(S)-(-)-3-bromo-2-hydroxy-2-methyl-N-[(4-nitro-3-trifluoromethyl)phenyl]propanamide | 216665-24-6

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: (S)-(-)-3-bromo-2-hydroxy-2-methyl-N-[(4-nitro-3-trifluoromethyl)phenyl]propanamide
• 英文别名: N-[4-nitro-3-(trifluoromethyl)phenyl]-(2S)-3-bromo-2-hydroxy-2-methylpropanamide；S-NTBA；3-Bromo-2-hydroxy-2-methyl-N-(4-nitro-3-trifluoromethyl-phenyl)-propionamide；(2S)-3-bromo-2-hydroxy-2-methyl-N-[4-nitro-3-(trifluoromethyl)phenyl]propanamide
• CAS: 216665-24-6
• 化学式: C₁₁H₁₀BrF₃N₂O₄
• 分子量: 371.111
• InChiKey: QDSWNDMHSBZXKX-SNVBAGLBSA-N

物化性质

• 熔点：
  101.5-102 °C
• 沸点：
  491.7±45.0 °C(Predicted)
• 密度：
  1.753±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  21
• 可旋转键数：
  3
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  95.2
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  (S)-(-)-3-bromo-2-hydroxy-2-methyl-N-[(4-nitro-3-trifluoromethyl)phenyl]propanamide 在 potassium carbonate 作用下， 以 丙酮 为溶剂， 生成 (S)-2-甲基-N-(4-硝基-3-(三氟甲基)苯基)环氧乙烷-2-甲酰胺
  参考文献：
  名称：

  前列腺癌的芳基异硫氰基选择性雄激素受体调节剂（SARM）。

  摘要：

  制备了一系列新的雄激素受体靶向剂（ARTA），并在雄激素依赖性和非依赖性前列腺癌细胞系中进行了测试。这些试剂是具有异硫氰酸根基取代的B环的比卡鲁胺类似物。同样，R-比卡鲁胺的连接基砜被保持或替换为几个可选的连接基，包括醚，胺，N-甲胺，硫醚和亚甲基（在这种情况下，该产品是外消旋混合物）在X位置的官能团。为了扩大这些芳基异硫氰酸根基AR配体的结构活性关系（SAR），还制备并测试了B环卤代芳基异硫氰酸根基配体。芳基异硫氰酸根基AR配体对AR的结合亲和力范围为0.6到54 nM。其中，硫醚和醚键表现出高结合亲和力（0.6和4.6 nM，与雄激素非依赖性前列腺癌细胞系（DU145，PC-3和PPC-1）相比，对LNCaP（一种雄激素依赖性前列腺癌细胞系）分别具有选择性和选择性的细胞生长抑制作用（约3至6倍），并且膀胱细胞系（TSU-Pr1）。但是，配体在正常猴肾细胞系（CV-1）中是无活性的（IC50>

  DOI：

  10.1016/j.bmc.2006.06.019
• 作为产物：
  描述：

  5-氨基-2-硝基三氟甲苯 、 (2S)-3-溴-2-羟基-2-甲基丙酸 在 氯化亚砜 作用下， 以 N,N-二甲基乙酰胺 为溶剂， 反应 8.5h， 以56.9%的产率得到(S)-(-)-3-bromo-2-hydroxy-2-methyl-N-[(4-nitro-3-trifluoromethyl)phenyl]propanamide
  参考文献：
  名称：

  一种合成光学活性α-羟基丙酰胺衍生物的方法

  摘要：

  本发明公开了一种合成光学活性α‑羟基丙酰胺衍生物的方法，属于有机合成领域。通过以脯氨酸为手性助剂，与甲基丙烯酰氯经酰化、溴化、脱手性助剂、与4‑氰基‑3‑三氟甲基苯胺发生亲核取代反应，得3‑溴‑2‑羟基‑2‑甲基‑N‑[(4‑氰基‑3‑三氟甲基)苯基]丙酰胺。再与对氰基苯酚发生亲核取代反应，制得光学活性化合物3‑(4‑氰基苯氧基)‑N‑[4‑氰基‑3‑三氟甲基苯基]‑2‑羟基‑2‑甲基丙酰胺。利用光学活性的3‑溴‑2‑羟基‑2‑甲基丙酸与4‑硝基‑3‑三氟甲基苯胺发生氨解、与对乙酰胺基苯酚发生亲核取代反应，制得光学活性化合物3‑(4‑乙酰氧基苯氧基)‑N‑[4‑硝基‑3‑三氟甲基苯基]‑2‑羟基‑2‑甲基丙酰胺。本发明是一种高效合成光学活性α‑羟基丙酰胺衍生物的方法。

