(1-oxoisoindolin-5-yl)boronic acid | 1346526-56-4

• 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: (1-oxoisoindolin-5-yl)boronic acid
• 英文别名: (1-Oxo-2,3-dihydro-1H-isoindol-5-YL)boronic acid；(1-oxo-2,3-dihydroisoindol-5-yl)boronic acid
• CAS: 1346526-56-4
• 化学式: C₈H₈BNO₃
• 分子量: 176.967
• InChiKey: PHNVHDUWRDWRJL-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -1.39
• 重原子数：
  13
• 可旋转键数：
  1
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.12
• 拓扑面积：
  69.6
• 氢给体数：
  3
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  tert-butyl ((2S,3R)-1-(3-bromo-N-methylbenzenesulfonamido)-3-(tert-butoxy)-1-oxobutan-2-yl)carbamate 、 (1-oxoisoindolin-5-yl)boronic acid 在 bis-triphenylphosphine-palladium(II) chloride 、 sodium carbonate 作用下， 以 水 为溶剂， 以55%的产率得到tert-butyl N-[(2S,3R)-1-[methyl-[3-(1-oxo-2,3-dihydroisoindol-5-yl)phenyl]sulfonylamino]-3-[(2-methylpropan-2-yl)oxy]-1-oxobutan-2-yl]carbamate
  参考文献：
  名称：

  Identification of Bacteria-Selective Threonyl-tRNA Synthetase Substrate Inhibitors by Structure-Based Design

  摘要：

  A series of potent and bacteria-selective threonyl-tRNA synthetase (ThrRS) inhibitors have been identified using structure-based drug design. These compounds occupied the substrate binding site of ThrRS and showed excellent binding affinities for all of the bacterial orthologues tested. Some of the compounds displayed greatly improved bacterial selectivity. Key residues responsible for potency and bacteria/human ThrRS selectivity have been identified. Antimicrobial activity has been achieved against wild-type Haemophilus influenzae and efflux-deficient mutants of Escherichia coli and Burkholderia thailandensis.

  DOI：

  10.1021/jm301756m

文献信息

• Design, Synthesis and Biological Evaluation of Coumarin Derivatives as NEDD8 Activating Enzyme Inhibitors in Pancreatic Cancer Cells
  作者：Yubin Wang、Lei Gong、Peng Lu、Cheng Lu、Mengli Li、Huiyang Wan

  DOI：10.2174/1573406418666211210163817

  日期：2022.7

  NEDD8 (neural precursor cell expressed developmentally downregulated protein 8) is one of the ubiquitin-like proteins which is activated by the NEDD8 activating enzyme (NAE). The overexpressed NAE can cause a variety of diseases such as numerous cancer types and inflammatory diseases. The selective inhibition of NAE could mediate the rate of ubiquitination and the subsequent degradation of proteins associated with cancer so as to achieve the purpose of treatment.

  In this article, we decided to study the synthesis and screening of coumarin scaffold derivatives against cancer cell lines, specifically the human pancreatic cancer cell line BxPC-3.

  Twenty-four targeted compounds were synthesized, and their anti-proliferative activity against three cancer cell lines, cytotoxicity against three normal cell lines through CCK-8 and MTT assay were evaluated to screen out the candidate compound. Then the target was further confirmed by both enzyme and cell-based experiments, as well as cell apoptosis research.

  Several new 4-position substituted coumarin derivatives (12a~x) were synthesized and most of them exhibit antiproliferative activity in three cancer cell lines. A series of experiments were performed to identify the best candidate compound 12v. This compound displayed the highest potency against BxPC-3 with an IC50 value of 0.28 μM. It can also inhibit NAE activity in enzyme and cellbased assay, and induce CRLs-mediated accumulation of the substrate and apoptosis in BxPC-3 cells. Meanwhile, it exhibited relatively low toxicity in three normal cells.

  Based on these results, we found that compound 12v inhibited NAE activity in enzyme and cell-based systems and induced apoptosis in BxPC-3 cells. Additionally, it also had a low toxicity. These results suggested that 12v may be promising lead compounds for the development of new anticancer drugs.

