3-hydroxy-1,3,5(10)-estratriene-17β-O,17α-(3'-allylbutanolactone) | 243638-62-2

• 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: 3-hydroxy-1,3,5(10)-estratriene-17β-O,17α-(3'-allylbutanolactone)
• 英文别名: (8R,9S,13S,14S,17R)-3-hydroxy-13-methyl-3'-prop-2-enylspiro[7,8,9,11,12,14,15,16-octahydro-6H-cyclopenta[a]phenanthrene-17,6'-oxane]-2'-one
• CAS: 243638-62-2
• 化学式: C₂₅H₃₂O₃
• 分子量: 380.527
• InChiKey: OKENEFVVCRNONQ-PTCVVWTPSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.9
• 重原子数：
  28
• 可旋转键数：
  2
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.64
• 拓扑面积：
  46.5
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  3-hydroxy-1,3,5(10)-estratriene-17β-O,17α-(3'-allylbutanolactone) 在 palladium on activated charcoal 氢气 作用下， 以 乙酸乙酯 为溶剂， 以95%的产率得到3-hydroxy-1,3,5(10)-estratriene-17β-O,17α-(3'-propylbutanolactone)
  参考文献：
  名称：

  Inhibition of type 2 17β-hydroxysteroid dehydrogenase by estradiol derivatives bearing a lactone on the D-ring: structure–activity relationships

  摘要：

  The peripheral conversion of steroid precursors into biologically active forms can be a major source of steroid synthesis, and these steroids support the growth of hormone-dependent diseases. The 17beta-hydroxysteroid dehydrogenase (17beta-HSD) enzyme family is involved in the biosynthesis of active steroids and its inhibition constitutes an interesting approach for treating estrogen- and androgen-dependent cancers. We previously found that a compound formed by the introduction of a spiro-gamma-lactone at position 17 of estradiol (E,) produces a significant inhibition of type 2 17beta-HSD. To optimize the inhibitory potency of such compounds, we synthesized a series of estradiol derivatives bearing a lactone on the D-ring and tested their ability to inhibit the type 2 17beta-HSD transformation of 4-androstenedione into testosterone. The results of our structure-activity relationship study determined the importance of the 17beta-orientation of the oxygen atom. Indeed, the 17beta-O-isomer of spiro-gamma-lactone-E, is a much more potent inhibitor than the 17alpha-O-analog (respectively 85 and 9% of inhibition at I muM). The carbonyl function is essential since the percentage of inhibition shifts from 85 to 30%, 15, or 3%, when the carbonyl group is transformed into a hydroxyl, a methoxy or a methylene (cycloether) group, respectively. Our results lead us to realize the importance of the spirolactone versus the C17beta-O/C16beta lactone (respectively 32 and 2% of inhibition at 0.1 muM, for the same size of lactone ring). The optimal size for the spirolactone was also established to be six members. All the types of substituents (methyl, dimethyl, allyl, propyl, and methoxycarbonyl) that we added on the spiro-delta-tactone moiety decreased the inhibitory activity, suggesting steric restrictions for the space that can be occupied in proximity of the spiro-delta-lactone functionality. 17-(Spiro-delta-lactone)-E-2, compound 6, was thus the most potent inhibitor of type 2 17beta-HSD with a K-i value of 29 +/- 5 nM. This compound reversibly inhibits type 2 17beta-HSD in a non-competitive manner. (C) 2004 Elsevier Inc. All rights reserved.

  DOI：

  10.1016/j.steroids.2004.03.002
• 作为产物：
  描述：

  雌酚酮 在 palladium on activated charcoal 咪唑 、 六甲基磷酰三胺 、 正丁基锂 、 jones' reagent 、 四丁基氟化铵 、 氢气 、 对甲苯磺酸 、 lithium diisopropyl amide 作用下， 以 四氢呋喃 、 甲醇 、 正己烷 、 乙酸乙酯 、 N,N-二甲基甲酰胺 、 丙酮 为溶剂， 反应 17.0h， 生成 3-hydroxy-1,3,5(10)-estratriene-17β-O,17α-(3'-allylbutanolactone)
  参考文献：
  名称：

  Inhibition of type 2 17β-hydroxysteroid dehydrogenase by estradiol derivatives bearing a lactone on the D-ring: structure–activity relationships

