benzyl 4-(4-formylphenyl)butanoate | 1370290-50-8

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: benzyl 4-(4-formylphenyl)butanoate
• 英文别名: 4-Formylbenzenebutanoic acid phenylmethyl ester
• CAS: 1370290-50-8
• 化学式: C₁₈H₁₈O₃
• 分子量: 282.339
• InChiKey: HLIGZXVLEPDXLJ-UHFFFAOYSA-N

物化性质

• 沸点：
  436.3±33.0 °C(Predicted)
• 密度：
  1.140±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  21
• 可旋转键数：
  8
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.22
• 拓扑面积：
  43.4
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  benzyl 4-(4-formylphenyl)butanoate 在 水 、 sodium hydroxide 作用下， 以 乙醇 、 甲苯 为溶剂， 反应 160.0h， 生成 2-[[4-[4-[[3-[(2-甲基-6-苯并噻唑基)氨基]-3-氧代丙基]氨基]-4-氧代丁基]苯基]甲基]丙二酸
  参考文献：
  名称：

  Design and Synthesis of Novel Lactate Dehydrogenase A Inhibitors by Fragment-Based Lead Generation

  摘要：

  Lactate dehydrogenase A (LDHA) catalyzes the conversion of pyruvate to lactate, utilizing NADH as a cofactor. It has been identified as a potential therapeutic target in the area of cancer metabolism. In this manuscript we report our progress using fragment-based lead generation (FBLG), assisted by X-ray crystallography to develop small molecule LDHA inhibitors. Fragment hits were identified through NMR and SPR screening and optimized into lead compounds with nanomolar binding affinities via fragment linking. Also reported is their modification into cellular active compounds suitable for target validation work.

  DOI：

  10.1021/jm201734r
• 作为产物：
  描述：

  4-苯基丁酸 在 咪唑 、 lithium hydroxide monohydrate 、 硫酸 、 N,N'-羰基二咪唑 、 三氟乙酸 作用下， 以 四氢呋喃 、 乙醇 、 二氯甲烷 、 水 为溶剂， 反应 71.0h， 生成 benzyl 4-(4-formylphenyl)butanoate
  参考文献：
  名称：

  Design and Synthesis of Novel Lactate Dehydrogenase A Inhibitors by Fragment-Based Lead Generation

  摘要：

  Lactate dehydrogenase A (LDHA) catalyzes the conversion of pyruvate to lactate, utilizing NADH as a cofactor. It has been identified as a potential therapeutic target in the area of cancer metabolism. In this manuscript we report our progress using fragment-based lead generation (FBLG), assisted by X-ray crystallography to develop small molecule LDHA inhibitors. Fragment hits were identified through NMR and SPR screening and optimized into lead compounds with nanomolar binding affinities via fragment linking. Also reported is their modification into cellular active compounds suitable for target validation work.

  DOI：

  10.1021/jm201734r

文献信息

• Artificial Protein Crosstalk with a Molecule that Exchanges Binding Partners
  作者：Ohad Suss、Olga Halfin、Ziv Porat、Yael Fridmann Sirkis、Leila Motiei、David Margulies

  DOI：10.1002/anie.202312461

  日期：2024.2.12

  Drawing inspiration from allosteric signaling enzymes, whose catalytic and regulatory units are non‐covalently linked, we have devised a method to establish unnatural, effector‐mediated enzyme activation within native cells. The feasibility of this approach is demonstrated by introducing a synthetic regulatory unit (sRU) onto glycogen synthase kinase 3 (GSK‐3) through non‐covalent means. Our study reveals that this synthetic regulator mediates an unnatural crosstalk between GSK‐3 and lactate dehydrogenase A (LDHA), whose expression is regulated by cellular oxygen levels. Specifically, with this approach, the constitutively active GSK‐3 is transformed into an activable enzyme, whereas LDHA is repurposed as an unnatural effector protein that controls the activity of the kinase, making it unnaturally dependent on the cell‘s hypoxic response. These findings demonstrate a step toward imitating the function of effector‐regulated cell‐signaling enzymes, which play a key biological role in mediating the response of cells to changes in their environment. In addition, at the proof‐of‐principle level, our results indicate the potential to develop a new class of protein inhibitors whose inhibitory effect in cells is dictated by the cell‘s environment and consequent protein expression profile.