  背景：NEDD8（神经前体细胞表达发育下调蛋白8）是一种类似泛素的蛋白质之一，由NEDD8激活酶（NAE）激活。过表达的NAE可能导致多种疾病，如多种癌症类型和炎症性疾病。选择性抑制NAE可以调节泛素化速率和与癌症相关的蛋白质的后续降解，从而实现治疗目的。 目的：在本文中，我们决定研究库马林骨架衍生物针对癌细胞系的合成和筛选，特别是人胰腺癌细胞系BxPC-3。 方法：合成了24种靶向化合物，并通过CCK-8和MTT分析评估它们对三种癌细胞系的抗增殖活性，对三种正常细胞系的细胞毒性，以筛选出候选化合物。然后通过酶和基于细胞的实验以及细胞凋亡研究进一步确认目标。 结果：合成了几种新的4-位取代库马林衍生物（12a~x），其中大多数在三种癌细胞系中表现出抗增殖活性。进行了一系列实验以确定最佳候选化合物12v。该化合物对BxPC-3显示出最高的活性，IC50值为0.28μM。它还可以在酶和基于细胞的实验中抑制NAE活性，并诱导CRLs介导的底物积累和BxPC-3细胞凋亡。同时，它在三种正常细胞中显示出相对较低的毒性。 结论：根据这些结果，我们发现化合物12v在酶和基于细胞的系统中抑制了NAE活性，并在BxPC-3细胞中诱导了凋亡。此外，它还具有较低的毒性。这些结果表明，12v可能是新抗癌药物开发的有希望的先导化合物。
• Design, Synthesis, and Proof-of-Concept of Triple-Site Inhibitors against Aminoacyl-tRNA Synthetases
  作者：Zhengjun Cai、Bingyi Chen、Ying Yu、Junsong Guo、Zhiteng Luo、Bao Cheng、Jun Xu、Qiong Gu、Huihao Zhou

  DOI：10.1021/acs.jmedchem.2c00134

  日期：2022.4.14

  Aminoacyl-tRNA synthetases (aaRSs) are promising drug targets due to their essential roles in protein translation. Although current inhibitors primarily occupy one or two of the three substrate binding sites on aaRSs, we report here the structure-based design of the first class of triple-site aaRS inhibitors by targeting Salmonella enterica threonyl-tRNA synthetase (SeThrRS). Competition of our compounds

  氨基酰基-tRNA 合成酶 (aaRS) 因其在蛋白质翻译中的重要作用而成为有前途的药物靶点。尽管目前的抑制剂主要占据 aaRS 上三个底物结合位点中的一个或两个，但我们在此报告了基于结构的第一类三重位点 aaRS 抑制剂的设计，它以肠沙门氏菌苏氨酰-tRNA 合成酶 ( Se ThrRS) 为靶点。我们的化合物与所有三种底物对Se ThrRS 结合的竞争通过等温滴定量热测定得到证实。与Se ThrRS结合的三种化合物的共晶结构明确证实了它们的底物模拟三点结合模式。化合物36j对Se ThrRS表现出最好的酶活性，IC 50 = 19 nM 和K d = 35.4 nM。化合物36b、36k和36l表现出抗菌活性，对受试细菌的最小抑制浓度值为 2-8 μg/mL，优于已报道的双位点 ThrRS 抑制剂。我们的研究为开发针对 aaRS 的三位点抑制剂提供了第一个概念验证，从而激发了未来基于 aaRS
• Development of Pyridine-based Inhibitors for the Human Vaccinia-related Kinases 1 and 2
  作者：Ricardo A. M. Serafim、Fernando H. de Souza Gama、Luiz A. Dutra、Caio V. dos Reis、Stanley N. S. Vasconcelos、André da Silva Santiago、Jéssica E. Takarada、Fúlvia Di Pillo、Hatylas Azevedo、Alessandra Mascarello、Jonathan M. Elkins、Katlin B. Massirer、Opher Gileadi、Cristiano R. W. Guimarães、Rafael M. Couñago

  DOI：10.1021/acsmedchemlett.9b00082

  日期：2019.9.12

  Vaccinia-related kinases 1 and 2 (VRK1 and VRK2) are human Ser/Thr protein kinases associated with increased cell division and neurological disorders. Nevertheless, the cellular functions of these proteins are not fully understood. Despite their therapeutic potential, there are no potent and specific inhibitors available for VRK1 or VRK2. We report here the discovery and elaboration of an aminopyridine scaffold as a basis for VRK1 and VRK2 inhibitors. The most potent compound for VRK1 (26) displayed an IC50 value of 150 nM and was fairly selective in a panel of 48 human kinases (selectivity score S(50%) of 0.04). Differences in compound binding mode and substituent preferences between the two VRKs were identified by the structure-activity relationship combined with the crystallographic analysis of key compounds. We expect our results to serve as a starting point for the design of more specific and potent inhibitors against each of the two VRKs.
• Identification of Bacteria-Selective Threonyl-tRNA Synthetase Substrate Inhibitors by Structure-Based Design
  作者：Min Teng、Mark T. Hilgers、Mark L. Cunningham、Allen Borchardt、Jeffrey B. Locke、Sunny Abraham、Gregory Haley、Bryan P. Kwan、Courtney Hall、Grayson W. Hough、Karen J. Shaw、John Finn

  DOI：10.1021/jm301756m

  日期：2013.2.28

  A series of potent and bacteria-selective threonyl-tRNA synthetase (ThrRS) inhibitors have been identified using structure-based drug design. These compounds occupied the substrate binding site of ThrRS and showed excellent binding affinities for all of the bacterial orthologues tested. Some of the compounds displayed greatly improved bacterial selectivity. Key residues responsible for potency and bacteria/human ThrRS selectivity have been identified. Antimicrobial activity has been achieved against wild-type Haemophilus influenzae and efflux-deficient mutants of Escherichia coli and Burkholderia thailandensis.