(2Z,4E,6E,8E)-N-(4-hydroxybenzyl)-9-(3′-methoxy-2,4,4-trimethyl-4,5-dihydro[1,1′-biphenyl]-3-yl)-3,7-dimethylnona-2,4,6,8-tetraenamide

• 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)-N-(4-hydroxybenzyl)-9-(3′-methoxy-2,4,4-trimethyl-4,5-dihydro[1,1′-biphenyl]-3-yl)-3,7-dimethylnona-2,4,6,8-tetraenamide
• 英文别名: (2Z,4E,6E,8E)-N-(4-hydroxybenzyl)-9-(3‘-methoxy-2,4,4-trimethyl-4,5-dihydro-[1,1‘-biphenyl]-3-yl)-3,7-dimethylnona-2,4,6,8-tetraenamide；(2Z,4E,6E,8E)-N-[(4-hydroxyphenyl)methyl]-9-[3-(3-methoxyphenyl)-2,6,6-trimethylcyclohexa-1,3-dien-1-yl]-3,7-dimethylnona-2,4,6,8-tetraenamide
• 化学式: C₃₄H₃₉NO₃
• 分子量: 509.689
• InChiKey: WSGGTDBOYTXDLN-LTNKNITMSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.7
• 重原子数：
  38
• 可旋转键数：
  9
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.26
• 拓扑面积：
  58.6
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为产物：
  描述：

  异维A酸 在 manganese(IV) oxide 、 四(三苯基膦)钯 、 cerium(II) carbonate 、 sodium hexamethyldisilazane 、 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 四氢呋喃 、 1,4-二氧六环 、 甲醇 、 正己烷 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 、 苯 为溶剂， 反应 43.75h， 生成 (2Z,4E,6E,8E)-N-(4-hydroxybenzyl)-9-(3′-methoxy-2,4,4-trimethyl-4,5-dihydro[1,1′-biphenyl]-3-yl)-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

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。
• 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 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.