(3α,5α)-3-{[(2ξ,5ξ)-2,5-dimethyl-4-{[2-(trifluoromethyl)phenyl]sulfonyl}piperazin-1-yl]methyl}-3-hydroxyandrostan-17-one

• 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: (3α,5α)-3-{[(2ξ,5ξ)-2,5-dimethyl-4-{[2-(trifluoromethyl)phenyl]sulfonyl}piperazin-1-yl]methyl}-3-hydroxyandrostan-17-one
• 英文别名: (3R,5S,8R,9S,10S,13S,14S)-3-[[2,5-dimethyl-4-[2-(trifluoromethyl)phenyl]sulfonylpiperazin-1-yl]methyl]-3-hydroxy-10,13-dimethyl-2,4,5,6,7,8,9,11,12,14,15,16-dodecahydro-1H-cyclopenta[a]phenanthren-17-one
• 化学式: C₃₃H₄₇F₃N₂O₄S
• 分子量: 624.808
• InChiKey: IYHGEKFCMCXIEF-UUVSWYNWSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.1
• 重原子数：
  43
• 可旋转键数：
  4
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.79
• 拓扑面积：
  86.3
• 氢给体数：
  1
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  (3α,5α)-3-{[(2ξ,5ξ)-2,5-dimethyl-4-{[2-(trifluoromethyl)phenyl]sulfonyl}piperazin-1-yl]methyl}-3-hydroxyandrostan-17-one 在 硫酸 、 Selectfluor 作用下， 以 甲醇 、 水 为溶剂， 反应 72.0h， 以14%的产率得到(3α,16α)-3-[(trans-2,5-dimethyl-4-{[2-(trifluoromethyl)phenyl]sulfonyl}piperazin-1-yl)methyl]-16-fluoro-3-hydroxyandrostan-17-one
  参考文献：
  名称：

  雄甾酮衍生物抑制17β-羟基类固醇脱氢酶类型3的A和D环结构修饰：化学合成与结构-活性关系。

  摘要：

  通过使用3β17β-羟基类固醇脱氢酶（17β-HSD3）抑制剂来减少肿瘤内雄激素的生物合成是治疗前列腺癌的策略。雄甾酮（ADT）衍生物1（RM-532-105）对17β-HSD3具有强抑制活性，但有待改进。在这里，我们描述了两个系列类似物的化学合成和表征，以解决A和D环修饰对17β-HSD3抑制活性，雄激素作用和代谢稳定性的影响。通过在C16 / C17上添加不同的基团（D环多样化）或用正雄烷或雌激素骨架取代ADT骨架（A环多样化）来生成结构活性关系。与铅化合物1相比，D环衍生物的抑制剂作用更弱 而甾体骨架（A环）的变化导致鉴定出有前途的新型雌激素衍生物。最后用有效的17β-HSD3抑制剂23、27、31和33（IC50分别为0.10、0.02、0.13和0.17μM）达到终点，该抑制剂不刺激LAPC-4细胞增殖，并且在小鼠中的血浆浓度高于铅。化合物1。

  DOI：

  10.1021/acs.jmedchem.9b00624
• 作为产物：
  描述：

  2,5-dimethyl-piperazine 在 三乙胺 作用下， 以 乙醇 、 二氯甲烷 为溶剂， 反应 8.0h， 生成 (3α,5α)-3-{[(2ξ,5ξ)-2,5-dimethyl-4-{[2-(trifluoromethyl)phenyl]sulfonyl}piperazin-1-yl]methyl}-3-hydroxyandrostan-17-one
  参考文献：
  名称：

  Development of 3-substituted-androsterone derivatives as potent inhibitors of 17β-hydroxysteroid dehydrogenase type 3

  摘要：

  17Beta-hydroxysteroid dehydrogenase type 3 (17 beta-HSD3) is a steroidogenic enzyme that catalyzes the transformation of 4-androstene-3,17-dione (Delta(4)-dione) into androgen testosterone (T). To provide effective inhibitors of androgen biosynthesis, we synthesized two different series (amines and carbamates) of 3 beta-substituted-androsterone derivatives and we tested their inhibitory activity on 17 beta-HSD3. From the results of our structure-activity relationship study, we identified a series of compounds producing a strong inhibition of 17 beta-HSD3 overexpressed in HEK-293 cells (homogenized cells). The most active compound when tested in intact HEK-293 transfected cells, namely (3 alpha,5 alpha)-3-{[trans-2,5-dimethyl-4-{[2-(trifluoromethyl)phenyl] sulfonyl}piperazin-1-yl]methyl}-3-hydroxyandrostan-17-one (15b), shows an IC50 value of 6 nM, this compound is thus eight times more active than our reference compound D-5-2 (IC50 = 51 nM). This new improved inhibitor did not stimulate the proliferation of androgen-sensitive Shionogi cells, suggesting a non-androgenic profile. Compound 15b is thus a good candidate for further in vivo studies on rodents. (C) 2011 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2011.06.003

文献信息

• [EN] INHIBITORS OF 17ß-HSD1, 17ß-HSD3 AND 17ß-HSD10<br/>[FR] INHIBITEURS DE 17SS-HSD1, 17SS-HSD3 ET 17SS-HSD10
  申请人：UNIV LAVAL

  公开号：WO2012129673A1

  公开（公告）日：2012-10-04

  The present application discloses 17β hydroxy steroid dehydrogenase (17β HSD) type 1, 3, 10 inhibitors and use thereof (alone and in combination) in the treatment of cancer and other afflictions. 17β HSDl inhibitors include estradiol derivatives with a nieta-carbamoylbenzyl substituent at C 16. 17β HSD3/HSD10 inhibitors include androsterone derivatives substituted at the C3 position with a sulfonamide piperazine. Also disclosed are compounds that are inhibitors of both 17β HSDl and 17β HSD3 that have a spiro-morpholine substituent at C20.

