4-{(2E,4E,6E,8E)-[3,7-dimethyl-9-(2,6,6-trimethyl-1-cyclohexenyl)nona-2,4,6,8-tetraenoylamino]}-phenyl butanoate

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 异戊烯醇脂质
• 英文名称: 4-{(2E,4E,6E,8E)-[3,7-dimethyl-9-(2,6,6-trimethyl-1-cyclohexenyl)nona-2,4,6,8-tetraenoylamino]}-phenyl butanoate
• 英文别名: [4-[[(2E,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohexen-1-yl)nona-2,4,6,8-tetraenoyl]amino]phenyl] butanoate
• 化学式: C₃₀H₃₉NO₃
• 分子量: 461.645
• InChiKey: RKRGYUVSVWQYCE-DCCFLZCMSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  8.2
• 重原子数：
  34
• 可旋转键数：
  10
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  55.4
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为产物：
  描述：

  维A酸 在 N-甲基吗啉 、 氯化亚砜 、 三乙胺 、 N,N-二甲基甲酰胺 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 3.25h， 生成 4-{(2E,4E,6E,8E)-[3,7-dimethyl-9-(2,6,6-trimethyl-1-cyclohexenyl)nona-2,4,6,8-tetraenoylamino]}-phenyl butanoate
  参考文献：
  名称：

  新型视黄酰胺和视黄酸酯衍生物的合成及其生物活性。

  摘要：

  视黄酸及其酰胺衍生物N-（4-羟苯基）视黄酰胺（4-HPR）已被提议作为化学预防剂和化学治疗剂。然而，它们的低细胞毒性活性和水溶性限制了它们的临床应用。在这项研究中，我们合成了新型类维生素A衍生物，具有改善的针对癌细胞的细胞毒性和增加的吸湿性。在我们的合成之前，先进行选择性的O-酰化和N-酰化，这导致在没有保护的情况下直接从氨基酚衍生物和视黄酸直接在一个罐中生产视黄酸酯和视黄酰胺衍生物。COS-1细胞中的转录分析表明，与全部反式维甲酸（ATRA）相比，维甲酸受体（RAR）的所有三种亚型的N-酰化衍生物（2A-5A）和4-HPR（1A）的配体弱得多，尽管它们对RARbeta和RARgamma表现出一定的选择性。相反，O-酰化的视黄酸酯衍生物（1B-5B）激活了所有三种RAR同种型，而没有与ATRA相似的特异性。使用HCT116结肠癌细胞使用MTT分析确定细胞毒性，N-酰化视黄酰胺衍生物4A和

  DOI：

  10.1248/cpb.52.501

文献信息

• Novel retinoid derivatives and methods for producing said compounds and anti-cancer pharmaceutical composition comprising said compounds
  申请人：——

  公开号：US20030171339A1

  公开（公告）日：2003-09-11

  The present invention relates to a novel retinoid derivative compound represented by the formula I: 1 wherein X, R 1 , R 2 and R 3 are as defined herein or pharmaceutically acceptalbe salts thereof. Also, the present invention relates to processes for producing the compound of the formula I and to an anti-cancer composition comprising the compound of the formula I. The compound of the formula I according to the present invention exerts high anti-cancer effects while not causing undesirable side effects.

  本发明涉及一种由公式I表示的新型维甲酸衍生物化合物，其中X、R1、R2和R3如本文所定义，或其药用可接受盐。此外，本发明涉及制备公式I化合物的方法，以及包括公式I化合物的抗癌组合物。根据本发明的公式I化合物具有高抗癌效果，同时不会引起不良副作用。
• Potent Cytotoxic Effects of Novel Retinamide Derivatives in Ovarian Cancer Cells
  作者：Soo-Jong Um、Hong-Sig Sin、Hye-Sook Han、Youn-Ja Kwon、Eun-Joo Kim、Si-Ho Park、Sun-Young Kim、Tae-Sung Bae、Jong-Sup Park、Young-Soy Rho

