N-(4-Carboxybenzyl)phenylacetamide | 112916-53-7

• 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: N-(4-Carboxybenzyl)phenylacetamide
• 英文别名: 4-{[(Phenylacetyl)amino]methyl}benzoic acid；4-[[(2-phenylacetyl)amino]methyl]benzoic acid
• CAS: 112916-53-7
• 化学式: C₁₆H₁₅NO₃
• 分子量: 269.3
• InChiKey: DSCHTBMANZRZIL-UHFFFAOYSA-N

物化性质

• 熔点：
  220-221 °C
• 沸点：
  557.1±50.0 °C(Predicted)
• 密度：
  1.235±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  20
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.12
• 拓扑面积：
  66.4
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  N-(4-Carboxybenzyl)phenylacetamide 在 palladium on activated charcoal TEA 、 氢气 、 双(2-氧代-3-恶唑烷基)次磷酰氯 作用下， 以 四氢呋喃 、 甲醇 为溶剂， 反应 2.0h， 生成 N-hydroxy-4-(phenylacetylamino-methyl)benzamide
  参考文献：
  名称：

  Zn²⁺-Chelating Motif-Tethered Short-Chain Fatty Acids as a Novel Class of Histone Deacetylase Inhibitors

  摘要：

  Among various classes of histone deacetylase (HDAC) inhibitors, short-chain fatty acids exhibit the least potency, with IC50 in the millimolar range. We rationalized that this weak potency was, in part, attributable to their inability to access the zinc cation in the HDAC active-site pocket, which is pivotal to the deacetylation catalysis. We thus explored the structural optimization of valproate, butyrate, phenylacetate, and phenylbutyrate by coupling them with Zn2+-chelating motifs (hydroxamic acid and o-phenylenediamine) through aromatic W-amino acid linkers. This strategy has led to a novel class of Zn2+ -chelating, motif-tethered, short-chain fatty acids that exhibited varying degrees of HDAC inhibitory potency. One hydroxamate-tethered phenylbutyrate compound, N-hydroxy-4-(4-phenylbutyrylamino)benzamide (HTPB), displayed nanomolar potency in inhibiting HDAC activity. Exposure of several cancer cell lines to HTPB at the submicromolar level showed reduced cell proliferation accompanied by histone hyperacetylation and elevated p21(WAF/CIPI) expression, which are hallmark features associated with intracellular HDAC inhibition.

  DOI：

  10.1021/jm0303655
• 作为产物：
  描述：

  4-(Phenylacetylamino-methyl)-benzoic acid methyl ester 在 氢氧化钾 作用下， 以 甲醇 为溶剂， 反应 1.0h， 生成 N-(4-Carboxybenzyl)phenylacetamide
  参考文献：
  名称：

  Zn²⁺-Chelating Motif-Tethered Short-Chain Fatty Acids as a Novel Class of Histone Deacetylase Inhibitors

  摘要：

  Among various classes of histone deacetylase (HDAC) inhibitors, short-chain fatty acids exhibit the least potency, with IC50 in the millimolar range. We rationalized that this weak potency was, in part, attributable to their inability to access the zinc cation in the HDAC active-site pocket, which is pivotal to the deacetylation catalysis. We thus explored the structural optimization of valproate, butyrate, phenylacetate, and phenylbutyrate by coupling them with Zn2+-chelating motifs (hydroxamic acid and o-phenylenediamine) through aromatic W-amino acid linkers. This strategy has led to a novel class of Zn2+ -chelating, motif-tethered, short-chain fatty acids that exhibited varying degrees of HDAC inhibitory potency. One hydroxamate-tethered phenylbutyrate compound, N-hydroxy-4-(4-phenylbutyrylamino)benzamide (HTPB), displayed nanomolar potency in inhibiting HDAC activity. Exposure of several cancer cell lines to HTPB at the submicromolar level showed reduced cell proliferation accompanied by histone hyperacetylation and elevated p21(WAF/CIPI) expression, which are hallmark features associated with intracellular HDAC inhibition.

  DOI：

  10.1021/jm0303655

文献信息

• Development of New Inhibitors of HDAC1–3 Enzymes Aided by <i>In Silico</i> Design Strategies
  作者：Narges Cheshmazar、Salar Hemmati、Maryam Hamzeh-Mivehroud、Babak Sokouti、Matthes Zessin、Mike Schutkowski、Wolfgang Sippl、Hojjatollah Nozad Charoudeh、Siavoush Dastmalchi

  DOI：10.1021/acs.jcim.1c01557

  日期：2022.5.23

  active site of HDAC I and ranked using a calculated binding affinity. Top-ranking structures were inspected manually, and, considering the ease of synthesis and drug-likeness, two new structures (3a and 3b) were proposed for synthesis and biological evaluation. The synthesized compounds were purified to a degree of more than 95% and structurally verified using various methods. The designed compounds 3a and

