(6S,8R,9S,10R,13S,14S)-6-乙基-10,13-二甲基-2,6,7,8,9,11,12,14,15,16-十氢-1H-环戊二烯并[a]菲-3,17-二酮 | 156264-67-4

• 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
• 中文名称: (6S,8R,9S,10R,13S,14S)-6-乙基-10,13-二甲基-2,6,7,8,9,11,12,14,15,16-十氢-1H-环戊二烯并[a]菲-3,17-二酮
• 英文名称: 6α-ethylandrost-4-ene-3,17-dione
• 英文别名: 6-Ethylandrost-4-ene-3,17-dione；(6S,8R,9S,10R,13S,14S)-6-ethyl-10,13-dimethyl-2,6,7,8,9,11,12,14,15,16-decahydro-1H-cyclopenta[a]phenanthrene-3,17-dione
• CAS: 156264-67-4
• 化学式: C₂₁H₃₀O₂
• 分子量: 314.468
• InChiKey: FCLHZVTXXAVKHH-QAXSQSOOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  23
• 可旋转键数：
  1
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.81
• 拓扑面积：
  34.1
• 氢给体数：
  0
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  (6S,8R,9S,10R,13S,14S)-6-乙基-10,13-二甲基-2,6,7,8,9,11,12,14,15,16-十氢-1H-环戊二烯并[a]菲-3,17-二酮 在 2,3-二氯-5,6-二氰基-1,4-苯醌 作用下， 以 苯 为溶剂， 反应 18.0h， 以50%的产率得到(6S,8R,9S,10R,13S,14S)-6-Ethyl-10,13-dimethyl-7,8,9,10,11,12,13,14,15,16-decahydro-6H-cyclopenta[a]phenanthrene-3,17-dione
  参考文献：
  名称：

  时间依赖性灭活的6-烷基androsta-1,4-diene-3,17-diones芳香化酶。长度和6-烷基构型的影响。

  摘要：

  合成了一系列6α-和6β-烷基雄甾烯-1,4-二烯-3,17-二酮（3和4），并作为人类胎盘微粒体中芳香化酶的时间依赖性灭活剂进行了评估，以了解其结构活性关系。将6-正烷基取代基（C-1--C-7）改变为随时间变化的灭活活性。合成的所有抑制剂均是芳香酶的良好竞争抑制剂，其表观Ki范围为4.7至54 nM。6beta-乙基（4b）和6beta-n-戊基（4e）化合物是其中最有效的化合物（4b和4e的Ki分别为4.7和5.0 nM）。在一系列的6-α-烷基甾族化合物中，在6-位具有C-1--C-4的抑制剂3a-d以及6个α-正庚基（3g）化合物没有。相反，在6β-烷基甾族化合物系列中，只有甲基类似物4a会以时间依赖性方式使芳香化酶失活，而在C-6beta处具有两个以上碳原子的其他烷基类固醇则没有。底物雄烯二酮可防止失活，并且在每种情况下均未观察到L-半胱氨酸对失活的显着影响。这些结果以及使用P

  DOI：

  10.1021/jm950720u
• 作为产物：
  描述：

  3,3:17,17-bis(ethylendioxy)-5α,6α-epoxyandrostane 在 吡啶 、 盐酸 、 氯化亚砜 、 高氯酸 作用下， 以 四氢呋喃 、 乙醇 为溶剂， 反应 9.05h， 生成 (6S,8R,9S,10R,13S,14S)-6-乙基-10,13-二甲基-2,6,7,8,9,11,12,14,15,16-十氢-1H-环戊二烯并[a]菲-3,17-二酮
  参考文献：
  名称：

  6-Alkyl- and 6-Arylandrost-4-ene-3,17-diones as Aromatase Inhibitors. Synthesis and Structure-Activity Relationships

  摘要：

  Two series of 6 beta- and 6 alpha-substituted androst-4-ene-3,17-diones (5 and 6) were synthesized as aromatase inhibitors to gain insights of structure-activity relationships of varying substituents (methyl, ethyl, n-propyl, isopropyl, n-butyl, phenyl, benzyl, vinyl, and ethynyl) to the inhibitory activity. All of the inhibitors synthesized prevented human placental aromatase in a competitive manner. The inhibition activities of all the 6-n-alkylated steroids 5a-d and 6a-d (K-i = 1.4-12 nM) as well as the 6 beta-vinyl (5h), 6 alpha-benzyl (6g), and 6-methylene (10) compounds (K-i = 5.1, 10, and 4.9 nM, respectively) were very powerful whereas those of the g-isopropyl (5e and 6e), 6-phenyl (5f and 6f), 6 beta-benzyl (5g), and 6 beta-ethynyl (5i) steroids, having a bulky or polar substituent, were relatively weak. The 6 beta-ethyl derivative 5b was the most potent inhibitor among those synthesized. Inhibitors 5a, 5f, 5h, 5i, 6b, and 10 did not cause a time-dependent inactivation of aromatase. The 6 beta-alkyl steroids essentially had higher affinity for the enzyme than the corresponding 6 alpha-isomers, whereas the opposite relation was observed in a series of the aryl steroids. These results along with molecular modeling with the PM3 method clearly indicate that aromatase has a hydrophobic binding pocket with a limited accessible volume in the active site in the region corresponding to the beta-side rather than the alpha-side of the C-6 position of the substrate.