  DOI：10.1248/bpb.26.1412

  日期：——

  4-(N-Hydroxyphenyl)retinamide (also known as 4-HPR or fenretinide), a synthetic amide of all-trans retinoic acid (RA), has been implicated as a promising anticancer agent associated with reducing the toxicity related to RA. However, the low plasma levels of 4-HPR in patients limited clinical trials, leading to a search for derivatives with better efficacy. In this study, we synthesized a series of 4-HPR derivatives in good yields by introducing acetate (compound 1), propionate (2), pyruvate (3), butyrate (4), or stearate (5) to the 4-hydroxylphenyl moiety of 4-HPR. In our initial proliferation assays, we identified compound 3 as the most cytotoxic of the series against four ovarian cancer cell lines (OVCAR-3, PA-1, 2774, and SKOV-3). Dose–response curves yielded IC50 values of 3.75—7.75 μM for AtRA, 2.80—5.50 μM for 9-cis RA, 0.65—4.05 μM for 4-HPR, and 0.25—0.75 μM for compound 3, depending on the cell type treated. Nuclear staining with 4′,6-diamidino-2-phenylindole (DAPI) and DNA fragmentation assays clearly indicated that the antiproliferative effect of compound 3 was mediated by apoptosis. In contrast to natural retinoids, both 4-HPR and compound 3 activated two (RARβ and RARγ) of the three retinoic acid receptor (RAR) subtypes tested, but did not activate any of the three retinoid X receptors (RXRs), as determined by transcription assays in OVCAR-3 cells. However, like natural retinoids, 4-HPR and compound 3 actively suppressed c-Jun transcriptional activity. Thus, compound 3 not only showed more potent antiproliferative activity than any other retinoid derivatives tested, but also effectively inhibited the c-Jun activity that has been implicated in tumor promotion and invasion. These results, together with compound 3's selectivity for RAR subtypes, suggest that compound 3 could be an effective anticancer drug for ovarian cancer, with less toxicity than RA.

  4-(N-羟基苯基)视黄酰胺（也称为 4-HPR 或芬维A胺）是一种全反式视黄酸 (RA) 的合成酰胺，被认为是一种有前途的抗癌剂，可减少与 RA 相关的毒性。然而，患者中 4-HPR 血浆水平较低限制了临床试验，因此需要寻找具有更好疗效的衍生物。在本研究中，我们通过在 4-羟基苯基部分引入乙酸盐（化合物 1）、丙酸盐（2）、丙酮酸盐（3）、丁酸盐（4）或硬脂酸盐（5），以良好的产率合成了一系列 4-HPR 衍生物。 4-HPR。在我们最初的增殖测定中，我们确定化合物 3 是该系列中针对四种卵巢癌细胞系（OVCAR-3、PA-1、2774 和 SKOV-3）最具细胞毒性的化合物。剂量反应曲线得出 AtRA 的 IC50 值为 3.75—7.75 μM，9-cis RA 的 IC50 值为 2.80—5.50 μM，0.65—4.05 μM< /small> 对于 4-HPR，0.25—0.75 μM 对于化合物 3，具体取决于所处理的细胞类型。 4',6-二脒基-2-苯基吲哚 (DAPI) 核染色和 DNA 片段化分析清楚地表明化合物 3 的抗增殖作用是由细胞凋亡介导的。与天然类视黄醇相比，4-HPR 和化合物 3 都激活了所测试的三种视黄酸受体 (RAR) 亚型中的两种（RARβ 和 RARγ），但没有激活三种视黄酸 X 受体 (RXR) 中的任何一种，如通过OVCAR-3 细胞中的转录测定。然而，与天然类视黄醇一样，4-HPR 和化合物 3 积极抑制 c-Jun 转录活性。因此，化合物3不仅表现出比任何其他测试的类维生素A衍生物更有效的抗增殖活性，而且还有效抑制与肿瘤促进和侵袭有关的c-Jun活性。这些结果，加上化合物3对RAR亚型的选择性，表明化合物3可能是一种有效的卵巢癌抗癌药物，且毒性低于RA。
• Method to incorporate N-(4-hydroxyphenyl) retinamide in liposomes
  申请人：Board of Regents, The University of Texas System