  摘要从异位信号酶（其催化和调控单元是非共价连接的）中汲取灵感，我们设计了一种在原生细胞内建立非自然的、效应器介导的酶激活的方法。通过非共价方式在糖原合酶激酶 3（GSK-3）上引入合成调控单元（sRU），证明了这种方法的可行性。我们的研究发现，这种合成调节因子介导了 GSK-3 与乳酸脱氢酶 A（LDHA）之间的非自然串扰，而后者的表达受细胞氧水平的调节。具体来说，通过这种方法，组成型活性 GSK-3 被转化为一种可激活的酶，而 LDHA 则被改造为一种非天然的效应蛋白，可控制激酶的活性，从而使其不自然地依赖于细胞的缺氧反应。这些发现表明，在模仿效应器调控的细胞信号酶的功能方面迈出了一步，这种酶在介导细胞对环境变化的反应方面发挥着关键的生物学作用。此外，在原理验证层面，我们的研究结果表明有可能开发出一类新的蛋白质抑制剂，其对细胞的抑制作用取决于细胞的环境和随之而来的蛋白质表达谱。
• Design, synthesis, and structure–activity relationships of a series of 4-benzyl-5-isopropyl-1H-pyrazol-3-yl β-d-glycopyranosides substituted with novel hydrophilic groups as highly potent inhibitors of sodium glucose co-transporter 1 (SGLT1)
  作者：Nobuhiko Fushimi、Hirotaka Teranishi、Kazuo Shimizu、Shigeru Yonekubo、Kohsuke Ohno、Takashi Miyagi、Fumiaki Itoh、Toshihide Shibazaki、Masaki Tomae、Yukiko Ishikawa-Takemura、Takeshi Nakabayashi、Noboru Kamada、Yuji Yamauchi、Susumu Kobayashi、Masayuki Isaji

  DOI：10.1016/j.bmc.2012.11.041

  日期：2013.2

  Sodium glucose co-transporter 1 (SGLT1) plays a dominant role in the absorption of glucose in the gut and is considered a promising target in the development of therapeutic options for postprandial hyperglycemia. Previously, we reported potent and selective SGLT1 inhibitors 1 and 2 showing efficacy in oral carbohydrate tolerance tests in diabetic rat models. In a pharmacokinetic (PK) study of 2, excessive systemic exposure to metabolites of 2 was observed, presumably due to the high permeability of its aglycone (2a). To further improve SGLT1 inhibitory activity and reduce aglycone permeability, a series of 4-benzyl-5-isopropyl-1H-pyrazol-3-yl beta-D-glycopyranoside derivatives bearing novel hydrophilic substitution groups on the phenyl ring were synthesized and their inhibitory activity toward SGLTs was evaluated. Optimized compound 14c showed an improved profile satisfying both higher activity and lower permeability of its aglycone (22f) compared with initial leads 1 and 2. Moreover, the superior efficacy of 14c in various carbohydrate tolerance tests in diabetic rat models was confirmed compared with acarbose, an alpha-glucosidase inhibitor (alpha-GI) widely used in the clinic. (C) 2012 Elsevier Ltd. All rights reserved.
• Design and Synthesis of Novel Lactate Dehydrogenase A Inhibitors by Fragment-Based Lead Generation
  作者：Richard A. Ward、Claire Brassington、Alexander L. Breeze、Alessandro Caputo、Susan Critchlow、Gareth Davies、Louise Goodwin、Giles Hassall、Ryan Greenwood、Geoffrey A. Holdgate、Michael Mrosek、Richard A. Norman、Stuart Pearson、Jonathan Tart、Julie A. Tucker、Martin Vogtherr、David Whittaker、Jonathan Wingfield、Jon Winter、Kevin Hudson

  DOI：10.1021/jm201734r

  日期：2012.4.12

  Lactate dehydrogenase A (LDHA) catalyzes the conversion of pyruvate to lactate, utilizing NADH as a cofactor. It has been identified as a potential therapeutic target in the area of cancer metabolism. In this manuscript we report our progress using fragment-based lead generation (FBLG), assisted by X-ray crystallography to develop small molecule LDHA inhibitors. Fragment hits were identified through NMR and SPR screening and optimized into lead compounds with nanomolar binding affinities via fragment linking. Also reported is their modification into cellular active compounds suitable for target validation work.