6β-spirooxiranandrosta-1,4-diene-3,17-dione | 152764-31-3

• 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: 6β-spirooxiranandrosta-1,4-diene-3,17-dione
• 英文别名: 6α-spirooxiranandrosta-1,4-diene-3,17-dione；Epoxy Exemestane (6-Beta Isomer)；(6R,8R,9S,10R,13S,14S)-10,13-dimethylspiro[7,8,9,11,12,14,15,16-octahydrocyclopenta[a]phenanthrene-6,2'-oxirane]-3,17-dione
• CAS: 152764-31-3
• 化学式: C₂₀H₂₄O₃
• 分子量: 312.409
• InChiKey: GFNJDRLFFJDJAC-FLVPGIQOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  23
• 可旋转键数：
  0
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.7
• 拓扑面积：
  46.7
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为产物：
  描述：

  依西美坦 在 甲酸 、 双氧水 作用下， 以 二氯甲烷 为溶剂， 反应 96.0h， 以21%的产率得到6β-spirooxiranandrosta-1,4-diene-3,17-dione
  参考文献：
  名称：

  Exemestane metabolites: Synthesis, stereochemical elucidation, biochemical activity and anti-proliferative effects in a hormone-dependent breast cancer cell line

  摘要：

  Exemestane is a third-generation steroidal aromatase inhibitor that has been used in clinic for hormone-dependent breast cancer treatment in post-menopausal women. It is known that exemestane undergoes a complex metabolization, giving rise to some already identified metabolites, the 17 beta-hydroxy-6-methylenandrosta-1,4-dien-3-one (17-beta HE) and the 6-(hydroxymethyl)androsta-1,4,6-triene-3,17-dione (6-HME). In this study, four metabolites of exemestane have been analyzed, three of them were synthesized (6 beta-spirooxiranandrosta-1,4-diene-3,17-dione (2), 1 alpha,2 alpha-epoxy-6-methylenandrost-4-ene-3,17-dione (3) and 17-beta HE (4)) while one was acquired, the 6-HME (6). The stereochemistry of the epoxide group of 2 and 3 has been unequivocally elucidated for the first time on the basis of NOESY experiments. New structure-activity relationships (SAR) have been established through the observation that the substitution of the double bonds by epoxide groups led to less potent derivatives in microsomes. However, the reduction of the C-17 carbonyl group to a hydroxyl group originating 17-beta HE (4) resulted in a significant increase in activity in MCF-7aro cells when compared to exemestane (IC50 0.25 mu M vs 0.90 mu M, respectively). All the studied metabolites reduced MCF-7aro cells viability in a dose and time-dependent manner, and metabolite 3 was the most potent one. Altogether our results showed that not only exemestane but also its main metabolites are potent aromatase inhibitors and reduce breast cancer cells viability. This suggests that exemestane efficacy may also be due to the active metabolites that result from its metabolic transformation. Our results emphasize the importance of performing further studies to expand our understanding of exemestane actions in breast cancer cells. (C) 2014 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2014.09.074

文献信息

• Exemestane metabolites: Synthesis, stereochemical elucidation, biochemical activity and anti-proliferative effects in a hormone-dependent breast cancer cell line
  作者：Carla L. Varela、Cristina Amaral、Elisiário Tavares da Silva、Andreia Lopes、Georgina Correia-da-Silva、Rui A. Carvalho、Saul C.P. Costa、Fernanda M.F. Roleira、Natércia Teixeira

  DOI：10.1016/j.ejmech.2014.09.074

  日期：2014.11

  Exemestane is a third-generation steroidal aromatase inhibitor that has been used in clinic for hormone-dependent breast cancer treatment in post-menopausal women. It is known that exemestane undergoes a complex metabolization, giving rise to some already identified metabolites, the 17 beta-hydroxy-6-methylenandrosta-1,4-dien-3-one (17-beta HE) and the 6-(hydroxymethyl)androsta-1,4,6-triene-3,17-dione (6-HME). In this study, four metabolites of exemestane have been analyzed, three of them were synthesized (6 beta-spirooxiranandrosta-1,4-diene-3,17-dione (2), 1 alpha,2 alpha-epoxy-6-methylenandrost-4-ene-3,17-dione (3) and 17-beta HE (4)) while one was acquired, the 6-HME (6). The stereochemistry of the epoxide group of 2 and 3 has been unequivocally elucidated for the first time on the basis of NOESY experiments. New structure-activity relationships (SAR) have been established through the observation that the substitution of the double bonds by epoxide groups led to less potent derivatives in microsomes. However, the reduction of the C-17 carbonyl group to a hydroxyl group originating 17-beta HE (4) resulted in a significant increase in activity in MCF-7aro cells when compared to exemestane (IC50 0.25 mu M vs 0.90 mu M, respectively). All the studied metabolites reduced MCF-7aro cells viability in a dose and time-dependent manner, and metabolite 3 was the most potent one. Altogether our results showed that not only exemestane but also its main metabolites are potent aromatase inhibitors and reduce breast cancer cells viability. This suggests that exemestane efficacy may also be due to the active metabolites that result from its metabolic transformation. Our results emphasize the importance of performing further studies to expand our understanding of exemestane actions in breast cancer cells. (C) 2014 Elsevier Masson SAS. All rights reserved.