  组蛋白去乙酰化酶 (HDAC) 在癌症中过度表达，它们的抑制在癌症治疗中显示出有希望的结果。特别是，选择性 I 类 HDAC 抑制剂如恩替司他被认为在乳腺癌治疗中更有益。计算药物设计是当今药物发现项目中不可避免的一部分，因为它在节省时间和成本方面具有明确的作用。使用三种 HDAC 抑制剂曲古抑菌素、伏立诺他和恩替司他作为模板结构和多样化的片段库，其所有可合成的化合物 (~3200) 都是虚拟生成的，并基于与模板的相似性和 PAINS 去除进行过滤。选择的 298 个结构与 HDAC I 的活性位点对接，并使用计算的结合亲和力进行排序。顶级结构是人工检查的，并且，考虑到合成的容易性和药物相似性，提出了两种新的结构（3a 和 3b）用于合成和生物学评价。合成的化合物被纯化到超过 95% 的程度，并使用各种方法进行结构验证。设计的化合物 3a 和 3b 分别在 10 μM 浓度下对 HDAC 1、2
• Benzoic acid and benzoic acid ester derivatives having anti-inflammatory and analgesic activity
  申请人：WARNER-LAMBERT COMPANY

  公开号：EP0226223A2

  公开（公告）日：1987-06-24

  Novel benzoic acid or benzoic acid ester derivatives, pharmaceutical compositions and methods of use thereof are the present invention. Utility is for the treatment of arthritis, asthma, Raynaud's disease, inflammatory bowel disorders, trigeminal or herpetic neuralgia, infiammatory eye disorders, psoriasis, dental pain, and headaches, particularly vascular headache, such as migraine, cluster, mixed vascular syndromes, as well as nonvascular, tension headaches.

  本发明是新型苯甲酸或苯甲酸酯衍生物、药物组合物及其使用方法。本发明可用于治疗关节炎、哮喘、雷诺氏病、炎症性肠病、三叉神经痛或疱疹性神经痛、炎症性眼病、牛皮癣、牙痛和头痛，特别是血管性头痛，如偏头痛、丛集性头痛、混合血管综合征以及非血管性紧张性头痛。
• 1,2-Benzisothiazol-3-one 1,1-Dioxide Inhibitors of Human Mast Cell Tryptase
  作者：Keith D. Combrink、H. Belgin Gülgeze、Nicholas A. Meanwell、Bradley C. Pearce、Pi Zulan、Gregory S. Bisacchi、Daniel G. M. Roberts、Paul Stanley、Steven M. Seiler

  DOI：10.1021/jm9804580

  日期：1998.11.1

  A library of compounds were prepared by reacting 2-(bromomethyl)-1,2-benzisothiazol-3(2N) one 1,1-dioxide (5) with commercially available carboxylic acids in the presence of potassium carbonate or a tertiary amine base. From this library, (1,1-dioxido-3-oxo-1,2-benzisothiazol-2(SH)-yl)methyl N-[(phenylmethoxy)carbonyl]-beta-alanate (7b) emerged as a potent inhibitor of human mast cell tryptase (IC50 = 0.85 mu M) Extension of the side chain of 7b by two carbons gave (1,1-dioxido-3-oxo-1,2-benzisothiazol-2(3H)-yl)methyl 5-[[(phenylmethoxy)carbonyl]amino]-pentanoate (7d) which was an 8-fold more potent inhibitor (IC50 = 0.1 mu M). Further modification of this series produced benzoic acid derivative (1,1-dioxido-3-oxo-1,2-benzisothiazol-2(3H)-yl)-methyl 4-[[(phenylmethoxy)carbonyl] amino]benzo ate (7n) which is the most potent inhibitor identified in this series (IC50 = 0.064 mu M). These compounds exhibit time-dependent inhibition consistent with mechanism-based inhibition. For 7b, the initial enzyme velocity is not a saturable function of the inhibitor concentration and the initial Ki could not be determined (K-i > 10 mu M). The steady-state rate constant, K-i*, was determined to be 396 nM. On the other hand, compounds 7d and 7n are time-dependent inhibitors with a saturable initial complex. From these studies, an initial rate constant, K-i, for 7d and 7n was found to be 345 and 465 nM, respectively. The steady-state inhibition constants, K-i*, for 7d and 7n were calculated to be 60 and 52 nM, respectively. Compound 7n is a 13-fold more potent inhibitor than 7b, and these kinetic studies indicate that the increase in inhibitory activity is due to an increase in initial affinity toward the enzyme and not an increase in chemical reactivity. These inhibitors generally show high selectivity for tryptase, being 40-fold weaker inhibitors of elastase, being 100-fold weaker against trypsin, and showing no inhibition against thrombin. These compounds are not inhibitors of thrombin, plasmin t-PA, urokinase and factor Xa (IC50 > 33 mu M). In the delayed-type hypersensitivity (DTH) mouse model, a model of skin inflammation, a 5% solution of 7d reduced edema by 69% compared to control animals.
• US4689182A
  申请人：——

  公开号：US4689182A

  公开（公告）日：1987-08-25
• US4719234A
  申请人：——

  公开号：US4719234A

  公开（公告）日：1988-01-12