N-(α-(2,4,6-triisopropylphenylsulfonyl)-3-amidino-(L)-phenylalanine)-4-ethoxycarbonylpiperazide | 220355-63-5

• 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: N-(α-(2,4,6-triisopropylphenylsulfonyl)-3-amidino-(L)-phenylalanine)-4-ethoxycarbonylpiperazide
• 英文别名: WX-UK1；Wx-uk1 free base；ethyl 4-[(2S)-3-(3-carbamimidoylphenyl)-2-[[2,4,6-tri(propan-2-yl)phenyl]sulfonylamino]propanoyl]piperazine-1-carboxylate
• CAS: 220355-63-5；255374-84-6
• 化学式: C₃₂H₄₇N₅O₅S
• 分子量: 613.822
• InChiKey: ISJSHQTWOHGCMM-NDEPHWFRSA-N

物化性质

• 沸点：
  745.5±70.0 °C(Predicted)
• 密度：
  1.23±0.1 g/cm3(Predicted)
• 溶解度：
  二甲基亚砜：≥28mg/mL（45.62mM）

计算性质

• 辛醇/水分配系数(LogP)：
  4.8
• 重原子数：
  43
• 可旋转键数：
  12
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.53
• 拓扑面积：
  154
• 氢给体数：
  3
• 氢受体数：
  7

制备方法与用途

生物活性

UKI-1 (UKI-1C) 是一种有效的尿激酶型纤溶酶原激活剂 (uPA) 抑制剂，其 Ki 值为 0.41 μM。此外，它还是一种低分子量的丝氨酸蛋白酶抑制剂。UKI-1 被证实是有效的抗转移剂，能够显著抑制癌细胞的侵袭能力。

靶点

• Ki: 0.41 μM (尿激酶型纤溶酶原激活剂 (uPA))
• 丝氨酸蛋白酶

体外研究

在体外实验中，UKI-1 (WX-UK1) 处理（浓度范围：0.1-1.0 μg/mL）能够将肿瘤细胞的侵袭能力降低至 50%。这种效果在 FaDu 腭咽癌系和 HeLa 宫颈癌系模型中均得到了验证。UKI-1 还通过直接抑制纤溶酶生成及间接抑制尿激酶型纤溶酶原激活剂 (uPA) 的方式，干扰了纤溶酶原活化系统。在高度侵袭性的纤维肉瘤和乳腺癌细胞的体外侵袭模型中，UKI-1 有效地抑制了细胞通过纤维蛋白矩阵的迁移。

体内研究

在体内实验中，UKI-1 (WX-UK1) 的治疗显著减少了转移性胰腺和乳房腺癌肿瘤模型中的转移病灶数量及肿瘤生长。

反应信息

• 作为产物：
  描述：

  L-3-氰基苯丙氨酸 在 钯 盐酸羟胺 、 benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate 、 氢气 、 溶剂黄146 、 N,N-二异丙基乙胺 作用下， 以 乙醇 为溶剂， 生成 N-(α-(2,4,6-triisopropylphenylsulfonyl)-3-amidino-(L)-phenylalanine)-4-ethoxycarbonylpiperazide
  参考文献：
  名称：

  3-Amidinophenylalanine-based inhibitors of urokinase

  摘要：

  Synthesis and anti-uPA activity of a series of N alpha-triisopropyl-phenylsulfonyl-protecte 3-amidinophenylalanine amides are described. We have explored SAR around the C-terminal amide part for inhibition of uPA, plasmin and trypsin. Modification of the amide part has been found to affect potency but not selectivity. With a K-i of 0.41 mu M 2r-L is one of the most potent uPA inhibitors described so far. The X-ray crystal structure of 2r-L was solved in complex with trypsin, superimposed with uPA and the results suggest an unique binding mode of this inhibitor type. (C) 1999 Published by Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0960-894x(99)00541-7

文献信息

• Secondary Amides of Sulfonylated 3-Amidinophenylalanine. New Potent and Selective Inhibitors of Matriptase
  作者：Torsten Steinmetzer、Andrea Schweinitz、Anne Stürzebecher、Daniel Dönnecke、Kerstin Uhland、Oliver Schuster、Peter Steinmetzer、Friedemann Müller、Rainer Friedrich、Manuel E. Than、Wolfram Bode、Jörg Stürzebecher

  DOI：10.1021/jm051272l

  日期：2006.7.1

  Matriptase is an epithelium-derived type II transmembrane serine protease and has been implicated in the activation of substrates such as pro-HGF/SF and pro-uPA, which are likely involved in tumor progression and metastasis. Through screening, we have identified bis-basic secondary amides of sulfonylated 3-amidinophenylalanine as matriptase inhibitors. X-ray analyses of analogues 8 and 31 in complex with matriptase revealed that these inhibitors occupy, in addition to part of the previously described S4-binding site, the cleft formed by the molecular surface and the unique 60 loop of matriptase. Therefore, optimization of the inhibitors included the incorporation of appropriate sulfonyl substituents that could improve binding of these inhibitors into both characteristic matriptase subsites. The most potent derivatives inhibit matriptase highly selective with K(i) values below 5 nM. Molecular modeling revealed that their improved affinity results from interaction with the S4 site of matriptase. Analogues 8 and 59 were studied in an orthotopic xenograft mouse model of prostate cancer. Compared to control, both inhibitors reduced tumor growth, as well as tumor dissemination.
• 3-Amidinophenylalanine-based inhibitors of urokinase
  作者：Jörg Stürzebecher、Helmut Vieweg、Torsten Steinmetzer、Andrea Schweinitz、Milton T. Stubbs、Martin Renatus、Peter Wikström

  DOI：10.1016/s0960-894x(99)00541-7

  日期：1999.11

  Synthesis and anti-uPA activity of a series of N alpha-triisopropyl-phenylsulfonyl-protecte 3-amidinophenylalanine amides are described. We have explored SAR around the C-terminal amide part for inhibition of uPA, plasmin and trypsin. Modification of the amide part has been found to affect potency but not selectivity. With a K-i of 0.41 mu M 2r-L is one of the most potent uPA inhibitors described so far. The X-ray crystal structure of 2r-L was solved in complex with trypsin, superimposed with uPA and the results suggest an unique binding mode of this inhibitor type. (C) 1999 Published by Elsevier Science Ltd. All rights reserved.