6-(aminooxy)-N-(benzyloxy)hexanamide | 1418033-03-0

• 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: 6-(aminooxy)-N-(benzyloxy)hexanamide
• 英文别名: 6-aminooxy-N-phenylmethoxyhexanamide
• CAS: 1418033-03-0
• 化学式: C₁₃H₂₀N₂O₃
• 分子量: 252.313
• InChiKey: XLGOZNDOLJMSJH-UHFFFAOYSA-N

物化性质

• 密度：
  1?+-.0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.2
• 重原子数：
  18
• 可旋转键数：
  9
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.46
• 拓扑面积：
  73.6
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  6-(aminooxy)-N-(benzyloxy)hexanamide 在 三乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 20.0h， 生成 N-(benzyloxy)-6-((3-(quinolin-3-yl)ureido)oxy)hexanamide
  参考文献：
  名称：

  Histone Deacetylase (HDAC) Inhibitors with a Novel Connecting Unit Linker Region Reveal a Selectivity Profile for HDAC4 and HDAC5 with Improved Activity against Chemoresistant Cancer Cells

  摘要：

  The synthesis and biological evaluation of new potent hydroxamate-based HDAC inhibitors with a novel alkoxyamide connecting unit linker region are described. Biological evaluation includes MTT and cellular HDAC assays on sensitive and chemoresistant cancer cell lines as well as HDAC profiling of selected compounds. Compound 191 (LMK235) (N-((6-(hydroxyamino)-6-oxohexyl)oxy)-3,5-dimethylbenzamide) showed similar effects compared to vorinostat on inhibition of cellular HDACs in a pan-HDAC assay but enhanced cytotoxic effects against the human cancer cell lines A2780, Cal27, Kyse510, and MDA-MB231. Subsequent HDAC profiling yielded a novel HDAC isoform selectivity profile of 19i in comparison to vorinostat or trichostatin A (TSA). 19i shows nanomolar inhibition of HDAC4 and HDAC5, whereas vorinostat and TSA inhibit HDAC4 and HDAC5 in the higher micromolar range.

  DOI：

  10.1021/jm301254q
• 作为产物：
  描述：

  6-溴己酸 在 N-甲基吗啉 、 三乙胺 、 甲基肼 作用下， 以 四氢呋喃 、 二氯甲烷 、 乙腈 为溶剂， 反应 12.75h， 生成 6-(aminooxy)-N-(benzyloxy)hexanamide
  参考文献：
  名称：

  Alkoxyurea-Based Histone Deacetylase Inhibitors Increase Cisplatin Potency in Chemoresistant Cancer Cell Lines

  摘要：

  The synthesis and biological evaluation of potent hydroxamate-based dual HDAC1/6 inhibitors with modest HDAC6 preference and a novel alkoxyurea connecting unit linker region are described. The biological studies included the evaluation of antiproliferative effects and HDAC inhibitory activity in the human ovarian cancer cell line A2780, the human squamous carcinoma cell line Cal27, and their cisplatin resistant sublines A2780CisR and Cal27CisR. The three most potent compounds 1gi showed IC50 values in the low mu M and sub-mu M range. 1gi revealed low nM IC50 values for HDAC6 with up to 15-fold preference over HDAC1, >3500-fold selectivity over HDAC4, and >100-fold selectivity over HDAC8. Furthermore, their ability to enhance cisplatin sensitivity was analyzed in Cal27 and Cal27CisR cells. Notably, a 48 h preincubation of 1-gi significantly enhanced the antiproliferative effects of cisplatin in Cal27 and Cal27CisR. 1-gi interacted synergistically with cisplatin. These effects were more pronounced for the cisplatin resistant subline Cal27CisR.

  DOI：

  10.1021/acs.jmedchem.6b01538

文献信息

• Lysine Acetylation in Sexual Stage Malaria Parasites Is a Target for Antimalarial Small Molecules
  作者：Katharine Trenholme、Linda Marek、Sandra Duffy、Gabriele Pradel、Gillian Fisher、Finn K. Hansen、Tina S. Skinner-Adams、Alice Butterworth、Che Julius Ngwa、Jonas Moecking、Christopher D. Goodman、Geoffrey I. McFadden、Subathdrage D. M. Sumanadasa、David P. Fairlie、Vicky M. Avery、Thomas Kurz、Katherine T. Andrews

