(2Z,4E,6E,8E)-9-(3-(1H-imidazol-1-yl)-2,6,6-trimethylcyclohex-1-en-1-yl)-3,7-dimethylnona-2,4,6,8-tetraenoic acid | 586372-50-1

• 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: (2Z,4E,6E,8E)-9-(3-(1H-imidazol-1-yl)-2,6,6-trimethylcyclohex-1-en-1-yl)-3,7-dimethylnona-2,4,6,8-tetraenoic acid
• 英文别名: 4-((+/-)-(1H-imidazol-1-yl)-(13Z)-retinoic acid；(2Z,4E,6E,8E)-9-(3-imidazol-1-yl-2,6,6-trimethylcyclohexen-1-yl)-3,7-dimethylnona-2,4,6,8-tetraenoic acid
• CAS: 586372-50-1
• 化学式: C₂₃H₃₀N₂O₂
• 分子量: 366.503
• InChiKey: MRFBVQCSZMKBFY-ARSQLPCUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5
• 重原子数：
  27
• 可旋转键数：
  6
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.39
• 拓扑面积：
  55.1
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  3-氟苄胺 、 (2Z,4E,6E,8E)-9-(3-(1H-imidazol-1-yl)-2,6,6-trimethylcyclohex-1-en-1-yl)-3,7-dimethylnona-2,4,6,8-tetraenoic acid 在 1-羟基苯并三唑 、 1,2-二氯乙烷 、 N,N-二异丙基乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 12.0h， 以54%的产率得到(2Z,4E,6E,8E)-9-(3-(1H-imidazol-1-yl)-2,6,6-trimethylcyclohex-1-en-1-yl)-N-(3-fluorobenzyl)-3,7-dimethylnona-2,4,6,8-tetraenamide
  参考文献：
  名称：

  Novel C-4 Heteroaryl 13-cis-Retinamide Mnk/AR Degrading Agents Inhibit Cell Proliferation and Migration and Induce Apoptosis in Human Breast and Prostate Cancer Cells and Suppress Growth of MDA-MB-231 Human Breast and CWR22Rv1 Human Prostate Tumor Xenografts in Mice

  摘要：

  The synthesis and in vitro and in vivo antibreast and antiprostate cancers activities of novel C-4 heteroaryl 13-cis-retinamides that modulate Mnk-eIF4E and AR signaling are discussed. Modifications of the C-4 heteroaryl substituents reveal that the 1H-imidazole is essential for high anticancer activity. The most potent compounds against a variety of human breast and prostate cancer (BC/PC) cell lines were compounds 16 (VNHM-1-66), 20 (VNHM-1-81), and 22 (VNHM-1-73). In these cell lines, the compounds induce Mnk1/2 degradation to substantially suppress eIF4E phosphorylation. In PC cells, the compounds induce degradation of both full-length androgen receptor (fAR) and splice variant AR (AR-V7) to inhibit AR transcriptional activity. More importantly, VNHM-1-81 has strong in vivo antibreast and antiprostate cancer activities, while VNHM-1-73 exhibited strong in vivo antibreast cancer activity, with no apparent host toxicity. Clearly, these lead compounds are strong candidates for development for the treatments of human breast and prostate cancers.

  DOI：

  10.1021/jm501792c
• 作为产物：
  描述：

  异维A酸 在 manganese(IV) oxide 、 氢氧化钾 、 sodium tetrahydroborate 作用下， 以 甲醇 、 正己烷 、 二氯甲烷 、 乙腈 、 苯 为溶剂， 反应 27.75h， 生成 (2Z,4E,6E,8E)-9-(3-(1H-imidazol-1-yl)-2,6,6-trimethylcyclohex-1-en-1-yl)-3,7-dimethylnona-2,4,6,8-tetraenoic acid
  参考文献：
  名称：

  具有多种生物活性的新型视黄酸代谢阻断剂是人乳腺癌和前列腺癌细胞在体外的有效生长抑制剂，以及裸鼠中人乳腺癌的异种移植。

  摘要：

  新型视黄酸代谢阻断剂（RAMBAs）已经合成和表征。合成特征包括在全反式视黄酸（ATRA）和13-顺式视黄酸的C-4处引入亲核配体，以及修饰末端羧酸基团。我们的大多数化合物都是仓鼠肝微粒ATRA代谢酶的强效抑制剂。最有效的化合物是甲基（2E，4E，6E，8E）-9-（3-咪唑基-2,6,6-三甲基环己-1-烯基）-3,7-二甲基壬基-2，4,6,8-四烯酸酯（5）的IC（50）值为0.009 nM，比有名的RAMBA利拉唑（Liazal，IC（50）= 6000 nM）强666,667倍。出乎意料的是，化合物5的两种对映异构体的酶抑制活性之间基本没有差异。在MCF-7细胞增殖实验中，RAMBAs也以浓度依赖的方式增强ATRA介导的抗增殖活性。除了在微粒体制剂和完整的人类癌细胞（MCF-7，T47D和LNCaP）中作为ATRA代谢的高效抑制剂外，新型非典型RAMBAs还表现出多种生物学活性，

  DOI：

  10.1021/jm0401457

文献信息

• Novel C-4 substituted retinoids
  申请人：University of Maryland

  公开号：US20030162823A1

  公开（公告）日：2003-08-28

  C-4 substituted retinoic acid analogs, synthesis methods of C-4 substituted retinoic acid analogs and methods of using C-4 substituted retinoic acid analogs to treat various cancers and dermatological diseases and conditions. The C-4 substituted retinoic acid analogs include C-4 all-trans retinoic acid (ATRA) and 13-cis retinoic acid (13-CRA) analogs. The C-4 substituted retinoic acid analogs inhibit all-trans retinoic acid (ATRA) 4-hydroxylase activity, thereby inhibiting the catabolism of ATRA. The C-4 substituted retinoic acid analogs also have ATRA-mimetic activity. The preferred substitutions at C-4 are an azole group, a sulfur, oxygen, or nitrogen containing group, a pyridyl group, an ethinyl group, a cyclopropyl-amine group, an ester group, or a cyano group, or forms, together with the C-4 carbon atom, an oxime, an oxirane or aziridine group.

