5-(4-dimethylaminobenzoyl)aminovaleric acid hydroxamate | 251456-58-3

• 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: 5-(4-dimethylaminobenzoyl)aminovaleric acid hydroxamate
• 英文别名: 5-(4-dimethylaminobenzoyl)aminovaleric acid hydroxamide；4-(dimethylamino)-N-[5-(hydroxyamino)-5-oxopentyl]benzamide
• CAS: 251456-58-3
• 化学式: C₁₄H₂₁N₃O₃
• 分子量: 279.339
• InChiKey: RMDLUKIPISOZHR-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.8
• 重原子数：
  20
• 可旋转键数：
  7
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  81.7
• 氢给体数：
  3
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  4-二甲氨基苯甲酸 在 palladium on activated charcoal lithium hydroxide 、 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 、 二氯甲烷 为溶剂， 20.0 ℃ 、101.33 kPa 条件下， 反应 10.0h， 生成 5-(4-dimethylaminobenzoyl)aminovaleric acid hydroxamate
  参考文献：
  名称：

  Amide Analogues of Trichostatin A as Inhibitors of Histone Deacetylase and Inducers of Terminal Cell Differentiation

  摘要：

  Inhibitors of histone deacetylase (HD) bear great potential as new drugs due to their ability to modulate transcription and to induce apoptosis or differentiation in cancer cells. We have described previously analogues of the complex natural HD inhibitors trapoxin B and trichostatin A with activities in the submicromolar range. Here we report structure-activity relationship analyses of further analogues of trichostatin A with respect to in vitro inhibition of maize HD-2 and their ability to induce terminal cell differentiation in Friend leukemic cells. This is the first report that shows the correlation between HD inhibitory activity and action on cancer cells on a larger series of similar compounds. Only the compounds that inhibit HD induce differentiation and/or exert antiproliferative activities in cell culture. Our studies support the use of in vitro systems as screening tools and provide structure-activity relationships that merit further investigation of this interesting target.

  DOI：

  10.1021/jm991091h

文献信息

• A Metabolic Screening Study of Trichostatin A (TSA) and TSA-Like Histone Deacetylase Inhibitors in Rat and Human Primary Hepatocyte Cultures
  作者：G. Elaut、G. Laus、E. Alexandre、L. Richert、P. Bachellier、D. Tourwé、V. Rogiers、T. Vanhaecke

  DOI：10.1124/jpet.106.116202

  日期：2007.4

  Hydroxamic acid (HA)-based histone deacetylase (HDAC) inhibitors, with trichostatin A (TSA) as the reference compound, are potential antitumoral drugs and show promise in the creation of long-term primary cell cultures. However, their metabolic properties have barely been investigated. TSA is rapidly inactivated in rodents both in vitro and in vivo. We previously found that 5-(4-dimethylaminobenzoyl)aminovaleric acid hydroxyamide or 4-Me2 N -BAVAH (compound 1 ) is metabolically more stable upon incubation with rat hepatocyte suspensions. In this study, we show that human hepatocytes also metabolize TSA more rapidly than compound 1 and that similar pathways are involved. Furthermore, structural analogs of compound 1 (compounds 2 - 9 ) are reported to have the same favorable metabolic properties. Removal of the dimethylamino substituent of compound 1 creates a very stable but 50% less potent inhibitor. Chain lengthening (4 to 5 carbon spacer) slightly improves both potency and metabolic stability, favoring HA reduction to hydrolysis. On the other hand, Cα-unsaturation and spacer methylation not only reduce HDAC inhibition but also increase the rate of metabolic inactivation approximately 2-fold, mainly through HA reduction. However, in rat hepatocyte monolayer cultures, compound 1 is shown to be extensively metabolized by phase II conjugation. In conclusion, this study suggests that simple structural modifications of amide-linked TSA analogs can improve their phase I metabolic stability in both rat and human hepatocyte suspensions. Phase II glucuronidation, however, can compensate for their lower phase I metabolism in rat hepatocyte monolayers and could play a yet unidentified role in the determination of their in vivo clearance.

