4-{[(2-hydroxyethyl)(2-naphthylmethyl)amino]methyl}-N-(tetrahydro-2H-pyran-2-yloxy)benzamide | 1198587-13-1

• 分子结构分类: 有机化合物 - 苯类化合物 - 萘
• 英文名称: 4-{[(2-hydroxyethyl)(2-naphthylmethyl)amino]methyl}-N-(tetrahydro-2H-pyran-2-yloxy)benzamide
• 英文别名: 4-[[2-hydroxyethyl(naphthalen-2-ylmethyl)amino]methyl]-N-(oxan-2-yloxy)benzamide
• CAS: 1198587-13-1
• 化学式: C₂₆H₃₀N₂O₄
• 分子量: 434.535
• InChiKey: YKHNRNMRCDJWJA-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：
  9
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  71
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  4-{[(2-hydroxyethyl)(2-naphthylmethyl)amino]methyl}-N-(tetrahydro-2H-pyran-2-yloxy)benzamide 、 2-{[(4-methoxyphenyl)(diphenyl)methyl]sulfanyl}ethanol 在 4-二甲氨基吡啶 、 三光气 作用下， 以 二氯甲烷 为溶剂， 反应 7.25h， 以55%的产率得到2-{[(4-methoxyphenyl)(diphenyl)methyl]sulfanyl}ethyl 2-[(2-naphthylmethyl)(4-{[(tetrahydro-2H-pyran-2-yloxy)amino]carbonyl}benzyl)amino]ethyl carbonate
  参考文献：
  名称：

  Antitumor Effect of Liposomal Histone Deacetylase Inhibitor-Lipid Conjugates in Vitro

  摘要：

  组蛋白去乙酰化酶抑制剂(HDACI)，例如已获食品和药物管理局(FDA)批准用于治疗皮肤T细胞淋巴瘤的辛二酰苯胺异羟肟酸(SAHA)，是一种有前景的多种癌症治疗新策略。在本研究中，我们假设HDACI的脂质体配方可能有效将HDACI递送至肿瘤。为了有效地将HDACI整合到脂质体膜中，我们合成了六种HDACI-脂质偶联物，其中聚乙二醇2000(PEG2000)-脂质或胆固醇(Chol)通过可裂解的连接子，例如酯、碳酰胺和二硫键，与强效异羟肟酸HDACI(SAHA或K-182)连接。使用二硬脂酰磷脂酰胆碱(DSPC)和HDACI-Chol偶联物或DSPC、Chol和HDACI-PEG-脂质偶联物制备脂质体HDACI-脂质偶联物，并评估它们对人宫颈肿瘤HeLa和小鼠结肠肿瘤Colon 26细胞的细胞毒性。在所有脂质体中，通过碳酰胺连接子与SAHA和油酰-PEG2000结合的脂质体油酰-PEG2000-SAHA显示出更高的细胞毒性，这通过组蛋白H3的高度乙酰化和caspase 3/7活性的诱导来体现。这些结果表明，脂质体HDACI-脂质偶联物可能是癌症治疗的潜在工具。

  DOI：

  10.1248/cpb.59.1386
• 作为产物：
  描述：

  4-{[(2-naphthylmethyl)amino]methyl}-N-(tetrahydro-2H-pyran-2-yloxy)benzamide 、 2-溴乙醇 在 三乙胺 作用下， 以 乙腈 为溶剂， 反应 6.0h， 以58.5%的产率得到4-{[(2-hydroxyethyl)(2-naphthylmethyl)amino]methyl}-N-(tetrahydro-2H-pyran-2-yloxy)benzamide
  参考文献：
  名称：

  Histone deacetylase inhibitor prodrugs in nanoparticle vector enhanced gene expression in human cancer cells

  摘要：

  We developed histone deacetylase inhibitor (HDACI) prodrugs to enhance the expression of the external genes transfected into human cells with cationic nanoparticles (NPs). We synthesized five kinds of lipid-linked HDACI prodrugs in which n-dodecanoic acid or cholesterol is linked with a potent HDACI, K-182, by an ester bond or a disulfide carbonate linker. The prodrugs were able to admix as a component of NPs, although the intact K-182 was not incorporated into NPs. Namely, NPs composed of cholesteryl-3 beta-carboxyamidoethylene-N-hydroxyethylamine and Tween 80 with the 10 mol% K-182 prodrug were prepared as a DNA vector to transfect plasmid DNAs into human prostate cancer cells, PC-3, or human breast cancer cells, Sk-Br-3. The NPs containing K-182 prodrugs with n-dodecanoic acid exhibited two to four times higher the gene expression than the original NPs. The enhancement of the gene expression will be due to the hyperacetylation of core histories caused by intact K-182 degraded from the prodrug in the vector incorporated into the cells. (C) 2009 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2009.06.036

