1-(4-ethylphenyl)-1,1-diphenylmethanol | 3139-88-6

• 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: 1-(4-ethylphenyl)-1,1-diphenylmethanol
• 英文别名: (4-ethylphenyl)(diphenyl)methanol；(4-ethylphenyl)diphenylmethanol；4-Ethyl-triphenylmethanol
• CAS: 3139-88-6
• 化学式: C₂₁H₂₀O
• 分子量: 288.389
• InChiKey: UIBCPAWITOXHRB-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.53
• 重原子数：
  22.0
• 可旋转键数：
  4.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.14
• 拓扑面积：
  20.23
• 氢给体数：
  1.0
• 氢受体数：
  1.0

反应信息

• 作为反应物：
  描述：

  1-(4-ethylphenyl)-1,1-diphenylmethanol 在 吡啶 、 正丁基锂 、 sodium azide 、 硼烷四氢呋喃络合物 、 palladium 10% on activated carbon 、 甲酸铵 作用下， 以 四氢呋喃 、 甲醇 、 正己烷 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 47.67h， 生成 4-(3-Ethylphenyl)-4,4-diphenylbutan-1-amine
  参考文献：
  名称：

  Optimized S-Trityl-l-cysteine-Based Inhibitors of Kinesin Spindle Protein with Potent in Vivo Antitumor Activity in Lung Cancer Xenograft Models

  摘要：

  The mitotic kinesin Eg5 is critical for the assembly of the mitotic spindle and is a promising chemotherapy target. Previously, we identified S-trityl-L-cysteine as a selective inhibitor of Eg5 and developed triphenylbutanamine analogues with improved potency, favorable drug-like properties, but moderate in vivo activity. We report here their further optimization to produce extremely potent inhibitors of Eg5 (K-i(app) < 10 nM) with broad-spectrum activity against cancer cell lines comparable to the Phase II drug candidates ispinesib and SB-743921. They have good oral bioavailability and pharmacolcinetics and induced complete tumor regression in nude mice explanted with lung cancer patient xenografts. Furthermore, they display fewer liabilities with CYP-metabolizing enzymes and hERG compared with ispinesib and SB-743921, which is important given the likely application of Eg5 inhibitors in combination therapies. We present the case for this preclinical series to be investigated in single and combination chemotherapies, especially targeting hematological malignancies.

  DOI：

  10.1021/jm3014597
• 作为产物：
  描述：

  4-乙基苯甲酮 、 苯基氯化镁 以 四氢呋喃 为溶剂， 反应 18.0h， 以87%的产率得到1-(4-ethylphenyl)-1,1-diphenylmethanol
  参考文献：
  名称：

  Optimized S-Trityl-l-cysteine-Based Inhibitors of Kinesin Spindle Protein with Potent in Vivo Antitumor Activity in Lung Cancer Xenograft Models

  摘要：

  The mitotic kinesin Eg5 is critical for the assembly of the mitotic spindle and is a promising chemotherapy target. Previously, we identified S-trityl-L-cysteine as a selective inhibitor of Eg5 and developed triphenylbutanamine analogues with improved potency, favorable drug-like properties, but moderate in vivo activity. We report here their further optimization to produce extremely potent inhibitors of Eg5 (K-i(app) < 10 nM) with broad-spectrum activity against cancer cell lines comparable to the Phase II drug candidates ispinesib and SB-743921. They have good oral bioavailability and pharmacolcinetics and induced complete tumor regression in nude mice explanted with lung cancer patient xenografts. Furthermore, they display fewer liabilities with CYP-metabolizing enzymes and hERG compared with ispinesib and SB-743921, which is important given the likely application of Eg5 inhibitors in combination therapies. We present the case for this preclinical series to be investigated in single and combination chemotherapies, especially targeting hematological malignancies.