  C-4 取代维甲酸类似物，C-4 取代维甲酸类似物的合成方法以及使用 C-4 取代维甲酸类似物治疗各种癌症和皮肤疾病和情况的方法。C-4 取代维甲酸类似物包括 C-4 全反式视黄酸（ATRA）和 13-顺式视黄酸（13-CRA）类似物。C-4 取代维甲酸类似物抑制全反式视黄酸（ATRA）4-羟基化酶的活性，从而抑制ATRA的分解代谢。C-4 取代维甲酸类似物也具有类似ATRA的活性。C-4 最受欢迎的取代物是氮杂环，含硫、氧或氮的基团，吡啶基团，乙炔基团，环丙胺基团，酯基团或氰基团，或与 C-4 碳原子一起形成肟，环氧乙烷或氮杂环丙烷基团。
• Novel C-4 Substituted Retinoids
  申请人：Njar Vincent C.O.

  公开号：US20120122908A1

  公开（公告）日：2012-05-17

  C-4 substituted retinoic acid analogs, synthesis methods of C-4 substituted retinoic acid analogs and methods of using C-4 substituted retinoic acid analogs to treat various cancers and dermatological diseases and conditions. The C-4 substituted retinoic acid analogs include C-4 all-trans retinoic acid (ATRA) and 13-cis retinoic acid (13-CRA) analogs. The C-4 substituted retinoic acid analogs inhibit all-trans retinoic acid (ATRA) 4-hydroxylase activity, thereby inhibiting the catabolism of ATRA. The C-4 substituted retinoic acid analogs also have ATRA-mimetic activity. The preferred substitutions at C-4 are an azole group, a sulfur, oxygen, or nitrogen containing group, a pyridyl group, an ethinyl group, a cyclopropyl-amine group, an ester group, or a cyano group, or forms, together with the C-4 carbon atom, an oxime, an oxirane or aziridine group.

  C-4取代维甲酸类似物、C-4取代维甲酸类似物的合成方法以及使用C-4取代维甲酸类似物治疗各种癌症和皮肤病的方法。 C-4取代维甲酸类似物包括C-4全反式维甲酸（ATRA）和13-顺式维甲酸（13-CRA）类似物。 C-4取代维甲酸类似物抑制全反式维甲酸（ATRA）4-羟化酶活性，从而抑制ATRA的分解代谢。 C-4取代维甲酸类似物还具有ATRA类似活性。 在C-4处的首选取代基是氮杂环基团、含硫、氧或氮的基团、吡啶基团、乙炔基团、环丙胺基团、酯基团或氰基团，或与C-4碳原子一起形成肟、环氧乙烷或氮杂环丙烷基团。
• 13-cis-RAMBA retinamides that degrade MNKs for treating cancer
  申请人：UNIVERSITY OF MARYLAND, BALTIMORE

  公开号：US10793525B2

  公开（公告）日：2020-10-06

  The synthesis and in vitro and in vivo anti-breast and anti-prostate cancers activities of novel C-4 heteroaryl 13-cis retinamides that modulate Mnk-eIF4E and AR signaling are discussed. In both breast and prostate cancer cell lines, these compounds induce Mnk1/2 degradation to substantially suppress eIF4E phosphorylation. In prostate cancer cells, the compounds induce degradation of both full-length androgen receptor (fAR) and splice variant AR (AR-V7) to inhibit AR transcriptional activity. The consequences of these multiple activities resulted in inhibition of cell growth and migration and induction of apoptosis. Finally and importantly, the compounds demonstrate strong in vitro and in vivo anti-breast and anti-prostate cancer activities, with no apparent host toxicities.

  本文讨论了能调节 Mnk-eIF4E 和 AR 信号转导的新型 C-4 杂芳基 13-顺式视黄酸的合成、体外和体内抗乳腺癌和抗前列腺癌活性。在乳腺癌和前列腺癌细胞系中，这些化合物都能诱导 Mnk1/2 降解，从而大幅抑制 eIF4E 磷酸化。在前列腺癌细胞中，这些化合物可诱导全长雄激素受体（fAR）和剪接变体 AR（AR-V7）降解，从而抑制 AR 的转录活性。这些多重活性的结果抑制了细胞的生长和迁移，并诱导了细胞凋亡。最后，也是最重要的一点是，这些化合物在体外和体内都表现出很强的抗乳腺癌和抗前列腺癌活性，而且没有明显的宿主毒性。
• [EN] 13-CIS-RAMBA RETINAMIDES THAT DEGRADE MNKS FOR TREATING CANCER<br/>[FR] RÉTINAMIDES 13-CIS-RAMBA QUI DÉGRADENT LES MNK POUR LE TRAITEMENT DU CANCER
  申请人：UNIV MARYLAND

  公开号：WO2016081589A3

  公开（公告）日：2016-10-13
• 13-CIS-RAMBA RETINAMIDES THAT DEGRADE MNKS FOR TREATING CANCER
  申请人：University of Maryland, Baltimore

  公开号：EP3221284A2

  公开（公告）日：2017-09-27