(5Z,7E)-(1R,2R,3S,20S)-2-Methyl-9,10-seco-5,7,10(19)-cholestatriene-1,3,25-triol

• 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: (5Z,7E)-(1R,2R,3S,20S)-2-Methyl-9,10-seco-5,7,10(19)-cholestatriene-1,3,25-triol
• 英文别名: 2α-methyl-20-epi-1α,3β,25-trihydroxyvitamin D₃；(5E,7E)-(1R,2R,3S,20S)-2-methyl-9,10-seco-5,7,10(19)-cholestatriene-1,3,25-triol；2beta-methyl-3-epi-20-epi-1beta,25-dihydroxyvitamin D3/2beta-methyl-3-epi-20-epi-1beta,25-dihydroxycholecalciferol；(1S,2R,3R,5Z)-5-[(2E)-2-[(1R,3aS,7aR)-1-[(2S)-6-hydroxy-6-methylheptan-2-yl]-7a-methyl-2,3,3a,5,6,7-hexahydro-1H-inden-4-ylidene]ethylidene]-2-methyl-4-methylidenecyclohexane-1,3-diol
• 化学式: C₂₈H₄₆O₃
• 分子量: 430.671
• InChiKey: PSWKLSOBPNHZSY-WIDHIJGDSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.5
• 重原子数：
  31
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.79
• 拓扑面积：
  60.7
• 氢给体数：
  3
• 氢受体数：
  3

反应信息

• 作为产物：
  描述：

  (20S)-25-hydroxy Grundmann's ketone 在 tris(dibenzylideneacetone)dipalladium (0) 、 camphor-10-sulfonic acid 、 sodium hexamethyldisilazane 、 三乙胺 、 三苯基膦 作用下， 以 四氢呋喃 、 甲醇 、 氯仿 、 甲苯 为溶剂， 生成 (5Z,7E)-(1R,2R,3S,20S)-2-Methyl-9,10-seco-5,7,10(19)-cholestatriene-1,3,25-triol
  参考文献：
  名称：

  Synthesis and biological activity of 2-methyl-20-epi analogues of 1α,25-dihydroxyvitamin D3

  摘要：

  Synthesis and biological evaluation of all eight possible A-ring diastereomers of 2-methyl-20-epi-1,25-dihydroxyvitamin D-3 are described. Among the analogues synthesized, 2 alpha-methyl-20-epi-1 alpha,25-dihydroxyvitamin D-3 exhibited exceptionally high potency. The double modification of 2-methyl substitution and 20-epimerization yielded analogues with unique activity profiles. (C) 1998 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0960-894x(98)00363-1

文献信息

• Synthesis, Biological Evaluation, and Conformational Analysis of A-Ring Diastereomers of 2-Methyl-1,25-dihydroxyvitamin D₃ and Their 20-Epimers:  Unique Activity Profiles Depending on the Stereochemistry of the A-Ring and at C-20
  作者：Katsuhiro Konno、Toshie Fujishima、Shojiro Maki、Zhaopeng Liu、Daishiro Miura、Manabu Chokki、Seiichi Ishizuka、Kentaro Yamaguchi、Yukiko Kan、Masaaki Kurihara、Naoki Miyata、Connie Smith、Hector F. DeLuca、Hiroaki Takayama

  DOI：10.1021/jm000261j

  日期：2000.11.1

  All eight; possible A-ring diastereomers of 2-methyl-1,25-dihydroxyvitamin D-3 (2) and 2-methyl-20-epi-1,25-dihydroxyvitamin D-3 (3) were convergently synthesized. The A-ring enyne synthons 19 were synthesized starting with methyl(S)-(+)- or (R)-(-)-3-hydroxy-2-methylpropionate (8). This was converted to the alcohol 14 as a 1:1 epimeric mixture in several steps. After having been separated by column chromatography, each isomer led to the requisite A-ring enyne synthons 19 again as 1:1 mixtures at C-1. Coupling of the resulting A-ring enynes 20a-h with the CD-ring portions 5a,b in the presence of a Pd catalyst afforded the 2-methyl analogues 2a-h and 3a-h in good yield. In this way, all possible A-ring diastereomers were synthesized. The synthesized analogues were biologically evaluated both in vitro and in vivo. The potency was highly dependent on the stereochemistry of each isomer. In particular, the alpha alpha beta -isomer 2g exhibited 4-fold higher potency than 1 alpha ,25-dihydroxyvitamin D-3 (1) both in bovine thymus VDR binding and in elevation of rat serum calcium concentration and was twice as potent, as the parent compound in HL-60 cell differentiation. Furthermore, its 20-epimer, that is, 20epi-alpha alpha beta 3g, exhibited exceptionally high activities: 12-fold higher in VDR binding affinity, 7-fold higher in calcium mobilization, and 590-fold higher in HL-60 cell differentiation, as compared to 1 alpha ,25-dihydroxyvitamin D3 (1). Accordingly, the double modification of 2-methyl substitution and 20-epimerization resulted in unique activity profiles. Conformational analysis of the A-ring by H-1 NMR and an X-ray crystallographic analysis of the alpha alpha beta -isomer 2g are also described.
• Synthesis and biological activity of 2-methyl-20-epi analogues of 1α,25-dihydroxyvitamin D3
  作者：Toshie Fujishima、Zhaopeng Liu、Daishiro Miura、Manabu Chokki、Seiichi Ishizuka、Katsuhiro Konno、Hiroaki Takayama

  DOI：10.1016/s0960-894x(98)00363-1

  日期：1998.8

  Synthesis and biological evaluation of all eight possible A-ring diastereomers of 2-methyl-20-epi-1,25-dihydroxyvitamin D-3 are described. Among the analogues synthesized, 2 alpha-methyl-20-epi-1 alpha,25-dihydroxyvitamin D-3 exhibited exceptionally high potency. The double modification of 2-methyl substitution and 20-epimerization yielded analogues with unique activity profiles. (C) 1998 Elsevier Science Ltd. All rights reserved.