3-(2,4-dichlorophenyl)pentanedioic acid | 103862-84-6

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 苯丙酸
• 英文名称: 3-(2,4-dichlorophenyl)pentanedioic acid
• CAS: 103862-84-6
• 化学式: C₁₁H₁₀Cl₂O₄
• 分子量: 277.104
• InChiKey: XTJLESBZLZRESI-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  17
• 可旋转键数：
  5
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  74.6
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  3-(2,4-dichlorophenyl)pentanedioic acid 在 三乙胺 作用下， 以 氯仿 为溶剂， 生成 3-(2,4-dichlorophenyl)-5-methoxy-5-oxopentanoic acid
  参考文献：
  名称：

  作为肉毒杆菌神经毒素 A 轻链抑制剂的异羟肟酸及其前药的合成/生物学评价

  摘要：

  肉毒杆菌神经毒素 A (BoNT/A) 是已知的最有效的毒素。不幸的是，它也是恐怖主义中的一种潜在生物武器，一旦发生细胞中毒，它就没有获得批准的治疗方法。以前，我们报道了异羟肟酸前药氨基甲酸酯如何增加细胞摄取，从而成功抑制这种神经毒素。在这项研究的基础上，我们详细介绍了 BoNT/A 蛋白酶分子建模研究，并伴随着基于 2,4-二氯肉桂异羟肟酸支架及其氨基甲酸酯前药衍生化的小型异羟肟酸文库的构建，以及对这些分子的酶促和评估细胞模型。

  DOI：

  10.1016/j.bmc.2013.11.053
• 作为产物：
  描述：

  dimethyl 2-(2,4-dichlorobenzylidene)malonate 在 盐酸 、 水 、 sodium methylate 作用下， 以 甲醇 为溶剂， 反应 1.0h， 生成 3-(2,4-dichlorophenyl)pentanedioic acid
  参考文献：
  名称：

  作为肉毒杆菌神经毒素 A 轻链抑制剂的异羟肟酸及其前药的合成/生物学评价

  摘要：

  肉毒杆菌神经毒素 A (BoNT/A) 是已知的最有效的毒素。不幸的是，它也是恐怖主义中的一种潜在生物武器，一旦发生细胞中毒，它就没有获得批准的治疗方法。以前，我们报道了异羟肟酸前药氨基甲酸酯如何增加细胞摄取，从而成功抑制这种神经毒素。在这项研究的基础上，我们详细介绍了 BoNT/A 蛋白酶分子建模研究，并伴随着基于 2,4-二氯肉桂异羟肟酸支架及其氨基甲酸酯前药衍生化的小型异羟肟酸文库的构建，以及对这些分子的酶促和评估细胞模型。

  DOI：

  10.1016/j.bmc.2013.11.053

文献信息

• 4-Benzimidazolyl-3-Phenylbutanoic Acids As Novel Pif-Pocket-Targeting Allosteric Inhibitors of Protein Kinase PKCζ
  作者：Wolfgang Fröhner、Laura A. Lopez-Garcia、Sonja Neimanis、Nadja Weber、Jeanette Navratil、Frauke Maurer、Adriana Stroba、Hua Zhang、Ricardo M. Biondi、Matthias Engel

