N-(benzyloxy)-6-bromohexaneamide | 94136-35-3

• 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: N-(benzyloxy)-6-bromohexaneamide
• 英文别名: N-(benzyloxy)-6-bromohexanamide；benzyl 6-bromocaprohydroxamate；N-benzyloxy-6-bromohexanoyl amide；6-bromo-N-phenylmethoxyhexanamide
• CAS: 94136-35-3
• 化学式: C₁₃H₁₈BrNO₂
• 分子量: 300.195
• InChiKey: XEBPGHLIUNKHQA-UHFFFAOYSA-N

物化性质

• 密度：
  1.303±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  17
• 可旋转键数：
  8
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.46
• 拓扑面积：
  38.3
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  N-(benzyloxy)-6-bromohexaneamide 在 吡啶 、 palladium 10% on activated carbon 、 氢气 、 三乙胺 、 甲基肼 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 乙腈 为溶剂， -10.0~70.0 ℃ 、100.0 kPa 条件下， 反应 13.0h， 生成 N-hydroxy-6-((3-(2-isopropoxy-6-methoxy-4-methyl-5-(3-(trifluoromethyl)phenoxy)quinolin-8-yl)ureido)oxy)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
• 作为产物：
  描述：

  6-溴己酸 在 N-甲基吗啉 作用下， 以 四氢呋喃 为溶剂， 反应 3.25h， 生成 N-(benzyloxy)-6-bromohexaneamide
  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

• Potent inducers of terminal differentiation and method of use thereof
  申请人：Sloan-Kettering Institute for Cancer Research

  公开号：US05700811A1

  公开（公告）日：1997-12-23

  This invention is directed to compounds having the structure: ##STR1## wherein R.sub.1 and R.sub.2 are independently the same as or different from each other; when R.sub.1 and R.sub.2 are the same, each is a substituted or unsubstituted arylamino, cycloalkylamino, pyridineamino, piperidino, 9-purine-6-amine or thiazoleamino group; when R.sub.1 and R.sub.2 are different, R.sub.1 =R.sub.3 --N--R.sub.4, and n is an integer from about 4 to about 8. This invention also provides a method of selectively inducing terminal differentiation of neoplastic cells and thereby inhibiting proliferation of such cells. The invention further provides pharmaceutical compositions comprising a therapeutically effective amount of the compounds of the present invention and a pharmaceutically acceptable carrier.

  这项发明涉及具有以下结构的化合物：##STR1## 其中 R.sub.1 和 R.sub.2 可以相同也可以不同；当 R.sub.1 和 R.sub.2 相同时，每个都是取代或未取代的芳胺基、环烷胺基、吡啶胺基、哌啶基、9-嘌呤-6-胺或噻唑胺基；当 R.sub.1 和 R.sub.2 不同时，R.sub.1 =R.sub.3 --N--R.sub.4，n 为大约 4 到大约 8 的整数。该发明还提供了一种选择性诱导肿瘤细胞终端分化从而抑制这些细胞增殖的方法。该发明还提供了包含本发明化合物的治疗有效量和药学可接受载体的药物组合物。
• Potent inducers of terminal differentiation and methods of use thereof
  申请人：Sloan-Kettering Institute for Cancer Research

  公开号：US05369108A1

  公开（公告）日：1994-11-29

  The present invention provides the compound having the structure: ##STR1## wherein each of R.sub.1 and R.sub.2 are independently the same as or different from each other; when R.sub.1 and R.sub.2 are the same, each is a substituted or unsubstituted arylamino, cycloalkylamino, pyridineamino, piperidino, 9-purine-6-amine, or thiozoleamino group; when R.sub.1 and R.sub.2 are different, R.sub.1 =R.sub.3 --N--R.sub.4, wherein each of R.sub.3 and R.sub.4 are independently the same as or different from each other and are a hydrogen atom, a hydroxyl group, a substituted or unsubstituted, branched or unbranched alkyl, alkenyl, cycloalkyl, aryl, alkyloxy, aryloxy, arylalkyloxy, or pyridine group, or R.sub.3 and R.sub.4 bond together to form a piperidine group and R.sub.2 is a hydroxylamino, hydroxyl, amino, alkylamino, dialkylamino or alkyloxy group; and n is an integer from about 4 to about 8. The present invention also provides a method of selectively inducing terminal differentiation of neoplastic cells and thereby inhibiting proliferation of such cells. Moreover, the present invention provides a method of treating a patient having a tumor characterized by proliferation of neoplastic cells. Lastly, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically acceptable amount of the compound above.

  本发明提供了具有以下结构的化合物：##STR1## 其中R.sub.1和R.sub.2各自独立地相同或不同; 当R.sub.1和R.sub.2相同时，每个都是取代或未取代的芳基氨基，环烷基氨基，吡啶氨基，哌啶，9-嘌呤-6-胺或噻唑基氨基基团; 当R.sub.1和R.sub.2不同时，R.sub.1 = R.sub.3 -N- R.sub.4，其中R.sub.3和R.sub.4各自独立地相同或不同，是氢原子，羟基，取代或未取代的支链或直链烷基，烯基，环烷基，芳基，烷氧基，芳氧基，芳基烷氧基或吡啶基，或R.sub.3和R.sub.4结合形成哌啶基团，而R.sub.2是羟胺基，羟基，氨基，烷基氨基，二烷基氨基或烷氧基基团; 而n是从约4到约8的整数。 本发明还提供了一种选择性诱导肿瘤细胞末端分化以抑制这些细胞增殖的方法。此外，本发明还提供了一种治疗具有由肿瘤细胞增殖所特征的肿瘤患者的方法。最后，本发明提供了一种制剂，包括药学上可接受的载体和上述化合物的治疗上可接受的量。
• Artificial siderophores. 2. Syntheses of trihydroxamate analogs of rhodotorulic acid and their biological iron transport capabilities in Escherichia coli
  作者：Byung Hyun Lee、Marvin J. Miller、Catherine A. Prody、John B. Neilands