  基于羟肟酸（HA）的组蛋白去乙酰化酶（HDAC）抑制剂，以三氢司他丁 A（TSA）为参照化合物，是一种潜在的抗肿瘤药物，在建立长期原代细胞培养物方面显示出前景。然而，对它们的代谢特性几乎没有进行过研究。TSA 在啮齿动物体内外都会迅速失活。我们之前发现，5-（4-二甲氨基苯甲酰基）氨基戊酸羟酰胺或 4-Me2 N -BAVAH（化合物 1）与大鼠肝细胞悬浮液培养后的代谢更稳定。在本研究中，我们发现人类肝细胞代谢 TSA 的速度也比化合物 1 快，而且涉及类似的途径。此外，据报道化合物 1 的结构类似物（化合物 2 - 9）也具有相同的良好代谢特性。去掉化合物 1 的二甲基氨基取代基后，会产生一种非常稳定的抑制剂，但药效会降低 50%。延长链（4 到 5 个碳间隔）可略微提高药效和代谢稳定性，使 HA 减少水解。另一方面，Cα-不饱和和间隔甲基化不仅会降低 HDAC 抑制作用，还会使代谢失活率提高约 2 倍，主要是通过 HA 还原。不过，在大鼠肝细胞单层培养物中，化合物 1 通过 II 期共轭作用被广泛代谢。总之，这项研究表明，对酰胺连接的 TSA 类似物进行简单的结构修饰就能提高它们在大鼠和人类肝细胞悬浮液中的 I 期代谢稳定性。然而，II 期葡糖醛酸化作用可弥补其在大鼠肝细胞单层中较低的 I 期代谢，并可在确定其体内清除率方面发挥尚未确定的作用。
• Imaging histone deacetylases with a radiotracer using positron emission tomography
  申请人：THE GENERAL HOSPITAL CORPORATION

  公开号：US10188756B2

  公开（公告）日：2019-01-29

  Disclosed herein are histone deacetylase imaging agents for positron emission tomography and related imaging methods using the histone deacetylase imaging agents. The histone deacetylase imaging agents may be a compound of formula (I): wherein R1 is a moiety including a positron emitter; R2 represents hydrogen, or substituted or unsubstituted alkyl, or substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and n is an integer selected from 0 or 1. In one version of the compound of formula (I), R1 is a moiety including an adamantyl group.

  本文公开了用于正电子发射断层扫描的组蛋白去乙酰化酶成像剂和使用组蛋白去乙酰化酶成像剂的相关成像方法。组蛋白去乙酰化酶成像剂可以是式 (I) 的化合物：其中 R1 是包括正电子发射体的分子；R2 代表氢，或取代或未取代的烷基，或取代或未取代的芳基，或取代或未取代的杂芳基；n 是选自 0 或 1 的整数。在一种式（I）化合物中，R1 是包括金刚烷基的分子。
• DIFFERENTIATION OF RAT LIVER EPITHELIAL CELLS INTO HEPATOCYTE-LIKE CELLS
  申请人：Rogiers Vera

  公开号：US20100278782A1

  公开（公告）日：2010-11-04

  Methods for differentiation of cells of a rat liver epithelial (RLEC) cell line to hepatocyte-like cells are disclosed. In particular, methods involve sequential exposure of the RLEC to two or more differentiation agents. Cells obtained by the method are described as well as their uses in various pharmacological, toxicological, therapeutic, diagnostic and research applications.
• IMAGING HISTONE DEACETYLASES WITH A RADIOTRACER USING POSITRON EMISSION TOMOGRAPHY
  申请人：THE GENERAL HOSPITAL CORPORATION

  公开号：US20160271276A1

  公开（公告）日：2016-09-22

  Disclosed herein are histone deacetylase imaging agents for positron emission tomography and related imaging methods using the histone deacetylase imaging agents. The histone deacetylase imaging agents may be a compound of formula (I): wherein R 1 is a moiety including a positron emitter; R 2 represents hydrogen, or substituted or unsubstituted alkyl, or substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and n is an integer selected from 0 or 1. In one version of the compound of formula (I), R 1 is a moiety including an adamantyl group.
• Amide Analogues of Trichostatin A as Inhibitors of Histone Deacetylase and Inducers of Terminal Cell Differentiation
  作者：Manfred Jung、Gerald Brosch、Doris Kölle、Hans Scherf、Clarissa Gerhäuser、Peter Loidl

  DOI：10.1021/jm991091h

  日期：1999.11.1

  Inhibitors of histone deacetylase (HD) bear great potential as new drugs due to their ability to modulate transcription and to induce apoptosis or differentiation in cancer cells. We have described previously analogues of the complex natural HD inhibitors trapoxin B and trichostatin A with activities in the submicromolar range. Here we report structure-activity relationship analyses of further analogues of trichostatin A with respect to in vitro inhibition of maize HD-2 and their ability to induce terminal cell differentiation in Friend leukemic cells. This is the first report that shows the correlation between HD inhibitory activity and action on cancer cells on a larger series of similar compounds. Only the compounds that inhibit HD induce differentiation and/or exert antiproliferative activities in cell culture. Our studies support the use of in vitro systems as screening tools and provide structure-activity relationships that merit further investigation of this interesting target.