ethyl 8β-[(tert-butyldimethylsilyl)oxy]-(20R,23)-epoxymethano-des-A,B-cholest-23E-en-25-oate | 1109291-91-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 氧唑烯
• 英文名称: ethyl 8β-[(tert-butyldimethylsilyl)oxy]-(20R,23)-epoxymethano-des-A,B-cholest-23E-en-25-oate
• 英文别名: (Z)-ethyl 2-((S)-dihydro-5-((3S,3aS,7S,7aR)-octahydro-7-(tert-butyldimethylsilyloxy)-3a-methyl-1H-inden-3-yl)-5-methylfuran-3(2H)-ylidene)acetate；(E)-ethyl 2-((S)-dihydro-5-((3S,3aS,7S,7aR)-octahydro-7-(tert-butyldimethylsilyloxy)-3a-methyl-1H-inden-3-yl)-5-methylfuran-3(2H)-ylidene)acetate；ethyl (2E)-2-[(5S)-5-[(1S,3aR,4S,7aS)-4-[tert-butyl(dimethyl)silyl]oxy-7a-methyl-1,2,3,3a,4,5,6,7-octahydroinden-1-yl]-5-methyloxolan-3-ylidene]acetate
• CAS: 1109291-91-9
• 化学式: C₂₅H₄₄O₄Si
• 分子量: 436.707
• InChiKey: HKKXZKIJWMXBOJ-YJBWWVIISA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.26
• 重原子数：
  30
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.88
• 拓扑面积：
  44.8
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  ethyl 8β-[(tert-butyldimethylsilyl)oxy]-(20R,23)-epoxymethano-des-A,B-cholest-23E-en-25-oate 在 potassium tert-butylate 、 (±)-2,2 '-二(二-对甲苯基膦)-1,1 '-联萘 、 异丙醇 、 copper(l) chloride 作用下， 以 正己烷 为溶剂， 反应 1.0h， 生成 C₂₅H₄₆O₄Si
  参考文献：
  名称：

  Structure−Function Relationships and Crystal Structures of the Vitamin D Receptor Bound 2α-Methyl-(20S,23S)- and 2α-Methyl-(20S,23R)-epoxymethano-1α,25-dihydroxyvitamin D₃

  摘要：

  The vitamin D nuclear receptor is a ligand-dependent transcription factor that controls multiple biological responses such as cell proliferation, immune responses, and bone mineralization. Numerous 1 alpha,25(OH)(2)D-3 analogues, which exhibit low calcemic side effects and/or antitumoral properties, have been synthesized. We recently showed that the synthetic analogue (20S,23S)-epoxymethano-1 alpha,25-dihydroxyvitamin D-3 (2a) acts as a 1 alpha,25(OH)(2)D-3 superagonist and exhibits both antiproliferative and prodifferentiating properties in vitro. Using this information and on the basis of the crystal structures of human VDR ligand binding domain (hVDR LBD) bound to 1 alpha,25(OH)(2)D-3,2 alpha-methyl-1 alpha,25(OH)(2)D-3, or 2a, we designed a novel analogue, 2 alpha-methyl-(20S,23S)-epoxymethano-1 alpha,25-dihydroxyvitamin D-3 (4a), in order to increase its transactivation potency. Here, we solved the crystal structures of the hVDR LBD in complex with the 4a (C23S) and its epimer 4b (C23R) and determined their correlation with specific biological outcomes.

  DOI：

  10.1021/jm9014636
• 作为产物：
  描述：

  ethyl 8β-[(tert-butyldimethylsilyl)oxy]-(20R,23)-epoxymethano-des-A,B-cholest-23-en-25-oate 在 Phenomenex Luna 5u Silica⁽²⁾ 100A 作用下， 以 正己烷 、 乙酸乙酯 为溶剂， 以46%的产率得到ethyl 8β-[(tert-butyldimethylsilyl)oxy]-(20R,23)-epoxymethano-des-A,B-cholest-23E-en-25-oate
  参考文献：
  名称：

  Structure−Function Relationships and Crystal Structures of the Vitamin D Receptor Bound 2α-Methyl-(20S,23S)- and 2α-Methyl-(20S,23R)-epoxymethano-1α,25-dihydroxyvitamin D₃

