(S)-tert-butyl 4-(1,3-dioxoisoindolin-2-yl)-2-hydroxybutanoate | 1061743-26-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 异吲哚及其衍生物
• 英文名称: (S)-tert-butyl 4-(1,3-dioxoisoindolin-2-yl)-2-hydroxybutanoate
• 英文别名: tert-butyl (2S)-4-(1,3-dioxoisoindol-2-yl)-2-hydroxybutanoate
• CAS: 1061743-26-7
• 化学式: C₁₆H₁₉NO₅
• 分子量: 305.331
• InChiKey: XHVXPOHJIBAIHP-LBPRGKRZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  22
• 可旋转键数：
  6
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.44
• 拓扑面积：
  83.9
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (S)-tert-butyl 4-(1,3-dioxoisoindolin-2-yl)-2-hydroxybutanoate 在 sodium azide 、 三乙胺 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 1.5h， 生成 (R)-tert-butyl 2-azido-4-(1,3-dioxoisoindolin-2-yl)butanoate
  参考文献：
  名称：

  1型膜基质金属蛋白酶（MT1-MMP）双功能抑制剂的设计、合成及生物学评价

  摘要：

  胶原蛋白降解和proMMP-2激活是MT1-MMP促进癌细胞侵袭的主要功能。由于这两个过程都需要细胞表面上的 MT1-MMP 同二聚化，因此我们提出使用该酶的双功能抑制剂可以代表一种有效减少肿瘤生长的创新方法。合成了源自先前描述的单体芳基磺酰胺异羟肟酸盐的一小组对称二聚体，并在分离的 MMP 上进行了体外测试。鉴定出一种纳摩尔 MT1-MMP 抑制剂（化合物6），然后对 HT1080 纤维肉瘤细胞进行基于细胞的测定。二聚体6以剂量依赖性方式减少 MT1-MMP 依赖性 proMMP-2 激活、胶原蛋白降解和胶原蛋白侵袭，甚至与其单体类似物相比，效果更好4。这项初步研究表明二聚体 MT1-MMP 抑制剂可能会被进一步开发和利用作为减少癌细胞侵袭的替代工具。

  DOI：

  10.1016/j.bmc.2018.11.041

文献信息

• Potent Arylsulfonamide Inhibitors of Tumor Necrosis Factor-α Converting Enzyme Able to Reduce Activated Leukocyte Cell Adhesion Molecule Shedding in Cancer Cell Models
  作者：Elisa Nuti、Francesca Casalini、Stanislava I. Avramova、Salvatore Santamaria、Marina Fabbi、Silvano Ferrini、Luciana Marinelli、Valeria La Pietra、Vittorio Limongelli、Ettore Novellino、Giovanni Cercignani、Elisabetta Orlandini、Susanna Nencetti、Armando Rossello

  DOI：10.1021/jm901868z

  日期：2010.3.25

  useful target in anticancer therapy. Herein, we report the synthesis and biological evaluation of new ADAM-17 inhibitors containing an arylsulfonamidic scaffold. Among the new potential inhibitors, two very promising compounds 17 and 18 were discovered, with a nanomolar activity for ADAM-17 isolated enzyme. These compounds proved to be also the most potent in inhibiting soluble ALCAM release in cancer

  活化的白细胞粘附分子（ALCAM）在肿瘤生物学和进展中起着重要作用。我们以前的研究表明，ALCAM在上皮性卵巢癌（EOC）细胞表面表达，并通过ADAM-17介导的脱落以可溶形式释放。此过程与EOC细胞的运动性和侵袭性有关，ADAM-17的非特异性抑制剂会降低EOC的细胞运动性和侵袭性。因此，ADAM-17可能代表抗癌治疗的新靶标。在此，我们报告了含有芳基磺酰胺基支架的新型ADAM-17抑制剂的合成和生物学评估。在新的潜在抑制剂中，两种非常有前途的化合物17和18被发现具有ADAM-17分离酶的纳摩尔活性。这些化合物被证明也是抑制癌细胞中可溶性ALCAM释放的最有效剂，对A2774和SKOV3细胞系表现出纳摩尔活性。
• Synthesis, experimental evaluation and molecular modelling of hydroxamate derivatives as zinc metalloproteinase inhibitors
  作者：Stian Sjøli、Elisa Nuti、Caterina Camodeca、Irina Bilto、Armando Rossello、Jan-Olof Winberg、Ingebrigt Sylte、Olayiwola A. Adekoya

