[1R-[1α(2E,4E,7E),3aβ,4α,7aα]]-5-[4-[[(1,1-dimethylethyl)dimethylsilyl]oxy]octahydro-7a-methyl-1H-inden-1-yl]-2,4,7-nonatrienedioic acid diethyl ester | 215257-73-1

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 脂肪酰基
• 英文名称: [1R-[1α(2E,4E,7E),3aβ,4α,7aα]]-5-[4-[[(1,1-dimethylethyl)dimethylsilyl]oxy]octahydro-7a-methyl-1H-inden-1-yl]-2,4,7-nonatrienedioic acid diethyl ester
• 英文别名: [1R-[1α(2E,4E,7E),3aβ,4α,7aα]]-5-[4-[[(1,1-dimethylethyl)dimethylsilyl]oxy] octahydro-7a-methyl-1H-inden-1-yl]-2,4,7-nonatrienedioic acid diethyl ester；diethyl (2E,4Z,7E)-5-[(1R,3aR,4S,7aR)-4-[tert-butyl(dimethyl)silyl]oxy-7a-methyl-1,2,3,3a,4,5,6,7-octahydroinden-1-yl]nona-2,4,7-trienedioate
• CAS: 215257-73-1
• 化学式: C₂₉H₄₈O₅Si
• 分子量: 504.783
• InChiKey: SDWLSNWHWOMBRR-BTNXQUQQSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.15
• 重原子数：
  35
• 可旋转键数：
  13
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.72
• 拓扑面积：
  61.8
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  [1R-[1α(2E,4E,7E),3aβ,4α,7aα]]-5-[4-[[(1,1-dimethylethyl)dimethylsilyl]oxy]octahydro-7a-methyl-1H-inden-1-yl]-2,4,7-nonatrienedioic acid diethyl ester 在 palladium 10% on activated carbon 重铬酸吡啶 、 六氟合硅酸 、 氢气 作用下， 以 四氢呋喃 、 乙醚 、 二氯甲烷 、 水 、 乙酸乙酯 、 乙腈 为溶剂， 反应 18.58h， 生成 [1S-(1α,3aβ,7aα)]-octahydro-7a-methyl-1-[5-methyl-1-[4-methyl-4-[(trimethylsilyl)oxy]pentyl]-5-[(trimethylsilyl)oxy]hexyl]-4H-inden-4-one
  参考文献：
  名称：

  WO2008/34908

  摘要：

  公开号：
• 作为产物：
  描述：

  艾地骨化醇起始原料杂质1 在 potassium tert-butylate 、 二氯乙基铝 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 43.25h， 生成 [1R-[1α(2E,4E,7E),3aβ,4α,7aα]]-5-[4-[[(1,1-dimethylethyl)dimethylsilyl]oxy]octahydro-7a-methyl-1H-inden-1-yl]-2,4,7-nonatrienedioic acid diethyl ester
  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

• 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：——
• 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.