(3R)-3-[(7aR)-7a-methyl-4-oxooctahydro-1H-inden-1-yl]butanenitrile | 266343-12-8

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: (3R)-3-[(7aR)-7a-methyl-4-oxooctahydro-1H-inden-1-yl]butanenitrile
• 英文别名: (3R)-3-[(1R,3aR,7aR)-7a-methyl-4-oxo-2,3,3a,5,6,7-hexahydro-1H-inden-1-yl]butanenitrile
• CAS: 266343-12-8
• 化学式: C₁₄H₂₁NO
• 分子量: 219.327
• InChiKey: RYTFTLPXJYNDBC-NRWUCQMLSA-N

物化性质

• 沸点：
  355.5±15.0 °C(Predicted)
• 密度：
  1.025±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  16
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.86
• 拓扑面积：
  40.9
• 氢给体数：
  0
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  (3R)-3-[(7aR)-7a-methyl-4-oxooctahydro-1H-inden-1-yl]butanenitrile 在 disodium hydrogenphosphate 、 正丁基锂 、 sodium amalgam 、 二异丁基氢化铝 作用下， 以 四氢呋喃 、 甲醇 、 正己烷 、 甲苯 为溶剂， 反应 3.17h， 生成
  参考文献：
  名称：

  对侧链和A环修饰的1,25-二羟基维生素D2衍生物的合成，CYP24A1依赖性代谢和对结肠直肠癌细胞的抗增殖潜力

  摘要：

  实验数据表明，低钙的维生素D衍生物（VDDs）在体外和体内均表现出抗癌特性。在寻找维生素D类似物作为潜在抗癌剂的过程中，我们研究了1,25-二羟基麦角钙化醇（1,25D2）衍生物侧链中的手性对其活性的影响。在这项研究中，我们在侧链和A环上合成了修饰的类似物，它们在C-24处的绝对构型彼此不同，即（24S）-和（24R）-1,25-二羟基-19- nor-20a-homo-ergocalciferols（分别为PRI-5105和PRI-5106），并评估了它们的活性。出乎意料的是，尽管引入了双点修饰，但两种类似物还是维生素D-羟化酶的非常好的底物。不管它们的绝对C-24配置如何，PRI-5105和PRI-5106对CYP24A1依赖性代谢失活显示出相对较低的耐药性。此外，两个VDD均显示出对HT-29大肠癌细胞具有相似的抗增殖活性，高于维生素D的主要生物活性代谢物1,25D3。此外，PRI-

  DOI：

  10.3390/ijms21020642
• 作为产物：
  描述：

  De-A,B-8β-hydroxy-23,24-dinorcholane-22-carbonitrile 在 四丙基高钌酸铵 、 N-甲基吗啉氧化物 作用下， 以 二氯甲烷 为溶剂， 反应 2.0h， 以91.5%的产率得到(3R)-3-[(7aR)-7a-methyl-4-oxooctahydro-1H-inden-1-yl]butanenitrile
  参考文献：
  名称：

  2-Methylene 19-nor-25-dehydro-1α-hydroxyvitamin D3 26,23-lactones: Synthesis, biological activities and molecular basis of passive antagonism

  摘要：

  To investigate the molecular mechanism of vitamin D receptor (VDR) antagonists having no structurally bulky group interfering with helix 12 of the ligand-binding domain of the VDR, we have synthesized four diastereomers at C(20) and C(23) of 19-nor-1 alpha-hydroxyvitamin D-3 25-methylene-26,23-lactone bearing a 2MD-type A-ring. All four analogs showed significant VDR affinity. Transactivation was tested by using Cos7 cells and HEK293 cells. In both types of cells, LAC67a showed little transactivation potency and inhibited the activation induced by the natural hormone concentration-dependently, indicating that LAC67a works as an antagonist for the VDR in these cells. LAC67b, LAC82a and LAC82b similarly acted as VDR antagonists in Cos7 cells, but in HEK293 cells they behaved as potent VDR agonists. Docking of four lactones into the VDR-LBD, followed by structural analysis, demonstrated that each lactone lacks the hydrophobic interaction with helix12 necessary for maintaining the active conformation of the VDR, indicating that these lactones are passive-type antagonists. Furthermore, each docking structure explained the characteristic transactivation profiles of the four lactones. On the basis of our present findings, we suggest that the ligand acts as an agonist if there are appropriate coactivators in the cells to bind to the looser VDR-ligand complex, and as an antagonist if there are no such appropriate coactivators. The molecular basis of the passive antagonism is discussed in detail. (c) 2007 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2007.09.017

