[1S-(1α,3aβ,4α,7aα)]-octahydro-1-[5-hydroxy-1-(4-hydroxy-4-methylpentyl)-5-methylhexyl]-7a-methyl-4H-inden-4-one | 215257-77-5

• 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: [1S-(1α,3aβ,4α,7aα)]-octahydro-1-[5-hydroxy-1-(4-hydroxy-4-methylpentyl)-5-methylhexyl]-7a-methyl-4H-inden-4-one
• 英文别名: (1R,3aR,7aR)-1-[5-hydroxy-1-(4-hydroxy-4-methyl-pentyl)-5-methyl-hexyl]-7a-methyl-octahydro-inden-4-one；[1S-[1α,3aβ,4α,7aα]]octahydro-1-[5-hydroxy-1-(4-hydroxy-4-methylpentyl)-5-methylhexyl]-7a-methyl-4H-inden-4-one；(1R,3aR,7aR)-1-(2,10-dihydroxy-2,10-dimethylundecan-6-yl)-7a-methyl-2,3,3a,5,6,7-hexahydro-1H-inden-4-one
• CAS: 215257-77-5
• 化学式: C₂₃H₄₂O₃
• 分子量: 366.585
• InChiKey: TYAVPQHATNKMKT-SELNLUPBSA-N

物化性质

• 沸点：
  483.7±10.0 °C(Predicted)
• 密度：
  1.006±0.06 g/cm3(Temp: 20 °C; Press: 760 Torr)(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.8
• 重原子数：
  26
• 可旋转键数：
  9
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.96
• 拓扑面积：
  57.5
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  [1S-(1α,3aβ,4α,7aα)]-octahydro-1-[5-hydroxy-1-(4-hydroxy-4-methylpentyl)-5-methylhexyl]-7a-methyl-4H-inden-4-one 在 正丁基锂 作用下， 以 四氢呋喃 为溶剂， 生成 (1R,3aS,7aR)-4-[2-[(3S,5R)-3,5-Bis-(tert-butyl-dimethyl-silanyloxy)-2-methylene-cyclohex-(Z)-ylidene]-eth-(E)-ylidene]-7a-methyl-1-[5-methyl-1-(4-methyl-4-trimethylsilanyloxy-pentyl)-5-trimethylsilanyloxy-hexyl]-octahydro-indene
  参考文献：
  名称：

  [3,3]-适马重排介导的手性构件的合成，用于制备双子座及其类似物†

  摘要：

  已经开发了用于制备双子座维生素D 3类似物的新颖的合成方法。我们的程序使用关键的σ重排，可以控制C-20立体化学，提供了一种将新的侧链引入维生素D支架的通用方法，从而可以使用具有潜在有趣生物学特性的新类似物。

  DOI：

  10.1039/c6ra08789b
• 作为产物：
  描述：

  艾地骨化醇起始原料杂质1 在 palladium on activated charcoal 重铬酸吡啶 、 六氟合硅酸 、 potassium tert-butylate 、 氢气 、 二氯乙基铝 作用下， 以 四氢呋喃 、 乙醚 、 二氯甲烷 、 乙酸乙酯 、 乙腈 为溶剂， 反应 53.75h， 生成 [1S-(1α,3aβ,4α,7aα)]-octahydro-1-[5-hydroxy-1-(4-hydroxy-4-methylpentyl)-5-methylhexyl]-7a-methyl-4H-inden-4-one
  参考文献：
  名称：

  Characterization of a Novel Analogue of 1α,25(OH)₂-Vitamin D₃ with Two Side Chains:  Interaction with Its Nuclear Receptor and Cellular Actions

  摘要：

  The hormone 1 alpha,25(OH)(2)-vitamin D-3 (125D) binds to its nuclear receptor (VDR) to stimulate gene transcription activity. Inversion of configuration at C-20 of the side chain to generate 20-epi-1 alpha,25(OH)(2)Da (20E-125D) increases transcription 200-5000-fold over 125D with its 20-normal (20N) side chain. This enhancement has been attributed to the VDR ligand-binding domain (LBD) having different contact sites for 20N and 20E side chains that generate different VDR conformations. We synthesized 1 alpha,25-dihydroxy-21-(3-hydroxy-3-methylbutyl) vitamin D-3 (Gemini) with two six-carbon side chains (both 20N and 20E orientations). Energy minimization calculations indicate the Gemini side chain possesses significantly more energy minima than either 125D or 20E-125D (2346, 207, and 127 minima, respectively). We compared activities of 125D, 20E-125D, and Gemini, respectively,in several assays: binding to wild-type (100%, 147%, and 38%)and C-terminal-truncated mutant VDR; transcriptional activity (of the transfected osteopontin promoter in ROS 17/2.8 cells: ED50 10, 0.005, and 1.0 nM) mediation of conformational changes in VDR assessed by protease clipping major trypsin-resistant fragment of 34, 34, and 28 kDa). For inhibition of cellular clonal growth of human leukemia (HL-60) and breast cancer (MCF7) cell lines, the ED50(125D)/ED50(Gem) was respectively 380 and 316. We conclude that while Gemini readily binds to the VDR and generates unique conformational changes, none of them is able to permit a superior gene transcription activity despite the presence of a 20E side chain.

