N,N'-[2,2'-disulfanediylbis(ethane-2,1-diyl)]bis[3-(3-bromo-4-hydroxyphenyl)propanamide] | 1314789-15-5

• 分子结构分类: 有机化合物 - 苯类化合物 - 酚类
• 英文名称: N,N'-[2,2'-disulfanediylbis(ethane-2,1-diyl)]bis[3-(3-bromo-4-hydroxyphenyl)propanamide]
• 英文别名: 3-(3-bromo-4-hydroxyphenyl)-N-[2-[2-[3-(3-bromo-4-hydroxyphenyl)propanoylamino]ethyldisulfanyl]ethyl]propanamide
• CAS: 1314789-15-5
• 化学式: C₂₂H₂₆Br₂N₂O₄S₂
• 分子量: 606.399
• InChiKey: DGTDUNCYVBWOAQ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4
• 重原子数：
  32
• 可旋转键数：
  13
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  149
• 氢给体数：
  4
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  N,N'-[2,2'-disulfanediylbis(ethane-2,1-diyl)]bis[3-(3-bromo-4-hydroxyphenyl)propanamide] 在 三(2-羰基乙基)磷盐酸盐 作用下， 以 水 、 二甲基亚砜 为溶剂， 反应 0.33h， 生成 3-(3-bromo-4-hydroxyphenyl)-N-(2-sulfanylethyl)propanamide
  参考文献：
  名称：

  Defining the Mechanism of Action and Enzymatic Selectivity of Psammaplin A against Its Epigenetic Targets

  摘要：

  Psammaplin A (11c) is a marine metabolite previously reported to be a potent inhibitor of two classes of epigenetic enzymes: histone deacetylases and DNA methyltransferases. The design and synthesis of a focused library based on the psammaplin A core has been carried out to probe the molecular features of this molecule responsible for its activity. By direct in vitro assay of the free thiol generated upon reduction of the dimeric psammaplin scaffold, we have unambiguously demonstrated that 11c functions as a natural prodrug, with the reduced form being highly potent against HDAC1 in vitro (IC50 0.9 nM). Furthermore, we have shown it to have high isoform selectivity, being 360-fold selective for HDAC1 over HDAC6 and more than 1000-fold less potent against HDAC7 and HDAC8. SAR around our focused library revealed a number of features, most notably the oxime functionality to be important to this selectivity. Many of the compounds show significant cytotoxicity in A549, MCF7, and W138 cells, with the SAR of cytotcodcity correlating to HDAC inhibition. Furthermore, compound treatment causes upregulation of histone acetylation but little effect on tubulin acetylation. Finally, we have found no evidence for 11c functioning as a DNMT inhibitor.

  DOI：

  10.1021/jm2016182
• 作为产物：
  描述：

  对羟基苯丙酸甲酯 在 N-溴代丁二酰亚胺(NBS) 、 N-羟基邻苯二甲酰亚胺 、 N,N'-二环己基碳二亚胺 、 lithium hydroxide 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 19.25h， 生成 N,N'-[2,2'-disulfanediylbis(ethane-2,1-diyl)]bis[3-(3-bromo-4-hydroxyphenyl)propanamide]
  参考文献：
  名称：

  Epigenetic profiling of the antitumor natural product psammaplin A and its analogues

  摘要：

  A collection of analogues of the dimeric natural product psammaplin A that differ in the substitution on the ( halo) tyrosine aryl ring, the oxime and the diamine connection has been synthesized. The effects on cell cycle, induction of differentiation and apoptosis of the natural-product inspired series were measured on the human leukaemia U937 cell line. Epigenetic profiling included induction of p21(WAF1), effects on global H3 histone and tubulin acetylation levels as well as in vitro enzymatic assays using HDAC1, DNMT1, DNMT3A, SIRT1 and a peptide domain with p300/CBP HAT activity. Whereas the derivatives of psammaplin A with modifications in the length of the connecting chain, the oxime bond and the disulfide unit showed lower potency, the analogues with changes on the bromotyrosine ring exhibited activities comparable to those of the parent compound in the inhibition of HDAC1 and in the induction of apoptosis. The lack of HDAC1 activity of analogues modified on the disulfide bond suggests that its cleavage must occur in cells to produce the monomeric Zn2+-chelating thiol. This assumption is consistent with the molecular modelling of the complex of psammaplin A thiol with h-HDAC8. Only a weak inhibition of DNMT1, DNMT3A and residual activities with SIRT1 and a p300/CBP HAT peptide were measured for these compounds. (C) 2010 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2010.12.026