  DOI：10.1021/jm2005892

  日期：2011.10.13

  Protein kinase inhibitors with an allosteric mode of action are expected to reach, in many cases, higher selectivity for the target enzyme than ATP-competitive compounds. Therefore, basic research is aiming at identifying and establishing novel sites on the catalytic domain of protein kinases which might be targeted by allosteric inhibitors. We previously published the first structure-activity relationships (SARs) for allosteric activators of protein kinase PDK1. Here, we present the design, synthesis, and SAR data on a series of novel compounds, 4-benzimidazolyl-3-phenylbutanoic acids, that inhibit the atypical protein kinace C (PKC) zeta via binding to the PIF-pocket. Key positions were identified in the compounds that can be modified to increase potency and selectivity. Some congeners showed a high selectivity toward PKC zeta, lacking inhibition of the most closely related isoform, PKCl, and of further AGC kinases. Furthermore, evidence is provided that these compounds are also active toward cellular PKC zeta without loss of potency compared to the cell-free assay.
• Catch and Anchor Approach To Combat Both Toxicity and Longevity of Botulinum Toxin A
  作者：Lucy Lin、Margaret E. Olson、Takashi Sugane、Lewis D. Turner、Margarita A. Tararina、Alexander L. Nielsen、Elbek K. Kurbanov、Sabine Pellett、Eric A. Johnson、Seth M. Cohen、Karen N. Allen、Kim D. Janda

  DOI：10.1021/acs.jmedchem.0c01006

  日期：2020.10.8

  Botulinum neurotoxins have remarkable persistence (similar to weeks to months in cells), outlasting the small-molecule inhibitors designed to target them. To address this disconnect, inhibitors bearing two pharmacophores.a zinc binding group and a Cys-reactive warhead.were designed to leverage both affinity and reactivity. A series of first-generation bifunctional inhibitors was achieved through structure-based inhibitor design. Through X-ray crystallography, engagement of both the catalytic Zn2+ and Cys165 was confirmed. A second-generation series improved on affinity by incorporating known reversible inhibitor pharmacophores; the mechanism was confirmed by exhaustive dialysis, mass spectrometry, and in vitro evaluation against the C165S mutant. Finally, a third-generation inhibitor was shown to have good cellular activity and low toxicity. In addition to our findings, an alternative method of modeling time-dependent inhibition that simplifies assay setup and allows comparison of inhibition models is discussed.
• Use of Crystallography and Molecular Modeling for the Inhibition of the Botulinum Neurotoxin A Protease
  作者：Lewis D. Turner、Alexander L. Nielsen、Lucy Lin、Antonio J. Campedelli、Nicholas R. Silvaggi、Jason S. Chen、Amanda E. Wakefield、Karen N. Allen、Kim D. Janda

  DOI：10.1021/acsmedchemlett.1c00325

  日期：2021.8.12
• Influence of Forest Clearing Methods on Nutrient Uptake of Some Tropical Food Crops
  作者：Anthony Egrinya Eneji、Benedict Bengyoushuye Ayade、Bernard Flannan Daniel Oko、Sadahiro Yamamoto、Toshimasa Honna、Tsuneyoshi Endo

  DOI：10.1007/bf02762719

  日期：2001.2
• Synthesis/biological evaluation of hydroxamic acids and their prodrugs as inhibitors for Botulinum neurotoxin A light chain
  作者：Hajime Seki、Sabine Pellett、Peter Šilhár、G. Neil Stowe、Beatriz Blanco、Matthew A. Lardy、Eric A. Johnson、Kim D. Janda

  DOI：10.1016/j.bmc.2013.11.053

  日期：2014.2

  Botulinum neurotoxin A (BoNT/A) is the most potent toxin known. Unfortunately, it is also a potential bioweapon in terrorism, which is without an approved therapeutic treatment once cellular intoxication takes place. Previously, we reported how hydroxamic acid prodrug carbamates increased cellular uptake, which translated to successful inhibition of this neurotoxin. Building upon this research, we

  肉毒杆菌神经毒素 A (BoNT/A) 是已知的最有效的毒素。不幸的是，它也是恐怖主义中的一种潜在生物武器，一旦发生细胞中毒，它就没有获得批准的治疗方法。以前，我们报道了异羟肟酸前药氨基甲酸酯如何增加细胞摄取，从而成功抑制这种神经毒素。在这项研究的基础上，我们详细介绍了 BoNT/A 蛋白酶分子建模研究，并伴随着基于 2,4-二氯肉桂异羟肟酸支架及其氨基甲酸酯前药衍生化的小型异羟肟酸文库的构建，以及对这些分子的酶促和评估细胞模型。