  DOI：10.1128/aac.02721-13

  日期：2014.7

  Therapies to prevent transmission of malaria parasites to the mosquito vector are a vital part of the global malaria elimination agenda. Primaquine is currently the only drug with such activity; however, its use is limited by side effects. The development of transmission-blocking strategies requires an understanding of sexual stage malaria parasite (gametocyte) biology and the identification of new drug leads. Lysine acetylation is an important posttranslational modification involved in regulating eukaryotic gene expression and other essential processes. Interfering with this process with histone deacetylase (HDAC) inhibitors is a validated strategy for cancer and other diseases, including asexual stage malaria parasites. Here we confirm the expression of at least one HDAC protein in Plasmodium falciparum gametocytes and show that histone and nonhistone protein acetylation occurs in this life cycle stage. The activity of the canonical HDAC inhibitors trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA; Vorinostat) and a panel of novel HDAC inhibitors on early/late-stage gametocytes and on gamete formation was examined. Several compounds displayed early/late-stage gametocytocidal activity, with TSA being the most potent (50% inhibitory concentration, 70 to 90 nM). In contrast, no inhibitory activity was observed in P. falciparum gametocyte exflagellation experiments. Gametocytocidal HDAC inhibitors caused hyperacetylation of gametocyte histones, consistent with a mode of action targeting HDAC activity. Our data identify HDAC inhibitors as being among a limited number of compounds that target both asexual and sexual stage malaria parasites, making them a potential new starting point for gametocytocidal drug leads and valuable tools for dissecting gametocyte biology.

  摘要 防止疟原虫向蚊媒传播的疗法是全球消除疟疾议程的重要组成部分。伯氨喹是目前唯一具有这种活性的药物，但其使用受到副作用的限制。要开发阻断传播的策略，就必须了解有性阶段疟原虫（配子体）的生物学特性，并找出新的药物线索。赖氨酸乙酰化是一种重要的翻译后修饰，参与调节真核基因表达和其他重要过程。用组蛋白去乙酰化酶（HDAC）抑制剂干扰这一过程是治疗癌症和其他疾病（包括无性阶段的疟原虫）的有效策略。在这里，我们证实了恶性疟原虫中至少有一种 HDAC 蛋白的表达。 恶性疟原虫 配子细胞中至少有一种 HDAC 蛋白的表达，并表明组蛋白和非组蛋白乙酰化发生在这一生命周期阶段。研究考察了典型 HDAC 抑制剂 trichostatin A (TSA) 和 suberoylanilide hydroxamic acid (SAHA; Vorinostat) 以及一系列新型 HDAC 抑制剂对早期/晚期配子细胞和配子形成的活性。有几种化合物显示出早期/晚期配子细胞杀伤活性，其中 TSA 的杀伤活性最强（50% 抑制浓度，70 至 90 nM）。相比之下，在恶性疟原虫中没有观察到抑制活性。 恶性疟原虫 配子细胞外排实验中未观察到抑制活性。配子细胞杀伤性 HDAC 抑制剂会引起配子细胞组蛋白的高乙酰化，这与针对 HDAC 活性的作用模式是一致的。我们的数据表明，HDAC抑制剂是少数同时针对无性和有性阶段疟原虫的化合物之一，因此它们可能成为配子细胞杀灭药物的新起点，也是研究配子细胞生物学的宝贵工具。
• Synthesis, Antimalarial Properties, and SAR Studies of Alkoxyurea-Based HDAC Inhibitors
  作者：Finn K. Hansen、Tina S. Skinner-Adams、Sandra Duffy、Linda Marek、Subathdrage D. M. Sumanadasa、Krystina Kuna、Jana Held、Vicky M. Avery、Katherine T. Andrews、Thomas Kurz

  DOI：10.1002/cmdc.201300469

  日期：2014.3

  Histone deacetylase (HDAC) inhibitors are an emerging class of potential antimalarial drugs. We investigated the antiplasmodial properties of 16 alkoxyurea‐based HDAC inhibitors containing various cap and zinc binding groups (ZBGs). Ten compounds displayed sub‐micromolar activity against the 3D7 line of Plasmodium falciparum. Structure–activity relationship studies revealed that a hydroxamic acid ZBG

  组蛋白脱乙酰基酶（HDAC）抑制剂是一类新兴的潜在抗疟药。我们研究了16种基于烷氧基脲的HDAC抑制剂的抗血浆特性，这些抑制剂含有各种帽和锌结合基团（ZBG）。十种化合物对恶性疟原虫的3D7品系表现出亚微摩尔活性。结构与活性之间的关系研究表明，异羟肟酸ZBG对于抗疟原虫活性至关重要，并且将大分子烷基取代基引入帽基团可增强抵抗无性血阶段寄生虫的能力。我们还证明了所选化合物可导致恶性疟原虫组蛋白H4过度乙酰化，表明抑制了一种或多种PfHDAC。为了评估烷氧基脲基HDAC抑制剂对正常哺乳动物细胞的寄生虫的选择性，评估了代表性化合物对新生儿包皮成纤维细胞（NFF）的细胞毒性。最活跃的化合物，6 - （（3-（4-（叔丁基）苯基）脲基）氧基） - ñ -hydroxyhexanamide（1e中，Pf的3D7 IC 50：0.16μ中号）为31倍的毒性对抗无性血液阶段要比正常哺乳动物细胞快。此外，四
• Alkoxyurea-Based Histone Deacetylase Inhibitors Increase Cisplatin Potency in Chemoresistant Cancer Cell Lines
  作者：Katharina Stenzel、Alexandra Hamacher、Finn K. Hansen、Christoph G. W. Gertzen、Johanna Senger、Viktoria Marquardt、Linda Marek、Martin Marek、Christophe Romier、Marc Remke、Manfred Jung、Holger Gohlke、Matthias U. Kassack、Thomas Kurz

