19-(tert-butyldimethylsilyloxy)androst-4-en-17-one | 129400-02-8

• 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: 19-(tert-butyldimethylsilyloxy)androst-4-en-17-one
• 英文别名: 19-(tert-butyldimethylsiloxy)androst-4-en-17-one；(8R,9S,10S,13S,14S)-10-[[tert-butyl(dimethyl)silyl]oxymethyl]-13-methyl-1,2,3,6,7,8,9,11,12,14,15,16-dodecahydrocyclopenta[a]phenanthren-17-one
• CAS: 129400-02-8
• 化学式: C₂₅H₄₂O₂Si
• 分子量: 402.693
• InChiKey: IQRHIZAIMUGQPU-MNUZBTPPSA-N

物化性质

• 熔点：
  67-68 °C(Solv: methanol (67-56-1))
• 沸点：
  460.2±45.0 °C(Predicted)
• 密度：
  1.01±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  6.91
• 重原子数：
  28
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.88
• 拓扑面积：
  26.3
• 氢给体数：
  0
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  19-(tert-butyldimethylsilyloxy)androst-4-en-17-one 在 盐酸 、 重铬酸吡啶 、 对甲苯磺酸 作用下， 以 四氢呋喃 、 二氯甲烷 、 异丙醇 、 甲苯 为溶剂， 反应 34.0h， 生成 17,17-(ethylenedioxy)androst-4-en-19-al
  参考文献：
  名称：

  Synthesis and biochemical studies of 16- or 19-substituted androst-4-enes as aromatase inhibitors

  摘要：

  Androst-4-en-17-one derivatives [19-acetoxide 4, 16-bromides 14 and 15, 19,19-difluoride 18, and (19R,S)-19-acetylenic alcohol 25] and androst-4-en-17-beta-ol derivatives 3, 5, 10, 12, and 19 were synthesized and tested for their ability to inhibit aromatase in human placental microsomes. All the 17-oxo steroids, except compound 25 and 17,19-diol 3 of this series, were effective competitive inhibitors with apparent K(i)'s ranging from 170 to 455 nM. 19,19-Difluoro steroid 18 and 19-acetylenic alcohol 25, a weak competitive inhibitor (K(i) = 7.75-mu-M), caused a time-dependent, pseudo-first-order inactivation of aromatase activity with k(inact)'s of 0.0213 and 0.1053 min-1 for compounds 18 and 25, respectively. NADPH and oxygen were required for the time-dependent inactivation, and the substrate, androst-4-ene-3,17-dione, prevented it, but a nucleophile, L-cysteine, did not in each case. The results strongly suggest that aromatase would attack the 19-carbon of steroids 18 and 25.

  DOI：

  10.1021/jm00112a028
• 作为产物：
  描述：

  19-(tert-butyldimethylsiloxy)-3,3-(ethylenedithio)androst-4-en-17-one 在 chromium(VI) oxide 、 硫酸 、 氨 、 sodium 作用下， 以 四氢呋喃 、 丙酮 为溶剂， 反应 1.08h， 生成 19-(tert-butyldimethylsilyloxy)androst-4-en-17-one
  参考文献：
  名称：

  Synthesis and biochemical studies of 16- or 19-substituted androst-4-enes as aromatase inhibitors

  摘要：

  Androst-4-en-17-one derivatives [19-acetoxide 4, 16-bromides 14 and 15, 19,19-difluoride 18, and (19R,S)-19-acetylenic alcohol 25] and androst-4-en-17-beta-ol derivatives 3, 5, 10, 12, and 19 were synthesized and tested for their ability to inhibit aromatase in human placental microsomes. All the 17-oxo steroids, except compound 25 and 17,19-diol 3 of this series, were effective competitive inhibitors with apparent K(i)'s ranging from 170 to 455 nM. 19,19-Difluoro steroid 18 and 19-acetylenic alcohol 25, a weak competitive inhibitor (K(i) = 7.75-mu-M), caused a time-dependent, pseudo-first-order inactivation of aromatase activity with k(inact)'s of 0.0213 and 0.1053 min-1 for compounds 18 and 25, respectively. NADPH and oxygen were required for the time-dependent inactivation, and the substrate, androst-4-ene-3,17-dione, prevented it, but a nucleophile, L-cysteine, did not in each case. The results strongly suggest that aromatase would attack the 19-carbon of steroids 18 and 25.

  DOI：

  10.1021/jm00112a028

文献信息

• Role of Hydrophilic Interaction in Binding of Hydroxylated 3-Deoxy C₁₉ Steroids to the Active Site of Aromatase
  作者：Mitsuteru Numazawa、Keiko Yamada、Syoko Nitta、Chika Sasaki、Kanae Kidokoro

  DOI：10.1021/jm010282t

  日期：2001.11.1

  relationship of a novel class of aromatase inhibitors, C(19) steroids having no oxygen function at C-3, we tested aromatase inhibition activity of polar diol compounds 4,19-dihydroxyandrost-5-en-17-ones (25 and 27) and 6,19-dihydroxyandrost-4-en-17-ones (36 and 37). 4alpha,19-Diol 25 was synthesized from tert-butyldimethylsilyoxyandrost-4-ene steroid (9) through its OsO(4) oxidation, giving the 4alpha,5alpha-dihydroxy