  公开号：

  CN109761778A

文献信息

• Novel nonsteroidal ligands with high binding affinity and potent functional activity for the androgen receptor
  作者：Yali He、Donghua Yin、Minoli Perera、Leonid Kirkovsky、Nina Stourman、Wei Li、James T Dalton、Duane D Miller

  DOI：10.1016/s0223-5234(02)01335-1

  日期：2002.8

  While nonsteroidal androgen receptor (AR) antagonists have been known for many years, and used in the clinic for the treatment of hormone dependent prostate cancer, very little is known about nonsteroidal AR agonists. We designed and synthesized a series of chiral bicalutamide analogs, which bear electron-withdrawing groups (either a cyano or a nitro group at the 4-position and a trifluoromethyl group at the 3-position) in the aromatic A ring, and different substituents at the para position in the aromatic B ring of the parent molecule. We also synthesized a series of racemic bicalutamide analogs, which have a trifluoromethyl group instead of a methyl group at the R, position. We examined AR binding affinities of our compounds in a competitive binding assay with a radiolabeled high affinity AR ligand, H-3-mibolerone, and also measured their abilities to stimulate AR-mediated transcriptional activation in a cotransfection assay. These studies demonstrated that (1) nonsteroidal ligands can be structurally modified from known nonsteroidal antiandrogens to generate, ligands capable of activating AR-mediated transcriptional activation. (2) R-isomer analogs exhibit higher AR binding affinity and more potent functional activity than their corresponding S-isomers in all cases. (3) All sulphide analogs show higher AR binding affinity and more potent functional activity than their corresponding sulphone analogs, with the exception of ligand R-8. Those ligands which exhibit high AR binding affinity and potent functional activity for human AR may provide effective clinical uses for male fertility, male contraception, and hormone replacement therapy. (C) 2002 Editions scientifiques et medicales Elsevier SAS.-All rights reserved.
• Prostate cancer PET bioprobes: Synthesis of [18F]-radiolabeled hydroxyflutamide derivatives
  作者：Orit Jacobson、Yossi Bechor、Avi Icar、Nurit Novak、Atalia Birman、Hanit Marom、Ludmila Fadeeva、Elizabeth Golan、Ilan Leibovitch、Mordechai Gutman、Einat Even-Sapir、Roland Chisin、Michael Gozin、Eyal Mishani

  DOI：10.1016/j.bmc.2005.06.033

  日期：2005.11

  Approximately 80-90% of prostate cancers are androgen dependent at initial diagnosis. The androgen receptor (AR) is present in most advanced prostate cancer specimens and is believed to have a critical role in its development. Today, treatment of prostate cancer is done by inhibition of AR using antiandrogens such as flutamide (pro-drug of hydroxyflutamide), nilutamide, and bicalutamide. However, there is currently no noninvasive imaging modalities to detect, guide, and monitor specific treatment of AR-positive prostate cancer. (R)-3-Bromo-N-(4-fluoro-3-(trifluoromethy, phenyl)-2-hydroxy-2-methyl-propanamide [F-18]-1 and N-(4fluoro-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropanamide [F-18]-2, derivatives of hydroxyflutamide, were synthesized as a fluorine-containing imaging agent candidates. A three-step fluorine-18 radiosynthesis route was developed, and the compounds were successfully labeled with a 10 +/- 3% decay corrected radiochemical yield, 95% radiochemical purity, and a specific activity of 1500 +/- 200 Ci/mmol end of bombardment (n = 10). These labeled biprobes not only may enable for the future quantitative molecular imaging of AR-positive prostate cancer using positron emission tomography but may also allow for image-guided treatment of prostate cancer. (c) 2005 Elsevier Ltd. All rights reserved.
• Design, Synthesis, and Biological Characterization of Metabolically Stable Selective Androgen Receptor Modulators
  作者：Craig A. Marhefka、Wenqing Gao、Kiwon Chung、Juhyun Kim、Yali He、Donghua Yin、Casey Bohl、James T. Dalton、Duane D. Miller