  摘要：

  The peripheral conversion of steroid precursors into biologically active forms can be a major source of steroid synthesis, and these steroids support the growth of hormone-dependent diseases. The 17beta-hydroxysteroid dehydrogenase (17beta-HSD) enzyme family is involved in the biosynthesis of active steroids and its inhibition constitutes an interesting approach for treating estrogen- and androgen-dependent cancers. We previously found that a compound formed by the introduction of a spiro-gamma-lactone at position 17 of estradiol (E,) produces a significant inhibition of type 2 17beta-HSD. To optimize the inhibitory potency of such compounds, we synthesized a series of estradiol derivatives bearing a lactone on the D-ring and tested their ability to inhibit the type 2 17beta-HSD transformation of 4-androstenedione into testosterone. The results of our structure-activity relationship study determined the importance of the 17beta-orientation of the oxygen atom. Indeed, the 17beta-O-isomer of spiro-gamma-lactone-E, is a much more potent inhibitor than the 17alpha-O-analog (respectively 85 and 9% of inhibition at I muM). The carbonyl function is essential since the percentage of inhibition shifts from 85 to 30%, 15, or 3%, when the carbonyl group is transformed into a hydroxyl, a methoxy or a methylene (cycloether) group, respectively. Our results lead us to realize the importance of the spirolactone versus the C17beta-O/C16beta lactone (respectively 32 and 2% of inhibition at 0.1 muM, for the same size of lactone ring). The optimal size for the spirolactone was also established to be six members. All the types of substituents (methyl, dimethyl, allyl, propyl, and methoxycarbonyl) that we added on the spiro-delta-tactone moiety decreased the inhibitory activity, suggesting steric restrictions for the space that can be occupied in proximity of the spiro-delta-lactone functionality. 17-(Spiro-delta-lactone)-E-2, compound 6, was thus the most potent inhibitor of type 2 17beta-HSD with a K-i value of 29 +/- 5 nM. This compound reversibly inhibits type 2 17beta-HSD in a non-competitive manner. (C) 2004 Elsevier Inc. All rights reserved.

  DOI：

  10.1016/j.steroids.2004.03.002

文献信息

• Inhibition of type 2 17β-hydroxysteroid dehydrogenase by estradiol derivatives bearing a lactone on the D-ring: structure–activity relationships
  作者：Patrick Bydal、Serge Auger、Donald Poirier

  DOI：10.1016/j.steroids.2004.03.002

  日期：2004.5

  The peripheral conversion of steroid precursors into biologically active forms can be a major source of steroid synthesis, and these steroids support the growth of hormone-dependent diseases. The 17beta-hydroxysteroid dehydrogenase (17beta-HSD) enzyme family is involved in the biosynthesis of active steroids and its inhibition constitutes an interesting approach for treating estrogen- and androgen-dependent cancers. We previously found that a compound formed by the introduction of a spiro-gamma-lactone at position 17 of estradiol (E,) produces a significant inhibition of type 2 17beta-HSD. To optimize the inhibitory potency of such compounds, we synthesized a series of estradiol derivatives bearing a lactone on the D-ring and tested their ability to inhibit the type 2 17beta-HSD transformation of 4-androstenedione into testosterone. The results of our structure-activity relationship study determined the importance of the 17beta-orientation of the oxygen atom. Indeed, the 17beta-O-isomer of spiro-gamma-lactone-E, is a much more potent inhibitor than the 17alpha-O-analog (respectively 85 and 9% of inhibition at I muM). The carbonyl function is essential since the percentage of inhibition shifts from 85 to 30%, 15, or 3%, when the carbonyl group is transformed into a hydroxyl, a methoxy or a methylene (cycloether) group, respectively. Our results lead us to realize the importance of the spirolactone versus the C17beta-O/C16beta lactone (respectively 32 and 2% of inhibition at 0.1 muM, for the same size of lactone ring). The optimal size for the spirolactone was also established to be six members. All the types of substituents (methyl, dimethyl, allyl, propyl, and methoxycarbonyl) that we added on the spiro-delta-tactone moiety decreased the inhibitory activity, suggesting steric restrictions for the space that can be occupied in proximity of the spiro-delta-lactone functionality. 17-(Spiro-delta-lactone)-E-2, compound 6, was thus the most potent inhibitor of type 2 17beta-HSD with a K-i value of 29 +/- 5 nM. This compound reversibly inhibits type 2 17beta-HSD in a non-competitive manner. (C) 2004 Elsevier Inc. All rights reserved.