(2Z,4E,6E,8E)-methyl 9-(3-hydroxy-2,6,6-trimethylcyclohex-1-en-1-yl)-3,7-dimethylnona-2,4,6,8-tetraenoate | 827029-81-2

• 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)-methyl 9-(3-hydroxy-2,6,6-trimethylcyclohex-1-en-1-yl)-3,7-dimethylnona-2,4,6,8-tetraenoate
• 英文别名: methyl (2Z,4E,6E,8E)-9-(3-hydroxy-2,6,6-trimethylcyclohex-1-en-1-yl)-3,7-dimethylnona-2,4,6,8-tetraenoate；4-(+/-)-hydroxy-(13Z)-methylretinoate；methyl (2Z,4E,6E,8E)-9-(3-hydroxy-2,6,6-trimethylcyclohexen-1-yl)-3,7-dimethylnona-2,4,6,8-tetraenoate
• CAS: 827029-81-2
• 化学式: C₂₁H₃₀O₃
• 分子量: 330.467
• InChiKey: RLAYPMFOLMBAIN-ZTXQEUQPSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.8
• 重原子数：
  24
• 可旋转键数：
  6
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.48
• 拓扑面积：
  46.5
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  (2Z,4E,6E,8E)-methyl 9-(3-hydroxy-2,6,6-trimethylcyclohex-1-en-1-yl)-3,7-dimethylnona-2,4,6,8-tetraenoate 在 1-羟基苯并三唑 、 1,2-二氯乙烷 、 N,N-二异丙基乙胺 、 potassium hydroxide 作用下， 以 甲醇 、 水 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 17.0h， 生成 (2Z,4E,6E,8E)-9-(3-(1H-imidazol-1-yl)-2,6,6-trimethylcyclohex-1-en-1-yl)-N-(4-fluorophenyl)-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 、 sodium tetrahydroborate 作用下， 以 甲醇 、 正己烷 、 二氯甲烷 、 苯 为溶剂， 反应 25.25h， 生成 (2Z,4E,6E,8E)-methyl 9-(3-hydroxy-2,6,6-trimethylcyclohex-1-en-1-yl)-3,7-dimethylnona-2,4,6,8-tetraenoate
  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

• 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：US20190002411A1

  公开（公告）日：2019-01-03

  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.
• Novel Retinoic Acid Metabolism Blocking Agents Endowed with Multiple Biological Activities Are Efficient Growth Inhibitors of Human Breast and Prostate Cancer Cells in Vitro and a Human Breast Tumor Xenograft in Nude Mice
  作者：Jyoti B. Patel、Carlic K. Huynh、Venkatesh D. Handratta、Lalji K. Gediya、Angela M. H. Brodie、Olga G. Goloubeva、Omoshile O. Clement、Ivo P. Nanne、Dianne Robert Soprano、Vincent C. O. Njar

  DOI：10.1021/jm0401457

  日期：2004.12.1

  antiproliferative activity in a concentration dependent manner. The novel atypical RAMBAs, in addition to being highly potent inhibitors of ATRA metabolism in microsomal preparations and in intact human cancer cells (MCF-7, T47D, and LNCaP), also exhibit multiple biological activities, including induction of apoptosis and differentiation, retinoic acid receptor binding, and potent antiproliferative activity on a

  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，
• Novel C-4 Heteroaryl 13-<i>cis</i>-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
  作者：Hannah W. Mbatia、Senthilmurugan Ramalingam、Vidya P. Ramamurthy、Marlena S. Martin、Andrew K. Kwegyir-Afful、Vincent C. O. Njar

  DOI：10.1021/jm501792c

  日期：2015.2.26

  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.