  DOI：10.1021/jm00381a011

  日期：1985.3

  isocyanurates 2a-c were synthesized from alpha, omega-dibromoalkanes 5 in four steps. The alkylation of the bromides 5a-c with O-benzyl-N-[(trichloroethoxy)carbonyl]hydroxylamine in the presence of DBU gave N-alkylation products 7a-c. The (trichloroethoxy)cabronyl protecting group of 7a-c was easily removed by Zn dust in acetic acid. When the reaction was performed with acetic anhydride, the desired N-acetylated

  由α，ω-二溴代烷烃5以四个步骤合成三[（乙酰羟基氨基）烷基]异氰脲酸酯2a-c。在DBU存在下，用O-苄基-N-[（三氯乙氧基）羰基]羟胺将溴化物5a-c烷基化，得到N-烷基化产物7a-c。锌粉尘在乙酸中很容易除去7a-c的（三氯乙氧基）炔基保护基。当用乙酸酐进行反应时，获得所需的N-乙酰化的材料10a-c。在碱存在下用12将氰尿酸烷基化，得到N-烷基化的物质13，将其氢化得到2a-c。为了确定结构修饰对生物活性的影响，利用了侧臂的各种链长，并制备了反向类似物3。所检查的大多数化合物在支持大肠杆菌铁营养方面起着铬铁的作用。但是，三[（乙酰羟基氨基）丁基]异氰脲酸酯2b，在某种程度上也可以是戊基类似物2c，显示出支持fhuB突变体生长的独特且引人注目的特性，而后者对其他类似物和所有测试的天然铁载体均无反应。
• [EN] NOVEL POTENT INDUCERS OF TERMINAL DIFFERENTIATION AND METHODS OF USE THEREOF
  申请人：SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH

  公开号：WO1993007148A1

  公开（公告）日：1993-04-15

  (EN) The present invention provides the compound having structure (I), wherein each of R1 and R2 are independently the same as or different from each other; when R1 and R2 are the same, each is a substituted or unsubstituted arylamino, cycloalkylamino, pyridineamino, piperidino, 9-purine-6-amine, or thiozoleamino group; when R1 and R2 are different, R1 = R3-N-R4, wherein each of R3 and R4 are independently the same as or different from each other and are a hydrogen atom, a hydroxyl group, a substituted or unsubstituted, branched or unbranched alkyl, alkenyl, cycloalkyl, aryl, alkyloxy, aryloxy, arylalkyloxy, or pyridine group, or R3 and R4 bond together to form a piperidine group and R2 is a hydroxylamino, hydroxyl, amino, alkylamino, dialkylamino or alkyloxy group; and n is an integer from about 4 to about 8. The present invention also provides a method of selectively inducing terminal differentiation of neoplastic cells and thereby inhibiting proliferation of such cells. Moreover, the present inventtion provides a method of treating a patient having a tumor characterized by proliferation of neoplastic cells. Lastly, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically acceptable amount of the compound above.(FR) La présente invention se rapporte à un procédé présentant la structure (I), dans laquelle R1 et R2 sont indépendamment identiques ou différents; lorsque R1 et R2 sont identiques, chacun représente un groupe arylamino, cycloalkylamino, pyridinamino, pipéridino, 9-purine-6-amine ou thiozolamino substitué ou non; lorsque R1 et R2 sont différents, R1 = R3-N-R4, R3 et R4 étant indépendamment identiques ou différents et représentant un atome d'hydrogène, un groupe hydroxyle, un groupe alkyle, alcényle, cycloalkyle, aryle, aryloxy, alkyloxy, aryalkyloxy ou pyridine substitué ou non, ramifié ou non ramifié, ou alors R3 et R4 se lient ensemble pour former un groupe hydroxylamino, hydroxyle, amino, alkylamino, dialkylamino ou alkyloxy; et n représente un nombre entier compris entre 4 et 8 environ. La présente invention se rapporte également à un procédé permettant d'induire sélectivement la différentiation terminale de cellules néoplasiques, et d'inhiber ainsi la prolifération de telles cellules. En outre, l'invention se rapporte à un procédé de traitement d'un patient souffrant d'une tumeur caractérisée par la prolifération de cellules néoplasiques, ainsi qu'à une composition pharmaceutique comprenant un véhicule pharmaceutiquement acceptable et une quantité thérapeutiquement acceptable du composé décrit ci-dessus.

  本发明提供具有结构(I)的化合物，其中R1和R2各自独立相同或不同; 当R1和R2相同时，每个都是取代或未取代的芳基氨基，环烷基氨基，吡啶氨基，哌啶，9-嘌呤-6-胺或噻唑氨基基团; 当R1和R2不同时，R1 = R3-N-R4，其中R3和R4各自独立相同或不同，并且是氢原子，羟基，取代或未取代，分支或非分支烷基，烯基，环烷基，芳基，烷氧基，芳氧基，芳基烷氧基或吡啶基，或R3和R4结合形成哌啶基团，而R2是羟胺基，羟基，氨基，烷基氨基，二烷基氨基或烷氧基; n是大约4到8的整数。本发明还提供了一种选择性诱导肿瘤细胞的末端分化，从而抑制这些细胞增殖的方法。此外，本发明提供了一种治疗患有以肿瘤细胞增殖为特征的患者的方法。最后，本发明提供了一种制药组合物，包括药学上可接受的载体和上述化合物的治疗上可接受的量。
• 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.