  作为我们对一类新型芳香酶抑制剂C（19）类固醇在C-3处无氧功能的构效关系的研究的一部分，我们测试了极性二醇化合物4,19-dihydroxyandrost-5-的芳香酶抑制活性en-17-ones（25和27）和6,19-dihydroxyandrost-4-en-17-ones（36和37）。由叔丁基二甲基甲硅烷氧基雄烷-4-烯类固醇（9）通过其OsO（4）氧化合成4alpha，19-Diol 25，得到4alpha，5alpha-dihydroxy衍生物12作为关键反应。乙酰化5beta，6alpha-dihydroxy-19-acetate 30及其5alpha，6beta-analogue 31，然后用SOCl（2）脱水和碱性羟基化分别得到6alpha，19-二醇36和6beta-异构体37。化合物（25）的C-4处的羟基的立体化学和化合物36和37的C-6处的羟基的立体化学分别基于（1）H
• Improved Synthesis and Molecular Modeling of 4.BETA.,19-Dihydroxyandrost-5-en-17-one, an Excellent Inhibitor of Aromatase.
  作者：Mitsuteru Numazawa、Keiko Yamada、Yoko Watari、Momoko Ando

  DOI：10.1248/cpb.50.703

  日期：——

  4β,19-Dihydroxyandrost-5-en-17-one (6) is an excellent competitive inhibitor of estrogen synthetase (aromatase). Alternate, improved synthesis of this inhibitor was established. Treatment of 19-(tert-butyldimethylsilyloxy)androst-4-en-17-one (8) with m-chloroperbenzoic acid gave a 1.4 : 1 mixture of 4α,5α-epoxide 9 and its 4β,5β-isomer 10. The mixture was reacted with dil. HClO4 in dioxane to produce principally 4β,5α-diol 11 (80%) of which acetylation followed by dehydration with SOCl2 yielded 4β,19-diacetoxy-5-ene compound 14 in good yield. Alkaline hydrolysis of diacetate 14 gave 4β,19-diol 6. The minimum energy conformation of the powerfull aromatase inhibitor 6 was obtained with the PM3 method and compared with that of the structurally related diol steroid, 4-ene-5β,19-diol 3, a weak competitive inhibitor.

  4β,19-二羟基雄甾-5-烯-17-酮（6）是雌激素合成酶（芳香酶）的一种极好的竞争性抑制剂。已建立这种抑制剂的替代改进合成方法。用间氯过氧苯甲酸处理19-(叔丁基二甲基硅氧基)雄甾-4-烯-17-酮（8）得到1.4 : 1的4α,5α-环氧化物9及其4β,5β-异构体10的混合物。将混合物与二氧六环中的稀HClO4反应，主要生成4β,5α-二醇11（80%），对其乙酰化，然后用SOCl2脱水，得到4β,19-二乙酰氧基-5-烯化合物14，收率较高。对二乙酸酯14进行碱性水解，得到4β,19-二醇6。用PM3方法得到强效芳香酶抑制剂6的最小能量构象，并将其与结构相关的二醇类固醇4-烯-5β,19-二醇3（一种弱竞争性抑制剂）的构象进行比较。
• NUMAZAWA, MITSUTERU;MUTSUMI, AYAKO;HOSHI, KUMIKO;OSHIBE, MARIKO;ISHIKAWA,+, J. MED. CHEM., 34,(1991) N, C. 2496-2504
  作者：NUMAZAWA, MITSUTERU、MUTSUMI, AYAKO、HOSHI, KUMIKO、OSHIBE, MARIKO、ISHIKAWA,+

  DOI：——

  日期：——
• Synthesis and biochemical studies of 16- or 19-substituted androst-4-enes as aromatase inhibitors
  作者：Mitsuteru Numazawa、Ayako Mutsumi、Kumiko Hoshi、Mariko Oshibe、Etsushi Ishikawa、Hiroki Kigawa

  DOI：10.1021/jm00112a028

  日期：1991.8

  Androst-4-en-17-one derivatives [19-acetoxide 4, 16-bromides 14 and 15, 19,19-difluoride 18, and (19R,S)-19-acetylenic alcohol 25] and androst-4-en-17-beta-ol derivatives 3, 5, 10, 12, and 19 were synthesized and tested for their ability to inhibit aromatase in human placental microsomes. All the 17-oxo steroids, except compound 25 and 17,19-diol 3 of this series, were effective competitive inhibitors with apparent K(i)'s ranging from 170 to 455 nM. 19,19-Difluoro steroid 18 and 19-acetylenic alcohol 25, a weak competitive inhibitor (K(i) = 7.75-mu-M), caused a time-dependent, pseudo-first-order inactivation of aromatase activity with k(inact)'s of 0.0213 and 0.1053 min-1 for compounds 18 and 25, respectively. NADPH and oxygen were required for the time-dependent inactivation, and the substrate, androst-4-ene-3,17-dione, prevented it, but a nucleophile, L-cysteine, did not in each case. The results strongly suggest that aromatase would attack the 19-carbon of steroids 18 and 25.