文献信息

• Antitumor Effect of Liposomal Histone Deacetylase Inhibitor-Lipid Conjugates in Vitro
  作者：Yoshiyuki Hattori、Yasuo Nagaoka、Manami Kubo、Haruka Yamasaku、Yuta Ishii、Hiroko Okita、Hiroki Nakano、Shinichi Uesato、Yoshie Maitani

  DOI：10.1248/cpb.59.1386

  日期：——

  Histone deacetylase inhibitor (HDACI), suberoylanilide hydroxamic acid (SAHA), approved by the Food and Drug Administration (FDA) for the treatment of cutaneous T cell lymphoma, is a promising new treatment strategy for various cancers. In this study, we hypothesized that a liposomal formulation of HDACI might efficiently deliver HDACI into tumors. To incorporate HDACI efficiently into the liposomal membrane, we synthesized six HDACI-lipid conjugates, in which polyethylene glycol2000 (PEG2000)-lipid or cholesterol (Chol) was linked with a potent hydroxamic acid, HDACI, SAHA or K-182, by cleavable linkers, such as ester, carbamide and disulfide bonds. Liposomal HDACI-lipid conjugates were prepared with distearoylphosphatidylcholine (DSPC) and HDACI-Chol conjugate or with DSPC, Chol and HDACI-PEG-lipid conjugates, and their cytotoxicities were evaluated for human cervix tumor HeLa and mouse colon tumor Colon 26 cells. Among the liposomes, liposomal oleyl-PEG2000-SAHA conjugated with SAHA and oleyl-PEG2000 via a carbamate linker showed higher cytotoxicity via hyperacetylation of histone H3 and induction of caspase 3/7 activity. These results suggested that liposomal HDACI-lipid conjugates may be a potential tool for cancer therapy.

  组蛋白去乙酰化酶抑制剂(HDACI)，例如已获食品和药物管理局(FDA)批准用于治疗皮肤T细胞淋巴瘤的辛二酰苯胺异羟肟酸(SAHA)，是一种有前景的多种癌症治疗新策略。在本研究中，我们假设HDACI的脂质体配方可能有效将HDACI递送至肿瘤。为了有效地将HDACI整合到脂质体膜中，我们合成了六种HDACI-脂质偶联物，其中聚乙二醇2000(PEG2000)-脂质或胆固醇(Chol)通过可裂解的连接子，例如酯、碳酰胺和二硫键，与强效异羟肟酸HDACI(SAHA或K-182)连接。使用二硬脂酰磷脂酰胆碱(DSPC)和HDACI-Chol偶联物或DSPC、Chol和HDACI-PEG-脂质偶联物制备脂质体HDACI-脂质偶联物，并评估它们对人宫颈肿瘤HeLa和小鼠结肠肿瘤Colon 26细胞的细胞毒性。在所有脂质体中，通过碳酰胺连接子与SAHA和油酰-PEG2000结合的脂质体油酰-PEG2000-SAHA显示出更高的细胞毒性，这通过组蛋白H3的高度乙酰化和caspase 3/7活性的诱导来体现。这些结果表明，脂质体HDACI-脂质偶联物可能是癌症治疗的潜在工具。
• Histone deacetylase inhibitor prodrugs in nanoparticle vector enhanced gene expression in human cancer cells
  作者：Yuta Ishii、Yoshiyuki Hattori、Toshiharu Yamada、Shinichi Uesato、Yoshie Maitani、Yasuo Nagaoka

  DOI：10.1016/j.ejmech.2009.06.036

  日期：2009.11

  We developed histone deacetylase inhibitor (HDACI) prodrugs to enhance the expression of the external genes transfected into human cells with cationic nanoparticles (NPs). We synthesized five kinds of lipid-linked HDACI prodrugs in which n-dodecanoic acid or cholesterol is linked with a potent HDACI, K-182, by an ester bond or a disulfide carbonate linker. The prodrugs were able to admix as a component of NPs, although the intact K-182 was not incorporated into NPs. Namely, NPs composed of cholesteryl-3 beta-carboxyamidoethylene-N-hydroxyethylamine and Tween 80 with the 10 mol% K-182 prodrug were prepared as a DNA vector to transfect plasmid DNAs into human prostate cancer cells, PC-3, or human breast cancer cells, Sk-Br-3. The NPs containing K-182 prodrugs with n-dodecanoic acid exhibited two to four times higher the gene expression than the original NPs. The enhancement of the gene expression will be due to the hyperacetylation of core histories caused by intact K-182 degraded from the prodrug in the vector incorporated into the cells. (C) 2009 Elsevier Masson SAS. All rights reserved.