  DOI：10.1016/j.ejmech.2015.11.019

  日期：2016.1

  Enzymes of the M4 family of zinc-metalloproteinases are virulence factors secreted from gram-positive or gram-negative bacteria, and putative drug targets in the treatment of bacterial infections. In order to have a therapeutic value such inhibitors should not interfere with endogenous zinc-metalloproteinases. In the present study we have synthesised a series of hydroxamate derivatives and validated the compounds as inhibitors of the M4 enzymes thermolysin and pseudolysin, and the endogenous metalloproteinases ADAM-17, MMP-2 and MMP-9 using experimental binding studies and molecular modelling. In general, the compounds are stronger inhibitors of the MMPs than of the M4 enzymes, however, an interesting exception is LM2. The compounds bound stronger to pseudolysin than to thermolysin, and the molecular modelling studies showed that occupation of the S-2' subpocket by an aromatic group is favourable for strong interactions with pseudolysin. (C) 2015 Elsevier Masson SAS. All rights reserved.
• <i>N</i>-<i>O</i>-Isopropyl Sulfonamido-Based Hydroxamates as Matrix Metalloproteinase Inhibitors: Hit Selection and in Vivo Antiangiogenic Activity
  作者：Elisa Nuti、Anna Rita Cantelmo、Cristina Gallo、Antonino Bruno、Barbara Bassani、Caterina Camodeca、Tiziano Tuccinardi、Laura Vera、Elisabetta Orlandini、Susanna Nencetti、Enrico A. Stura、Adriano Martinelli、Vincent Dive、Adriana Albini、Armando Rossello

  DOI：10.1021/acs.jmedchem.5b00367

  日期：2015.9.24

  Matrix metalloproteinases (MMPs) have been shown to be involved in tumor-induced angiogenesis. In particular, MMP-2, MMP-9, and MMP-14 have been reported to be crucial for tumor angiogenesis and the formation of metastasis, thus becoming attractive targets in cancer therapy. Here, we report our optimization effort to identify novel N-isopropoxy-arylsulfonamide hydroxamates with improved inhibitory activity toward MMP-2, MMP-9, and MMP-14 with respect to the previously discovered compound 1. A new series of hydroxamates was designed, synthesized, and tested for their antiangiogenic activity using in vitro assays with human umbilical vein endothelial cells (HUVECs). A nanomolar MMP-2, MMP-9, and MMP-14 inhibitor was identified, compound 3, able to potently inhibit angiogenesis in vitro and also in vivo in the matrigel sponge assay in mice. Finally, X-ray crystallographic and docking studies were conducted for compound 3 in order to investigate its binding mode to MMP-9 and MMP-14.
• Compounds Having Aryl-Sulphonamidic Structure Useful As Metalloproteases Inhibitors
  申请人：Balsamo Aldo

  公开号：US20100087505A1

  公开（公告）日：2010-04-08

  The invention relates to aryl-sulphonamido compounds endowed with inhibitory activity against metallo proteases MMP, having formula (I) below wherein R, R 1 , R 2 , R 3 , R 4 , R 5 , n and m have the meanings reported in the specification; the invention also refers to the process for their preparation, to pharmaceutical compositions comprising them and to their use as therapeutic agents, particularly in the treatment of degenerative disorders.
• US8329751B2
  申请人：——

  公开号：US8329751B2

  公开（公告）日：2012-12-11