  DOI：

  10.1021/jm0000160

文献信息

• High specific activity tritium labeling of vitamin D derivative RO275646
  作者：Steve A. de Keczer、Tim S. Lane、Tatyana Voronin、Mohammad R. Masjedizadeh

  DOI：10.1002/jlcr.1014

  日期：2005.12

  The octahydroindenone intermediate was tritium labeled using T2O isotope exchange labeling, and then elaborated to the vitamin D derivative RO275646. Though this method of labeling was expected to give the minor isomer, it was the shortest and most convenient route to the high specific activity metabolically stable labeled sites. A total of 34 mCi (from two separate runs) at 64 Ci/mmol of [3H]-RO275646

  八氢茚酮中间体使用 T2O 同位素交换标记进行氚标记，然后精制为维生素 D 衍生物 RO275646。尽管预计这种标记方法会产生次要异构体，但它是获得高比活性代谢稳定标记位点的最短和最方便的途径。通过该方法制备了总共 34 mCi（来自两次单独的运行），浓度为 64 Ci/mmol 的 [3H]-RO275646。版权所有 © 2005 John Wiley & Sons, Ltd.
• WO2008/43857
  申请人：——

  公开号：——

  公开（公告）日：——
• WO2008/34908
  申请人：——

  公开号：——

  公开（公告）日：——
• Synthesis and testing of 2α-Modified 1α,25-Dihydroxyvitamin D3 analogues with a double side chain: marked cell differentiation activity
  作者：Yoshitomo Suhara、Atsushi Kittaka、Seishi Kishimoto、Martin J. Calverley、Toshie Fujishima、Nozomi Saito、Takayuki Sugiura、Keizo Waku、Hiroaki Takayama

  DOI：10.1016/s0960-894x(02)00722-9

  日期：2002.11

  The 2alpha-methyl-, 2alpha-(3-hydroxypropyl)-, and 2alpha-(3-hydroxypropoxy)-derivatives of the 'double side chain' analogue of 1alpha,25-dihydroxyvitamin D-3 were synthesized using Trost A-ring/CD-ring connective strategy. Regarding the requisite A-ring building blocks, a new, high yield and stereoselective route to the 2alpha-methyl compound starting from D-glucose was developed. All three new analogues showed potent HL-60 cancer cell differentiation activity. (C) 2002 Elsevier Science Ltd. All rights reserved.
• Characterization of a Novel Analogue of 1α,25(OH)₂-Vitamin D₃ with Two Side Chains:  Interaction with Its Nuclear Receptor and Cellular Actions
  作者：Anthony W. Norman、Percy S. Manchand、Milan R. Uskokovic、William H. Okamura、Janet A. Takeuchi、June E. Bishop、Jun-Iichi Hisatake、H. Phillip Koeffler、Sara Peleg

  DOI：10.1021/jm0000160

  日期：2000.7.1

  The hormone 1 alpha,25(OH)(2)-vitamin D-3 (125D) binds to its nuclear receptor (VDR) to stimulate gene transcription activity. Inversion of configuration at C-20 of the side chain to generate 20-epi-1 alpha,25(OH)(2)Da (20E-125D) increases transcription 200-5000-fold over 125D with its 20-normal (20N) side chain. This enhancement has been attributed to the VDR ligand-binding domain (LBD) having different contact sites for 20N and 20E side chains that generate different VDR conformations. We synthesized 1 alpha,25-dihydroxy-21-(3-hydroxy-3-methylbutyl) vitamin D-3 (Gemini) with two six-carbon side chains (both 20N and 20E orientations). Energy minimization calculations indicate the Gemini side chain possesses significantly more energy minima than either 125D or 20E-125D (2346, 207, and 127 minima, respectively). We compared activities of 125D, 20E-125D, and Gemini, respectively,in several assays: binding to wild-type (100%, 147%, and 38%)and C-terminal-truncated mutant VDR; transcriptional activity (of the transfected osteopontin promoter in ROS 17/2.8 cells: ED50 10, 0.005, and 1.0 nM) mediation of conformational changes in VDR assessed by protease clipping major trypsin-resistant fragment of 34, 34, and 28 kDa). For inhibition of cellular clonal growth of human leukemia (HL-60) and breast cancer (MCF7) cell lines, the ED50(125D)/ED50(Gem) was respectively 380 and 316. We conclude that while Gemini readily binds to the VDR and generates unique conformational changes, none of them is able to permit a superior gene transcription activity despite the presence of a 20E side chain.