8-((benzyloxy)amino)-8-oxooctanoic acid | 251304-81-1

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 脂肪酰基
• 英文名称: 8-((benzyloxy)amino)-8-oxooctanoic acid
• 英文别名: 7-benzyloxycarbamoyl-heptanoic acid；8-oxo-8-(phenylmethoxyamino)octanoic acid
• CAS: 251304-81-1
• 化学式: C₁₅H₂₁NO₄
• 分子量: 279.336
• InChiKey: RHXABKLEBVKAQJ-UHFFFAOYSA-N

物化性质

• 密度：
  1.141±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  20
• 可旋转键数：
  10
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.47
• 拓扑面积：
  75.6
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  8-((benzyloxy)amino)-8-oxooctanoic acid 在 10percent Pd/C N-甲基吗啉 、 氢气 作用下， 以 四氢呋喃 、 甲醇 为溶剂， 反应 6.25h， 生成 (S)-2-(7-Hydroxycarbamoyl-heptanoylamino)-3-naphthalen-2-yl-propionic acid methyl ester
  参考文献：
  名称：

  Structure−Activity Relationships on Phenylalanine-Containing Inhibitors of Histone Deacetylase:  In Vitro Enzyme Inhibition, Induction of Differentiation, and Inhibition of Proliferation in Friend Leukemic Cells

  摘要：

  Inhibitors of histone deacetylases (HDACs) are a new class of anticancer agents that affect gene regulation. We had previously reported the first simple synthetic HDAC inhibitors with in vitro activity at submicromolar concentrations. Here, we present structure-activity data on modifications of a phenylalanine-containing lead compound including amino acid amides as well as variations of the amino acid part. The compounds were tested for inhibition of maize HD-2, rat liver HDAC, and for the induction of terminal cell differentiation and inhibition of proliferation in Friend leukemic cells. In the amide series, in vitro inhibition was potentiated up to 15-fold, but the potential to induce cell differentiation decreased. Interestingly, an HDAC class selectivity was indicated among some of these amides. In the amino acid methyl ester series, a biphenylalanine derivative was identified as a good enzyme inhibitor, which blocks proliferation in the submicromolar range and is also a potent inducer of terminal cell differentiation.

  DOI：

  10.1021/jm0208119
• 作为产物：
  描述：

  辛二酸 在 乙酸酐 、 三乙胺 作用下， 以 四氢呋喃 为溶剂， 反应 1.5h， 生成 8-((benzyloxy)amino)-8-oxooctanoic acid
  参考文献：
  名称：

  4-联苯丙氨酸和3-苯基酪氨酸衍生的异羟肟酸作为JumonjiC领域的组蛋白去甲基化酶KDM4A的抑制剂。

  摘要：

  调节H3K9和H3K36甲基化状态的组蛋白赖氨酸脱甲基酶KDM4A的过表达与几种人类癌症的病理学有关。我们发现以前报道的基于异羟肟酸酯的组蛋白脱乙酰基酶（HDAC）抑制剂（SW55）也能够以25.4μm的IC50值弱抑制这种脱甲基酶。在这里，我们报告了该铅结构的一系列衍生物的合成和生化评估，以及两个正交的体外测定。通过对前导结构进行广泛的化学修饰，还通过利用芳基重氮盐进行自由基芳基化的多功能性，我们能够将衍生物对KDM4A的效力提高至低微摩尔范围，更重要的是，获得了对KDM4A的脱甲基酶选择性。对HDAC的尊重。

  DOI：

  10.1002/cmdc.201600218

文献信息

• New histone deacetylase inhibitors based on 4-fluoro-2-amino acid esters: Synthesis and activity
  作者：Martin Lübke、Manfred Jung、Günter Haufe

  DOI：10.1016/j.jfluchem.2013.03.011

  日期：2013.8

  histone deacetylase inhibitors 25 was synthesized and their inhibitory activity was tested against rat liver histone deacetylase. The new inhibitors involve an enzyme binding element consisting of asparagine, glutamine or different short chain fluorinated or unfluorinated amino acids, a suberoyl spacer and a hydroxamic acid functionality, which is responsible for the inhibitory activity. The 4-fluoro-2-aminobutyric

  一系列的12氟化和非氟化的电位组蛋白脱乙酰酶抑制剂25合成和它们的抑制活性对大鼠肝脏组蛋白脱乙酰测试。新的抑制剂包括选自天冬酰胺，谷氨酰胺或不同的短链的酶结合元件的氟化或未氟化的氨基酸，一个辛二间隔物和异羟肟酸官能度，它负责的抑制活性。4-氟-2-氨基丁酸酯1A，B，它们的2-甲基衍生物图2a，2b和2-氨基-4- fluoropent -4-烯酸酯3A，3B由甘氨酸或分别与bromofluoroethane或2- fluoroallylbromide，丙氨酸酯酰亚胺烷基化合成。2-氨基-5- fluorohex -5-烯酸甲酯（图4a）中的溶液用3-氟丁-3-烯基甲苯磺酸酯或碘化物作为烷基化试剂来制备。一个替代途径由Boc-保护的起始3-碘-升-丙氨酸是更有效的。后一种方法也适用于合成母体的未氟化化合物4c中使用烯丙基溴作为烷基化试剂。的氟化化合物，测试了作为组蛋白脱乙酰酶抑制剂是略少活性比可比（小号）
• 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。
• HISTONE DEACETYLASE INHIBITORS
  申请人：Bradner James Elliot