  DOI：10.1021/acs.jmedchem.6b01538

  日期：2017.7.13

  The synthesis and biological evaluation of potent hydroxamate-based dual HDAC1/6 inhibitors with modest HDAC6 preference and a novel alkoxyurea connecting unit linker region are described. The biological studies included the evaluation of antiproliferative effects and HDAC inhibitory activity in the human ovarian cancer cell line A2780, the human squamous carcinoma cell line Cal27, and their cisplatin resistant sublines A2780CisR and Cal27CisR. The three most potent compounds 1gi showed IC50 values in the low mu M and sub-mu M range. 1gi revealed low nM IC50 values for HDAC6 with up to 15-fold preference over HDAC1, >3500-fold selectivity over HDAC4, and >100-fold selectivity over HDAC8. Furthermore, their ability to enhance cisplatin sensitivity was analyzed in Cal27 and Cal27CisR cells. Notably, a 48 h preincubation of 1-gi significantly enhanced the antiproliferative effects of cisplatin in Cal27 and Cal27CisR. 1-gi interacted synergistically with cisplatin. These effects were more pronounced for the cisplatin resistant subline Cal27CisR.
• Histone Deacetylase (HDAC) Inhibitors with a Novel Connecting Unit Linker Region Reveal a Selectivity Profile for HDAC4 and HDAC5 with Improved Activity against Chemoresistant Cancer Cells
  作者：Linda Marek、Alexandra Hamacher、Finn K. Hansen、Krystina Kuna、Holger Gohlke、Matthias U. Kassack、Thomas Kurz

  DOI：10.1021/jm301254q

  日期：2013.1.24

  The synthesis and biological evaluation of new potent hydroxamate-based HDAC inhibitors with a novel alkoxyamide connecting unit linker region are described. Biological evaluation includes MTT and cellular HDAC assays on sensitive and chemoresistant cancer cell lines as well as HDAC profiling of selected compounds. Compound 191 (LMK235) (N-((6-(hydroxyamino)-6-oxohexyl)oxy)-3,5-dimethylbenzamide) showed similar effects compared to vorinostat on inhibition of cellular HDACs in a pan-HDAC assay but enhanced cytotoxic effects against the human cancer cell lines A2780, Cal27, Kyse510, and MDA-MB231. Subsequent HDAC profiling yielded a novel HDAC isoform selectivity profile of 19i in comparison to vorinostat or trichostatin A (TSA). 19i shows nanomolar inhibition of HDAC4 and HDAC5, whereas vorinostat and TSA inhibit HDAC4 and HDAC5 in the higher micromolar range.
• Novel alkoxyamide-based histone deacetylase inhibitors reverse cisplatin resistance in chemoresistant cancer cells
  作者：Yodita Asfaha、Christian Schrenk、Leandro A. Alves Avelar、Friedrich Lange、Chenyin Wang、Jan J. Bandolik、Alexandra Hamacher、Matthias U. Kassack、Thomas Kurz

  DOI：10.1016/j.bmc.2019.115108

  日期：2020.1

  Although histone deacetylase inhibitors (HDACi) have shown promising antitumor effects in specific types of blood cancer, their effects on solid tumors are limited. Previously, we developed LMK235 (5), a class I and class IIb preferential HDACi with chemosensitizing effects on breast cancer, ovarian cancer and HNSCC. Based on its promising effects on solid tumor cells, we modified the cap group of 5 to improve its anticancer activity. The tri- and dimethoxy-phenyl substituted compounds 13a and 13d turned out to be the most potent HDAC inhibitors of this study. The isoform profiling revealed a dual HDAC2/HDAC6 inhibition profile, which was confirmed by the acetylation of a-tubulin and histone H3 in Cal27 and Cal27CisR. In combination with cisplatin, both compounds enhanced the cisplatin-induced cytotoxicity via caspase-3/7 activation. The effect was more pronounced in the cisplatin resistant subline Cal27CisR. The pretreatment with 13d resulted in a complete resensitisation of Cal27CisR with IC50 values in the range of the parental cell line. Therefore, 13d may serve as an epigenetic tool to analyze and modulate the cisplatin resistance of solid tumors.