  DOI：10.1021/jm030336u

  日期：2004.2.1

  A series of nonsteroidal ligands were synthesized as second-generation agonists for the androgen receptor (AR). These ligands were designed to eliminate metabolic sites identified in one of our first-generation AR agonists, which was inactive in vivo due to its rapid metabolism to inactive constituents. The binding affinity of these compounds was evaluated using AR isolated from rat ventral prostate. These second-generation compounds bound the AR in a high affinity and stereoselective manner, with K-i values ranging from about 4 to 130 nM. The ability of these ligands to stimulate AR-mediated transcriptional activation was examined in cells transfected with the human AR and a hormone-dependent luciferase reporter gene. Although some compounds were unable to stimulate AR-mediated transcription, several demonstrated activity similar to that of dihydrotestosterone (DHT, an endogenous steroidal ligand for the AR). We also evaluated the in vivo pharmacologic activity of selected compounds in castrated male rats. Three compounds were identified as selective androgen receptor modulators (SARMs), exhibiting significant anabolic activity while having only moderate to minimal androgenic activity in vivo.
• Homology Modeling Using Multiple Molecular Dynamics Simulations and Docking Studies of the Human Androgen Receptor Ligand Binding Domain Bound to Testosterone and Nonsteroidal Ligands
  作者：Craig A. Marhefka、Bob M. Moore、Thomas C. Bishop、Leonid Kirkovsky、Arnab Mukherjee、James T. Dalton、Duane D. Miller

  DOI：10.1021/jm0005353

  日期：2001.5.1

  To facilitate the rational design of novel and more potent androgen receptor ligands, three-dimensional models for the human androgen receptor ligand binding domain bound to testosterone have been developed. These models of the androgen receptor were based on the crystal structure of the highly homologous human progesterone receptor ligand binding domain. The homology modeled androgen receptor was refined using unrestrained multiple molecular dynamics simulations in explicit solvent, Key H-bonding partners with the 17-hydroxy group and 3-keto group of testosterone are Asn705 and Thr877, and Gln711 and Arg752, respectively. These models show the presence of a unique unoccupied cavity within the androgen receptor binding pocket which may be valuable in the development of novel selective androgen receptor ligands. A qualitative analysis of amino acid mutations within the hAR binding pocket that affect ligand binding are consistent with these androgen receptor models. In addition to testosterone, the binding modes of several hydroxyflutamide-like nonsteroidal ligands for the androgen receptor are investigated using flexible docking with FlexX followed by refinement of the initial complexes with molecular dynamics simulations. These docking studies indicate that Asn705 is an important determinant in binding hydroxyflutamide and its derivatives by participating in II-bond interactions with the a-hydroxy moiety of these ligands. In addition, the nitro functionality mimics the 3-keto group of the natural ligand testosterone and is involved in II-bonding interactions with Gln711 and Arg752. From these docking studies, we suggest a mechanism for the enantioselective binding of chiral hydroxyflutamide derivatives and expand upon the previously reported structure-activity relationship for hydroxyflutamide and its derivatives.
• Arylisothiocyanato selective androgen receptor modulators (SARMs) for prostate cancer
  作者：Dong Jin Hwang、Jun Yang、Huiping Xu、Igor M. Rakov、Michael L. Mohler、James T. Dalton、Duane D. Miller

  DOI：10.1016/j.bmc.2006.06.019

  日期：2006.10

  the linker sulfone of R-bicalutamide was maintained or replaced with several alternative linkages including ether, amine, N-methylamine, thioether, and methylene (in this case the product was a racemic mixture) functional groups at the X-position. To expand the structure-activity relationship (SAR) of these arylisothiocyanato AR ligands, B-ring halogenated arylisothiocyanato ligands were also prepared

  制备了一系列新的雄激素受体靶向剂（ARTA），并在雄激素依赖性和非依赖性前列腺癌细胞系中进行了测试。这些试剂是具有异硫氰酸根基取代的B环的比卡鲁胺类似物。同样，R-比卡鲁胺的连接基砜被保持或替换为几个可选的连接基，包括醚，胺，N-甲胺，硫醚和亚甲基（在这种情况下，该产品是外消旋混合物）在X位置的官能团。为了扩大这些芳基异硫氰酸根基AR配体的结构活性关系（SAR），还制备并测试了B环卤代芳基异硫氰酸根基配体。芳基异硫氰酸根基AR配体对AR的结合亲和力范围为0.6到54 nM。其中，硫醚和醚键表现出高结合亲和力（0.6和4.6 nM，与雄激素非依赖性前列腺癌细胞系（DU145，PC-3和PPC-1）相比，对LNCaP（一种雄激素依赖性前列腺癌细胞系）分别具有选择性和选择性的细胞生长抑制作用（约3至6倍），并且膀胱细胞系（TSU-Pr1）。但是，配体在正常猴肾细胞系（CV-1）中是无活性的（IC50>