalloproteinases and ADAMs.