  DOI：

  10.1021/jm3014597

文献信息

• Structure−Activity Relationship and Multidrug Resistance Study of New <i>S</i>-trityl-<scp>l</scp>-Cysteine Derivatives As Inhibitors of Eg5
  作者：Hung Yi Kristal Kaan、Johanna Weiss、Dominik Menger、Venkatasubramanian Ulaganathan、Katarzyna Tkocz、Christian Laggner、Florence Popowycz、Benoît Joseph、Frank Kozielski

  DOI：10.1021/jm100991m

  日期：2011.3.24

  The mitotic spindle is a validated target for cancer chemotherapy. Drugs such as taxanes and vinca alkaloids specifically target microtubules and cause the mitotic spindle to collapse. However, toxicity and resistance are problems associated with these drugs. Thus, alternative approaches to inhibiting the mitotic spindle are being pursued. These include targeting Eg5, a human kinesin involved in the formation of the bipolar spindle. We previously identified S-trityl-L-cysteine (STLC) as a potent allosteric inhibitor of Eg5. Here, we report the synthesis of a new series of STLC-like compounds with in vitro inhibition in the low nanomolar range. We also performed a multidrug resistance study in cell lines overexpressing P-glycoprotein and showed that some of these inhibitors may have the potential to overcome susceptibility to this efflux pump. Finally, we performed molecular docking of the compounds and determined the structures of two Eg5-inhibitor complexes to explain the structure-activity relationship of these compounds.
• Inhibition of hepatitis C virus NS5B polymerase by S-trityl-l-cysteine derivatives
  作者：Daniel B. Nichols、Guy Fournet、K.R. Gurukumar、Amartya Basu、Jin-Ching Lee、Naoya Sakamoto、Frank Kozielski、Ira Musmuca、Benoît Joseph、Rino Ragno、Neerja Kaushik-Basu

  DOI：10.1016/j.ejmech.2012.01.010

  日期：2012.3

  Structure-based studies led to the identification of a constrained derivative of S-trityl-c-cysteine (STLC) scaffold as a candidate inhibitor of hepatitis C virus (HCV) NS5B polymerase. A panel of STLC derivatives were synthesized and investigated for their activity against HCV NS5B. Three STLC derivatives, 9, F-3070, and F-3065, were identified as modest HCV NS5B inhibitors with IC50 values between 22.3 and 39.7 mu M. F-3070 and F-3065 displayed potent inhibition of intracellular NS5B activity in the BHK-NS5B-FRLuc reporter and also inhibited HCV RNA replication in the Huh7/Rep-Feo1b reporter system. Binding mode investigations suggested that the STLC scaffold can be used to develop new NS5B inhibitors by further chemical modification at one of the trityl phenyl group. (C) 2012 Elsevier Masson SAS. All rights reserved.
• Optimized <i>S</i>-Trityl-<scp>l</scp>-cysteine-Based Inhibitors of Kinesin Spindle Protein with Potent in Vivo Antitumor Activity in Lung Cancer Xenograft Models
  作者：James A. D. Good、Fang Wang、Oliver Rath、Hung Yi Kristal Kaan、Sandeep K. Talapatra、Dawid Podgórski、Simon P. MacKay、Frank Kozielski

  DOI：10.1021/jm3014597

  日期：2013.3.14

  The mitotic kinesin Eg5 is critical for the assembly of the mitotic spindle and is a promising chemotherapy target. Previously, we identified S-trityl-L-cysteine as a selective inhibitor of Eg5 and developed triphenylbutanamine analogues with improved potency, favorable drug-like properties, but moderate in vivo activity. We report here their further optimization to produce extremely potent inhibitors of Eg5 (K-i(app) < 10 nM) with broad-spectrum activity against cancer cell lines comparable to the Phase II drug candidates ispinesib and SB-743921. They have good oral bioavailability and pharmacolcinetics and induced complete tumor regression in nude mice explanted with lung cancer patient xenografts. Furthermore, they display fewer liabilities with CYP-metabolizing enzymes and hERG compared with ispinesib and SB-743921, which is important given the likely application of Eg5 inhibitors in combination therapies. We present the case for this preclinical series to be investigated in single and combination chemotherapies, especially targeting hematological malignancies.