  摘要：

  The vitamin D nuclear receptor is a ligand-dependent transcription factor that controls multiple biological responses such as cell proliferation, immune responses, and bone mineralization. Numerous 1 alpha,25(OH)(2)D-3 analogues, which exhibit low calcemic side effects and/or antitumoral properties, have been synthesized. We recently showed that the synthetic analogue (20S,23S)-epoxymethano-1 alpha,25-dihydroxyvitamin D-3 (2a) acts as a 1 alpha,25(OH)(2)D-3 superagonist and exhibits both antiproliferative and prodifferentiating properties in vitro. Using this information and on the basis of the crystal structures of human VDR ligand binding domain (hVDR LBD) bound to 1 alpha,25(OH)(2)D-3,2 alpha-methyl-1 alpha,25(OH)(2)D-3, or 2a, we designed a novel analogue, 2 alpha-methyl-(20S,23S)-epoxymethano-1 alpha,25-dihydroxyvitamin D-3 (4a), in order to increase its transactivation potency. Here, we solved the crystal structures of the hVDR LBD in complex with the 4a (C23S) and its epimer 4b (C23R) and determined their correlation with specific biological outcomes.

  DOI：

  10.1021/jm9014636

文献信息

• Vitamin D derivatives active on the vitamin D nuclear receptor, preparation and uses thereof
  申请人：CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE

  公开号：EP1777220A1

  公开（公告）日：2007-04-25

  The invention relates to vitamin D derivatives and their uses, particularly in the pharmaceutical industry. The invention discloses compounds having different interesting biological properties, including vitamin D nuclear receptor (VDR) agonist activity, as well as therapeutics methods by administering said compounds, in particular for treating cancer, psoriasis, autoimmune diseases, osteodistrophy and osteoporosis. It further relates to pharmaceutical compositions comprising said compounds and methods for preparing the same.

  本发明涉及维生素D衍生物及其用途，特别是在制药业中的应用。本发明揭示了具有不同有趣生物学特性的化合物，包括维生素D核受体（VDR）激动剂活性，以及通过给予这些化合物的治疗方法，特别是用于治疗癌症、银屑病、自身免疫疾病、骨营养不良和骨质疏松症。本发明还涉及包含这些化合物的制药组合物和制备这些组合物的方法。
• Structure−Function Relationships and Crystal Structures of the Vitamin D Receptor Bound 2α-Methyl-(20<i>S</i>,23<i>S</i>)- and 2α-Methyl-(20<i>S</i>,23<i>R</i>)-epoxymethano-1α,25-dihydroxyvitamin D₃
  作者：Pierre Antony、Rita Sigüeiro、Tiphaine Huet、Yoshiteru Sato、Nick Ramalanjaona、Luis Cezar Rodrigues、Antonio Mouriño、Dino Moras、Natacha Rochel

  DOI：10.1021/jm9014636

  日期：2010.2.11

  The vitamin D nuclear receptor is a ligand-dependent transcription factor that controls multiple biological responses such as cell proliferation, immune responses, and bone mineralization. Numerous 1 alpha,25(OH)(2)D-3 analogues, which exhibit low calcemic side effects and/or antitumoral properties, have been synthesized. We recently showed that the synthetic analogue (20S,23S)-epoxymethano-1 alpha,25-dihydroxyvitamin D-3 (2a) acts as a 1 alpha,25(OH)(2)D-3 superagonist and exhibits both antiproliferative and prodifferentiating properties in vitro. Using this information and on the basis of the crystal structures of human VDR ligand binding domain (hVDR LBD) bound to 1 alpha,25(OH)(2)D-3,2 alpha-methyl-1 alpha,25(OH)(2)D-3, or 2a, we designed a novel analogue, 2 alpha-methyl-(20S,23S)-epoxymethano-1 alpha,25-dihydroxyvitamin D-3 (4a), in order to increase its transactivation potency. Here, we solved the crystal structures of the hVDR LBD in complex with the 4a (C23S) and its epimer 4b (C23R) and determined their correlation with specific biological outcomes.