  该申请公开了17β羟基类固醇脱氢酶（17β HSD）类型1、3、10的抑制剂及其在癌症和其他疾病治疗中的使用（单独和组合使用）。17β HSD1抑制剂包括在C16处带有尼达-氨甲酰苯甲基取代基的雌二醇衍生物。17β HSD3/HSD10抑制剂包括在C3位置用磺胺基哌嗪取代的雄甾酮衍生物。还公开了既是17β HSD1又是17β HSD3抑制剂的化合物，其在C20处带有螺环吗啡基取代基。
• 16-Picolyl-androsterone derivative exhibits potent 17β-HSD3 inhibitory activity, improved metabolic stability and cytotoxic effect on various cancer cells: Synthesis, homology modeling and docking studies
  作者：Francisco Cortés-Benítez、Jenny Roy、Martin Perreault、René Maltais、Donald Poirier

  DOI：10.1016/j.jsbmb.2021.105846

  日期：2021.6

  (RM-532-105). We measured its inhibitory activity on 17β-HSD3 using microsomal fraction of rat testes as well as transfected LNCaP[17β-HSD3] cells. We then assessed its metabolic stability as well as its cytotoxic effect against a panel of cancer cell lines. The addition of a picolyl moiety at C-16 of RM-532-105 steroid core improves the 17β-HSD3 inhibitory activity in the microsomal fraction of rat testes

  由先导化合物1 (RM-532-105) 分四步合成带有 16β-吡啶甲基的新雄酮衍生物（化合物5 ；FCO-586-119）。我们使用大鼠睾丸微粒体部分以及转染的 LNCaP[17β-HSD3] 细胞测量了其对 17β-HSD3 的抑制活性。然后我们评估了它的代谢稳定性以及它对一组癌细胞系的细胞毒性作用。在 RM-532-105 类固醇核心的 C-16 处添加吡啶甲基部分可提高大鼠睾丸微粒体部分中的 17β-HSD3 抑制活性，但不能提高整个 LNCaP[17β-HSD3] 细胞的抑制活性。有趣的是，这种结构修饰将代谢稳定性提高了 3 倍，同时对胰腺癌细胞、卵巢癌细胞、乳腺癌细胞、肺癌细胞和前列腺癌细胞具有显着的细胞毒作用。由于针对 17β-HSD3 的抑制活性数据表明两种类固醇衍生物都是非竞争性抑制剂，因此我们使用这种膜相关酶的同源模型进行了对接和分子动力学模拟。这些模拟的结果表明，RM-532-105
• INHIBITORS OF 17Beta-HSD1, 17Beta-HSD3 AND 17Beta-HSD10
  申请人：Poirier Donald

  公开号：US20140088053A1

  公开（公告）日：2014-03-27

  The present application discloses 17β hydroxy steroid dehydrogenase (17β HSD) type 1, 3, 10 inhibitors and use thereof (alone and in combination) in the treatment of cancer and other afflictions. 17β HSD1 inhibitors include estradiol derivatives with a nieta-carbamoylbenzyl substituent at C 16. 17β HSD3/HSD10 inhibitors include androsterone derivatives substituted at the C3 position with a sulfonamide piperazine. Also disclosed are compounds that are inhibitors of both 17β HSD1 and 17β HSD3 that have a spiro-morpholine substituent at C20.

  本申请公开了17β羟基类固醇脱氢酶(17β HSD)类型1、3、10的抑制剂及其使用(单独或联合)治疗癌症和其他疾病的方法。17β HSD1抑制剂包括在C16处具有一个尼龙-氨基甲酰苯基取代基的雌二醇衍生物。17β HSD3/HSD10抑制剂包括在C3位被磺酰胺哌嗪取代的雄甾酮衍生物。还公开了既抑制17β HSD1又抑制17β HSD3的化合物，其在C20处具有一个螺环吡啶取代基。
• Inhibitors of 17β-HSD1, 17β-HSD3 and 17β-HSD10
  申请人：Poirier Donald

  公开号：US11072632B2

  公开（公告）日：2021-07-27

  The present application discloses 17β hydroxy steroid dehydrogenase (17β HSD) type 1, 3, 10 inhibitors and use thereof (alone and in combination) in the treatment of cancer and other afflictions. 17β HSD1 inhibitors include estradiol derivatives with a nieta-carbamoylbenzyl substituent at C 16. 17β HSD3/HSD10 inhibitors include androsterone derivatives substituted at the C3 position with a sulfonamide piperazine. Also disclosed are compounds that are inhibitors of both 17β HSD1 and 17β HSD3 that have a spiro-morpholine substituent at C20.

  本申请公开了17β羟基类固醇脱氢酶（17β HSD）1、3、10型抑制剂及其在治疗癌症和其他疾病中的用途（单独或联合使用）。17β HSD1 抑制剂包括雌二醇衍生物，其 C 16 位具有尼他-氨基甲酰基苄基取代基。17β HSD3/HSD10 抑制剂包括在 C3 位被磺酰胺哌嗪取代的雄甾酮衍生物。还公开了同时作为 17β HSD1 和 17β HSD3 抑制剂的化合物，这些化合物在 C20 位具有螺吗啉取代基。