  公开号：US20100056588A1

  公开（公告）日：2010-03-04

  In recognition of the need to develop novel therapeutic agents, the present invention provides novel histone deacetylase inhibitors. These compounds include an ester bond making them sensitive to deactivation by esterases. Therefore, these compounds are particularly useful in the treatment of skin disorders. When the compounds reaches the bloodstream, an esterase or an enzyme with esterase activity cleaves the compound into biologically inactive fragments or fragments with greatly reduced activity Ideally these degradation products exhibit a short serum and/or systemic half-life and are eliminated rapidly. These compounds and pharmaceutical compositions thereof are particularly useful in treating cutaneous T-cell lymphoma, neurofibromatosis, psoriasis, hair loss, skin pigmentation, and dermatitis, for example. The present invention also provides methods for preparing compounds of the invention and intermediates thereto.

  为了开发新型治疗剂，本发明提供了新型组蛋白去乙酰化酶抑制剂。这些化合物包括酯键，使它们对酯酶的失活敏感。因此，这些化合物在治疗皮肤疾病方面特别有用。当这些化合物进入血液循环时，酯酶或具有酯酶活性的酶将其裂解成生物学上不活性的碎片或具有大大降低活性的碎片。理想情况下，这些降解产物表现出短的血清和/或系统半衰期，并迅速被排出体外。这些化合物及其制剂在治疗切除性T细胞淋巴瘤、神经纤维瘤、银屑病、脱发、皮肤色素沉着和皮炎等方面特别有用。本发明还提供了制备本发明化合物及其中间体的方法。
• [EN] CARBAMIC ACID COMPOUNDS COMPRISING A PIPERAZINE LINKAGE AS HDAC INHIBITORS<br/>[FR] COMPOSES D'ACIDE CARBAMIQUE COMPRENANT UN CHAINON DE PIPERAZINE TELS QUE LES INHIBITEURS HDAC
  申请人：PROLIFIX LTD

  公开号：WO2003082288A1

  公开（公告）日：2003-10-09

  This invention pertains to certain carbamic acid compounds which inhibit HDAC (histone deacetylase) activity of the following formula:[Insert formula]wherein: Cy is independently a cyclyl group; Q1 is independently a covalent bond or cyclyl leader group; the piperazin-1,4-diyl group is optionally substituted; J1 is independently a covalent bond or -C(=O)- ; J2 is independently -C(=O)- or -S(=O)2- ; Q2 is independently an acid leader group; wherein: Cy is independently: C3-20carbocyclyl, C3-20heterocyclyl, or C5-20aryl; and is optionally substituted; Q1 is independently: a covalent bond; C1-7alkylene; or C1-7alkylene-X-C1-7alkylene, -X-C1-7alkylene, or C1-7alkylene-X-, wherein X is -O- or -S-; and is optionally substituted; Q2 is independently: C4-8alkylene; and is optionally substituted; and has a backbone length of at least 4 atoms; or: Q2 is independently: C5-20arylene; C5-20arylene-C1-7alkylene; C1-7alkylene-C5-20arylene; or, C1-7alkylene-C5-20arylene-C1-7alkylene; and is optionally substituted; and has a backbone length of at least 4 atoms; or a pharmaceutically acceptable salt, solvate, amide, ester, ether, chemically protected form, or prodrug thereof. The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit HDAC, and in the treatment of conditions mediated by HDAC, cancer, proliferative conditions, psoriasis, etc.

  本发明涉及一些碳酰胺化合物，其抑制以下式的HDAC（组蛋白去乙酰化酶）活性：[插入式]其中：Cy独立地是环烷基团；Q1独立地是共价键或环烷基团；哌嗪-1,4-二基基团可选地被取代；J1独立地是共价键或-C（=O）-；J2独立地是-C（=O）-或-S（=O）2-；Q2独立地是酸基团；其中：Cy独立地是C3-20碳环烷基、C3-20杂环烷基或C5-20芳基；并可选地被取代；Q1独立地是：共价键；C1-7烷基；或C1-7烷基-X-C1-7烷基、-X-C1-7烷基或C1-7烷基-X-，其中X是-O-或-S-；并可选地被取代；Q2独立地是：C4-8烷基；并可选地被取代；并且具有至少4个原子的骨架长度；或：Q2独立地是：C5-20芳基；C5-20芳基-C1-7烷基；C1-7烷基-C5-20芳基；或C1-7烷基-C5-20芳基-C1-7烷基；并可选地被取代；并且具有至少4个原子的骨架长度；或其药学上可接受的盐、溶剂化合物、酰胺、酯、醚、化学保护形式或前药。本发明还涉及包含这种化合物的制药组合物，以及这种化合物和组合物的使用，无论是体外还是体内，用于抑制HDAC，并用于治疗由HDAC介导的疾病，如癌症、增殖性疾病、牛皮癣等。