  公开号：US20020143062A1

  公开（公告）日：2002-10-03

  Disclosed herein are simple and unique methods of methods of preparing liposomal compositions of N-(4-hydroxyphenyl) retinamide (4HPR) and/or other retinoids. Also disclosed are liposomal 4HPR compositions prepared by such methods, and use of such compositions in the treatment of diseases, such as breast cancer. This invention further provides methods for improving the efficacy of N-(4-hydroxyphenyl) retinamide (4HPR) as a chemopreventive agent in the presence of agents that potentiates its ability increase the expression of inducible nitric oxide synthase (iNOS, and NO production in cells.

  本文披露了制备N-(4-羟基苯基)视黄酰胺（4HPR）和/或其他视黄醇脂质体组合物的简单且独特的方法。还披露了通过这些方法制备的脂质体4HPR组合物，并将这种组合物用于治疗疾病，如乳腺癌。本发明还提供了一种方法，通过增强诱导型一氧化氮合酶（iNOS）和细胞内NO产生的能力，提高N-(4-羟基苯基)视黄酰胺（4HPR）作为化学预防剂的功效。
• Retinol binding protein and transthyretin modulators for treating diabetes
  申请人：Sirion Therapeutics, Inc.

  公开号：EP1930046A1

  公开（公告）日：2008-06-11

  Described herein are methods and compositions for treating certain retionol-related diseases and conditions by modulation of transthyretin (TTR) and retinol binding protein (RBP) availability in the subject. For example, the methods and compositions provide for therapeutic agents for the treatment and/or prevention of age-related macular degeneration and/or dystrophies, metabolic disorders, idiopathic intracranial hypertension, hyperostosis, and protein misfolding and aggregation diseases. The compositions disclosed may be used as single agent therapy or in combination with other agents or therapies. In addition, described herein are methods and assays for selecting appropriate agents that can modulate the TTR and RBP availability in a subject.

  本文描述了通过调节受试者体内转甲状腺素（TTR）和视黄醇结合蛋白（RBP）的可用性来治疗某些视黄醇相关疾病和病症的方法和组合物。例如，这些方法和组合物提供了治疗和/或预防老年性黄斑变性和/或营养不良、代谢紊乱、特发性颅内高压、骨质疏松症以及蛋白质错误折叠和聚集疾病的治疗剂。所公开的组合物可用作单剂疗法，也可与其他制剂或疗法联合使用。此外，本文还描述了用于选择可调节受试者体内 TTR 和 RBP 可用性的适当制剂的方法和检测方法。
• Retinol binding protein and transthyretin modulators for treating hypertosis, Alzheimer's disease or idiopathic intracranial hypertension
  申请人：ReVision Therapeutics, Inc.

  公开号：EP2289500A1

  公开（公告）日：2011-03-02

  Described herein are methods and compositions for treating certain retinol-related diseases and conditions by modulation of transthyretin (TTR) and retinol binding protein (RBP) availability in the subject. For example, the methods and compositions provide for therapeutic agents for the treatment and/or prevention of age-related macular degeneration and/or dystrophies, metabolic disorders, idiopathic intracranial hypertension, hyperostosis, and protein misfolding and aggregation diseases. The compositions disclosed may be used as single agent therapy or in combination with other agents or therapies. In addition, described herein are methods and assays for selecting appropriate agents that can modulate the TTR and RBP availability in a subject.

  本文描述了通过调节受试者体内转甲状腺素（TTR）和视黄醇结合蛋白（RBP）的可用性来治疗某些视黄醇相关疾病和病症的方法和组合物。例如，这些方法和组合物提供了治疗和/或预防老年性黄斑变性和/或营养不良、代谢紊乱、特发性颅内高压、骨质疏松症以及蛋白质错误折叠和聚集疾病的治疗剂。所公开的组合物可用作单剂疗法，也可与其他制剂或疗法联合使用。此外，本文还描述了用于选择可调节受试者体内 TTR 和 RBP 可用性的适当制剂的方法和检测方法。