(20S)-2-methylene-22-(imidazol-1-yl)-19,23,24,25,26,27-esanor-1α-hydroxyvitamin D3 | 1258066-59-9

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 类固醇和类固醇衍生物
• 英文名称: (20S)-2-methylene-22-(imidazol-1-yl)-19,23,24,25,26,27-esanor-1α-hydroxyvitamin D3
• 英文别名: VIMI；(1R,3R)-5-[(2E)-2-[(1R,3aS,7aR)-1-[(2S)-1-imidazol-1-ylpropan-2-yl]-7a-methyl-2,3,3a,5,6,7-hexahydro-1H-inden-4-ylidene]ethylidene]-2-methylidenecyclohexane-1,3-diol
• CAS: 1258066-59-9
• 化学式: C₂₅H₃₆N₂O₂
• 分子量: 396.573
• InChiKey: FHDAHQFLZOYWQM-QDYAWOJKSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  29
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.64
• 拓扑面积：
  58.3
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为产物：
  描述：

  (S)-2-((3R,3aR,7S,7aR)-octahydro-7-hydroxy-3a-methyl-1H-inden-3-yl)propyl 4-methylbenzenesulfonate 在 N-甲基吗啉 、 四丙基高钌酸铵 、 氢氟酸 、 sodium hydride 、 苯基锂 作用下， 以 四氢呋喃 、 二氯甲烷 、 二丁醚 、 水 、 N,N-二甲基甲酰胺 、 乙腈 、 mineral oil 为溶剂， 反应 54.33h， 生成 (20S)-2-methylene-22-(imidazol-1-yl)-19,23,24,25,26,27-esanor-1α-hydroxyvitamin D3
  参考文献：
  名称：

  Synthesis and biological activities of vitamin D-like inhibitors of CYP24 hydroxylase

  摘要：

  Selective inhibitors of CYP24A1 represent an important synthetic target in a search for novel vitamin D compounds of therapeutic value. In the present work, we show the synthesis and biological properties of two novel side chain modified 2-methylene-19-nor-1,25(OH)(2)D-3 analogs, the 22-imidazole-1-yl derivative 2 (VIMI) and the 25-N-cyclopropylamine compound 3 (CPA1), which were efficiently prepared in convergent syntheses utilizing the Lythgoe type Horner-Wittig olefination reaction. When tested in a cell-free assay, both compounds were found to be potent competitive inhibitors of CYP24A1, with the cyclopropylamine analog 3 exhibiting an 80-1 selective inhibition of CYP24A1 over CYP27B1. Addition of 3 to a mouse osteoblast culture sustained the level of 1,25(OH)(2)D-3, further demonstrating its effectiveness in CYP24A1 inhibition. Importantly, the in vitro effects on human promyeloid leukemia (HL-60) cell differentiation by 3 were nearly identical to those of 1,25(OH)(2)D-3 and in vivo the compound showed low calcemic activity. Finally, the results of preliminary theoretical studies provide useful insights to rationalize the ability of analog 3 to selectively inhibit the cytochrome P450 isoform CYP24A1. (C) 2011 Elsevier Inc. All rights reserved.

  DOI：

  10.1016/j.steroids.2011.11.007

文献信息

• Synthesis and biological activities of vitamin D-like inhibitors of CYP24 hydroxylase
  作者：Grazia Chiellini、Simona Rapposelli、Jinge Zhu、Ilaria Massarelli、Marilena Saraceno、Anna Maria Bianucci、Lori A. Plum、Margaret Clagett-Dame、Hector F. DeLuca

  DOI：10.1016/j.steroids.2011.11.007

  日期：2012.2

  Selective inhibitors of CYP24A1 represent an important synthetic target in a search for novel vitamin D compounds of therapeutic value. In the present work, we show the synthesis and biological properties of two novel side chain modified 2-methylene-19-nor-1,25(OH)(2)D-3 analogs, the 22-imidazole-1-yl derivative 2 (VIMI) and the 25-N-cyclopropylamine compound 3 (CPA1), which were efficiently prepared in convergent syntheses utilizing the Lythgoe type Horner-Wittig olefination reaction. When tested in a cell-free assay, both compounds were found to be potent competitive inhibitors of CYP24A1, with the cyclopropylamine analog 3 exhibiting an 80-1 selective inhibition of CYP24A1 over CYP27B1. Addition of 3 to a mouse osteoblast culture sustained the level of 1,25(OH)(2)D-3, further demonstrating its effectiveness in CYP24A1 inhibition. Importantly, the in vitro effects on human promyeloid leukemia (HL-60) cell differentiation by 3 were nearly identical to those of 1,25(OH)(2)D-3 and in vivo the compound showed low calcemic activity. Finally, the results of preliminary theoretical studies provide useful insights to rationalize the ability of analog 3 to selectively inhibit the cytochrome P450 isoform CYP24A1. (C) 2011 Elsevier Inc. All rights reserved.