(S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(tritylamino)propanoic acid | 1357108-45-2

• 分子结构分类: 有机化合物 - 苯类化合物 - 三苯基化合物
• 英文名称: (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(tritylamino)propanoic acid
• CAS: 1357108-45-2
• 化学式: C₃₇H₃₂N₂O₄
• 分子量: 568.672
• InChiKey: KVSMZYQSBGEDCT-UMSFTDKQSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.56
• 重原子数：
  43.0
• 可旋转键数：
  10.0
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.14
• 拓扑面积：
  87.66
• 氢给体数：
  3.0
• 氢受体数：
  4.0

反应信息

• 作为反应物：
  描述：

  (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(tritylamino)propanoic acid 在 哌啶 作用下， 以 甲醇 为溶剂， 反应 2.0h， 以89%的产率得到(2S)-2-amino-3-(tritylamino)propanoic acid
  参考文献：
  名称：

  Triphenylbutanamines: Kinesin Spindle Protein Inhibitors with in Vivo Antitumor Activity

  摘要：

  The human mitotic kinesin Eg5 represents a novel mitotic spindle target for cancer chemotherapy. We previously identified S-trityl-L-cysteine (STLC) and related analogues as selective potent inhibitors of Eg5. We herein report on the development of a series of 4,4,4-triphenylbutan-1-amine inhibitors derived from the STLC scaffold. This new generation systematically improves on potency: the most potent C-trityl analogues exhibit K-i(aPP) <= 10 nM and GI(50) approximate to 50 nM, comparable to results from the phase II clinical benchmark ispinesib. Crystallographic studies reveal that they adopt the same overall binding configuration as S-trityl analogues at an allosteric site formed by loop L5 of Eg5. Evaluation of their druglike properties reveals favorable profiles for future development and, in the clinical candidate ispinesib, moderate hERG and CYP inhibition. One triphenylbutanamine analogue and ispinesib possess very good bioavailability (51% and 45%, respectively), with the former showing in vivo antitumor growth activity in nude mice xenograft studies.

  DOI：

  10.1021/jm201195m
• 作为产物：
  描述：

  Nα-Fmoc-L-2,3-二氨基丙酸 在 三乙胺 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 3.0h， 生成 (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(tritylamino)propanoic acid
  参考文献：
  名称：

  Triphenylbutanamines: Kinesin Spindle Protein Inhibitors with in Vivo Antitumor Activity

  摘要：

  The human mitotic kinesin Eg5 represents a novel mitotic spindle target for cancer chemotherapy. We previously identified S-trityl-L-cysteine (STLC) and related analogues as selective potent inhibitors of Eg5. We herein report on the development of a series of 4,4,4-triphenylbutan-1-amine inhibitors derived from the STLC scaffold. This new generation systematically improves on potency: the most potent C-trityl analogues exhibit K-i(aPP) <= 10 nM and GI(50) approximate to 50 nM, comparable to results from the phase II clinical benchmark ispinesib. Crystallographic studies reveal that they adopt the same overall binding configuration as S-trityl analogues at an allosteric site formed by loop L5 of Eg5. Evaluation of their druglike properties reveals favorable profiles for future development and, in the clinical candidate ispinesib, moderate hERG and CYP inhibition. One triphenylbutanamine analogue and ispinesib possess very good bioavailability (51% and 45%, respectively), with the former showing in vivo antitumor growth activity in nude mice xenograft studies.

  DOI：

  10.1021/jm201195m

文献信息

• Modified Peptide Inhibitors of the Keap1–Nrf2 Protein–Protein Interaction Incorporating Unnatural Amino Acids
  作者：Nikolaos D. Georgakopoulos、Sandeep K. Talapatra、Jemma Gatliff、Frank Kozielski、Geoff Wells

  DOI：10.1002/cbic.201800170

  日期：2018.9.4

  Increasing the activity: Peptide inhibitors of the Keap1–Nrf2 protein–protein interaction in which unnatural amino acids are incorporated in heptamer sequences have been developed. The starting sequence has been co‐crystallised with the Keap1 Kelch domain, and the best peptides have Keap1 affinities in the nanomolar range in fluorescence polarisation (FP) and isothermal titration calorimetry (ITC)

  提高活性：已开发出 Keap1-Nrf2 蛋白质-蛋白质相互作用的肽抑制剂，其中非天然氨基酸掺入七聚体序列中。起始序列已与 Keap1 Kelch 结构域共结晶，在荧光偏振 (FP) 和等温滴定量热法 (ITC) 结合测定中，最佳肽在纳摩尔范围内具有 Keap1 亲和力。