文献信息

• VITAMIN D3 LACTONE DERIVATIVE
  申请人：Teijin Pharma Limited

  公开号：EP1589009B1

  公开（公告）日：2014-10-08
• Highly antiproliferative, low-calcemic, side-chain ketone analogs of the hormone 1α,25-dihydroxyvitamin D3
  作者：Gary H. Posner、Hyung Jin Kim、Mehmet Kahraman、Heung Bae Jeon、Byung Chul Suh、Hongbin Li、Patrick Dolan、Thomas W. Kensler

  DOI：10.1016/j.bmc.2005.06.031

  日期：2005.10

  A series 2a-4b of seven new side-chain ketone analogs of calcitriol (1) have been prepared. Unexpectedly, several of these 24- and 25-tert-butyl ketones, even though lacking the classical side-chain tertiary hydroxyl group, are considerably more antiproliferative in vitro than the hormone calcitriol (1) even at physiologically relevant low nanomolar concentrations and are less calcemic than calcitriol (1) in vivo. In addition, ketone analog 19-nor-2a is not significantly less calcemic in vivo than 19-methylene analog 2a. (c) 2005 Elsevier Ltd. All rights reserved.
• WO2006/74227
  申请人：——

  公开号：——

  公开（公告）日：——
• US9073885B2
  申请人：——

  公开号：US9073885B2

  公开（公告）日：2015-07-07
• 2-Methylene 19-nor-25-dehydro-1α-hydroxyvitamin D3 26,23-lactones: Synthesis, biological activities and molecular basis of passive antagonism
  作者：Nobuko Yoshimoto、Yuka Inaba、Sachiko Yamada、Makoto Makishima、Masato Shimizu、Keiko Yamamoto

  DOI：10.1016/j.bmc.2007.09.017

  日期：2008.1

  To investigate the molecular mechanism of vitamin D receptor (VDR) antagonists having no structurally bulky group interfering with helix 12 of the ligand-binding domain of the VDR, we have synthesized four diastereomers at C(20) and C(23) of 19-nor-1 alpha-hydroxyvitamin D-3 25-methylene-26,23-lactone bearing a 2MD-type A-ring. All four analogs showed significant VDR affinity. Transactivation was tested by using Cos7 cells and HEK293 cells. In both types of cells, LAC67a showed little transactivation potency and inhibited the activation induced by the natural hormone concentration-dependently, indicating that LAC67a works as an antagonist for the VDR in these cells. LAC67b, LAC82a and LAC82b similarly acted as VDR antagonists in Cos7 cells, but in HEK293 cells they behaved as potent VDR agonists. Docking of four lactones into the VDR-LBD, followed by structural analysis, demonstrated that each lactone lacks the hydrophobic interaction with helix12 necessary for maintaining the active conformation of the VDR, indicating that these lactones are passive-type antagonists. Furthermore, each docking structure explained the characteristic transactivation profiles of the four lactones. On the basis of our present findings, we suggest that the ligand acts as an agonist if there are appropriate coactivators in the cells to bind to the looser VDR-ligand complex, and as an antagonist if there are no such appropriate coactivators. The molecular basis of the passive antagonism is discussed in detail. (c) 2007 Elsevier Ltd. All rights reserved.