文献信息

• Defining the Mechanism of Action and Enzymatic Selectivity of Psammaplin A against Its Epigenetic Targets
  作者：Matthias G. J. Baud、Thomas Leiser、Patricia Haus、Sharon Samlal、Ai Ching Wong、Robert J. Wood、Vanessa Petrucci、Mekala Gunaratnam、Siobhan M. Hughes、Lakjaya Buluwela、Fabrice Turlais、Stephen Neidle、Franz-Josef Meyer-Almes、Andrew J. P. White、Matthew J. Fuchter

  DOI：10.1021/jm2016182

  日期：2012.2.23

  Psammaplin A (11c) is a marine metabolite previously reported to be a potent inhibitor of two classes of epigenetic enzymes: histone deacetylases and DNA methyltransferases. The design and synthesis of a focused library based on the psammaplin A core has been carried out to probe the molecular features of this molecule responsible for its activity. By direct in vitro assay of the free thiol generated upon reduction of the dimeric psammaplin scaffold, we have unambiguously demonstrated that 11c functions as a natural prodrug, with the reduced form being highly potent against HDAC1 in vitro (IC50 0.9 nM). Furthermore, we have shown it to have high isoform selectivity, being 360-fold selective for HDAC1 over HDAC6 and more than 1000-fold less potent against HDAC7 and HDAC8. SAR around our focused library revealed a number of features, most notably the oxime functionality to be important to this selectivity. Many of the compounds show significant cytotoxicity in A549, MCF7, and W138 cells, with the SAR of cytotcodcity correlating to HDAC inhibition. Furthermore, compound treatment causes upregulation of histone acetylation but little effect on tubulin acetylation. Finally, we have found no evidence for 11c functioning as a DNMT inhibitor.
• Epigenetic profiling of the antitumor natural product psammaplin A and its analogues
  作者：José García、Gianluigi Franci、Raquel Pereira、Rosaria Benedetti、Angela Nebbioso、Fátima Rodríguez-Barrios、Hinrich Gronemeyer、Lucia Altucci、Angel R. de Lera

  DOI：10.1016/j.bmc.2010.12.026

  日期：2011.6

  A collection of analogues of the dimeric natural product psammaplin A that differ in the substitution on the ( halo) tyrosine aryl ring, the oxime and the diamine connection has been synthesized. The effects on cell cycle, induction of differentiation and apoptosis of the natural-product inspired series were measured on the human leukaemia U937 cell line. Epigenetic profiling included induction of p21(WAF1), effects on global H3 histone and tubulin acetylation levels as well as in vitro enzymatic assays using HDAC1, DNMT1, DNMT3A, SIRT1 and a peptide domain with p300/CBP HAT activity. Whereas the derivatives of psammaplin A with modifications in the length of the connecting chain, the oxime bond and the disulfide unit showed lower potency, the analogues with changes on the bromotyrosine ring exhibited activities comparable to those of the parent compound in the inhibition of HDAC1 and in the induction of apoptosis. The lack of HDAC1 activity of analogues modified on the disulfide bond suggests that its cleavage must occur in cells to produce the monomeric Zn2+-chelating thiol. This assumption is consistent with the molecular modelling of the complex of psammaplin A thiol with h-HDAC8. Only a weak inhibition of DNMT1, DNMT3A and residual activities with SIRT1 and a p300/CBP HAT peptide were measured for these compounds. (C) 2010 Elsevier Ltd. All rights reserved.