  DOI：

  10.1021/jm00035a011

文献信息

• 6-Alkylandrosta-4,6-diene-3,17-diones and their 1,4,6-triene analogs as aromatase inhibitors
  作者：Mitsuteru Numazawa、Mariko Oshibe、Satoshi Yamaguchi

  DOI：10.1016/s0039-128x(97)86814-6

  日期：1997.8

  Two series of 6-alkylandrosta-4,6-diene-3,17-diones (5) and their 1,4,6-triene analogs 6 were synthesized as aromatase inhibitors to gain insight into the structure-activity relationship between varying the 6-n-alkyl substituents (C-1-C-7) and inhibitory activity. All of the steroids synthesized were extremely powerful competitive inhibitors of aromatase in human placental microsomes, with apparent K-i values for the 6-alkyl-4,6-diene steroids 5 ranging from 17 to 36 nM and with those for the 1,4,6-triene steroids 6 ranging from 2.5 to 58 nM. The 6-ethyl-1,4,6-triene compound 6b (K-i = 2.5 nM) was the most potent inhibitor among them. The 6-alkyl-1,4,6-triene steroids 6, except for the 6-methyl analog 6a, had higher affinity for aromatase than the natural substrate androstenedione (K-m = 24 nM), and their inhibitory activities were more potent than the corresponding 4,6-diene steroids 5. In a series of the 4,6-diene steroids 5, compounds 5c-f with the n-alkyl chain substituents (C-3 to C-6) also had slightly higher affinity than androstenedione for aromatase. All of the 1,4,6-triene steroids 6 inactivated aromatase in a time-dependent manner, with k(inact) values ranging from 0.021 to 0.074 min(-1); in contrast, the 4,6-diene analogs 5 did not. The inactivation was prevented by androstenedione, and no significant effect of L-cysteine on the inactivation was observed in each case. These results indicate that the length of the n-alkyl substituent at C-6 of androsta-1,4,6-triene-3,17-dione (6h), rather than its 4,6-diene analog 5h, plays a critical role in tight binding to the active site of aromatase. No significant correlation was observed between affinity for the enzyme and the inactivation ability of the 6-alkyl-1,4,6-trienes. (C) 1997 by Elsevier Science Inc.
• 6-Alkyl- and 6-Arylandrost-4-ene-3,17-diones as Aromatase Inhibitors. Synthesis and Structure-Activity Relationships
  作者：Mitsuteru Numazawa、Mariko Oshibe

  DOI：10.1021/jm00035a011

  日期：1994.4

  Two series of 6 beta- and 6 alpha-substituted androst-4-ene-3,17-diones (5 and 6) were synthesized as aromatase inhibitors to gain insights of structure-activity relationships of varying substituents (methyl, ethyl, n-propyl, isopropyl, n-butyl, phenyl, benzyl, vinyl, and ethynyl) to the inhibitory activity. All of the inhibitors synthesized prevented human placental aromatase in a competitive manner. The inhibition activities of all the 6-n-alkylated steroids 5a-d and 6a-d (K-i = 1.4-12 nM) as well as the 6 beta-vinyl (5h), 6 alpha-benzyl (6g), and 6-methylene (10) compounds (K-i = 5.1, 10, and 4.9 nM, respectively) were very powerful whereas those of the g-isopropyl (5e and 6e), 6-phenyl (5f and 6f), 6 beta-benzyl (5g), and 6 beta-ethynyl (5i) steroids, having a bulky or polar substituent, were relatively weak. The 6 beta-ethyl derivative 5b was the most potent inhibitor among those synthesized. Inhibitors 5a, 5f, 5h, 5i, 6b, and 10 did not cause a time-dependent inactivation of aromatase. The 6 beta-alkyl steroids essentially had higher affinity for the enzyme than the corresponding 6 alpha-isomers, whereas the opposite relation was observed in a series of the aryl steroids. These results along with molecular modeling with the PM3 method clearly indicate that aromatase has a hydrophobic binding pocket with a limited accessible volume in the active site in the region corresponding to the beta-side rather than the alpha-side of the C-6 position of the substrate.
• Time-Dependent Inactivation of Aromatase by 6-Alkylandrosta-1,4-diene-3,17-diones. Effects of Length and Configuration of the 6-Alkyl Group
  作者：Mitsuteru Numazawa、Mariko Oshibe、Satoshi Yamaguchi、Mii Tachibana

  DOI：10.1021/jm950720u

  日期：1996.1.1

  structure-activity relationship of varying the 6-n-alkyl substituents (C-1--C-7) to the time-dependent inactivation activity. All of the inhibitors synthesized were powerful to good competitive inhibitors of aromatase, with apparent Ki's ranging from 4.7 to 54 nM. The 6beta-ethyl (4b) and 6beta-n-pentyl (4e) compounds were the most potent among them (Ki = 4.7 and 5.0 nM for 4b and 4e, respectively).

  合成了一系列6α-和6β-烷基雄甾烯-1,4-二烯-3,17-二酮（3和4），并作为人类胎盘微粒体中芳香化酶的时间依赖性灭活剂进行了评估，以了解其结构活性关系。将6-正烷基取代基（C-1--C-7）改变为随时间变化的灭活活性。合成的所有抑制剂均是芳香酶的良好竞争抑制剂，其表观Ki范围为4.7至54 nM。6beta-乙基（4b）和6beta-n-戊基（4e）化合物是其中最有效的化合物（4b和4e的Ki分别为4.7和5.0 nM）。在一系列的6-α-烷基甾族化合物中，在6-位具有C-1--C-4的抑制剂3a-d以及6个α-正庚基（3g）化合物没有。相反，在6β-烷基甾族化合物系列中，只有甲基类似物4a会以时间依赖性方式使芳香化酶失活，而在C-6beta处具有两个以上碳原子的其他烷基类固醇则没有。底物雄烯二酮可防止失活，并且在每种情况下均未观察到L-半胱氨酸对失活的显着影响。这些结果以及使用P