6,8-dicyclopentenyl-1,2-dihydro-2,2,4-trimethylquinoline | 1492019-86-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 英文名称: 6,8-dicyclopentenyl-1,2-dihydro-2,2,4-trimethylquinoline
• 英文别名: 6,8-di(cyclopenten-1-yl)-2,2,4-trimethyl-1H-quinoline
• CAS: 1492019-86-9
• 化学式: C₂₂H₂₇N
• 分子量: 305.463
• InChiKey: QRQOPIHCOKGAIT-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.1
• 重原子数：
  23
• 可旋转键数：
  2
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.45
• 拓扑面积：
  12
• 氢给体数：
  1
• 氢受体数：
  1

反应信息

• 作为产物：
  描述：

  2,2,4-三甲基-1,2-二氢喹啉 、 环戊酮 在 碘 作用下， 以 neat (no solvent) 为溶剂， 生成 6,8-dicyclopentenyl-1,2-dihydro-2,2,4-trimethylquinoline
  参考文献：
  名称：

  Multifaceted approach toward mapping out the anticancer properties of small molecules via in vitro evaluation on melanoma and nonmelanoma skin cancer cells, and in silico target fishing

  摘要：

  摘要 黑色素瘤和非黑色素瘤皮肤癌是发病率最高、致死率最高的皮肤癌之一。为了鉴定具有潜在抗癌特性的新先导化合物并进行进一步优化，我们采用体外试验结合体内靶标捕获和对接的方法，从我们实验室以前制备的小型化合物库中鉴定并进一步绘制出分子的抗增殖作用和潜在作用模式图。通过对 A375、SK-MEL-28、A431 和 SCC-12 皮肤癌细胞系进行体外筛选，35 个化合物显示出微摩水平的抗增殖活性，其中大多数化合物主要对 A431 和 SCC-12 鳞癌细胞系有效。活性最强的化合物 11（A431：IC50 = 5.0 μM；SCC-12：IC50 = 2.9 μM；SKMEL-28：IC50 = 4.9 μM；A375：IC50 = 6.7 μM）和 13（A431：IC50 = 5.0 μM，SCC-12：IC50 = 3.3 μM，SKMEL-28：IC50 = 13.8 μM，A375：两种药物都能显著诱导 SCC-12 和 SK-MEL-28 细胞凋亡，且呈剂量依赖性，表现为抑制 Bcl-2，上调 Bax、裂解的 caspase-3、caspase-9 和 PARP 蛋白表达水平。这两种制剂都能明显降低划痕伤口愈合、集落形成以及包括 RSK/Akt/ERK1/2 和 S6K1 在内的失调癌症分子靶点的表达水平。利用 SwissTargetPrediction 网络工具进行的硅学靶点预测和对接研究表明，CDK8、CLK4、核受体 ROR、酪氨酸蛋白激酶 Fyn/LCK、ROCK1/2 和 PARP（所有这些靶点在皮肤癌中都失调）可能是这两种活性最强的化合物的潜在靶点。通过西部印迹分析对这些靶点的进一步验证表明，ROCK/Fyn 及其相关的刺猬（Hh）通路受到这两种先导化合物的下调或调节。总之，这些结果为进一步验证观察到的活性以及通过制备和生物评估类似物来发展更全面的结构-活性关系提供了一个强有力的框架。

  DOI：

  10.1111/cbdd.14418

文献信息

• Iodine-catalyzed cycloalkenylation of dihydroquinolines and arylamines through a reaction with cyclic ketones under neat conditions
  作者：Jean Fotie、Suraj K. Ayer、Binit S. Poudel、Carolyn S. Reid

  DOI：10.1016/j.tetlet.2013.10.081

  日期：2013.12

  An iodine-catalyzed direct cycloalkenylation of dihydroquinolines and arylamines has been developed. This method consists of a Friedel-Crafts reaction between dihydroquinolines (or arylamines) and cyclic ketones in which the double bond is selectively generated throughout the course of the reaction resulting in a direct cycloalkenylation, under neat conditions. (C) 2013 Elsevier Ltd. All rights reserved.
• Multifaceted approach toward mapping out the anticancer properties of small molecules via in vitro evaluation on melanoma and nonmelanoma skin cancer cells, and in silico target fishing
  作者：Samuel T. Boateng、Tithi Roy、Mercy E. Agbo、Md Ashiq Mahmud、Sergette Banang‐Mbeumi、Roxane‐Cherille N. Chamcheu、Rajesh K. Yadav、Marion Bramwell、Long K. Pham、Danny D. Dang、Keith E. Jackson、Bolni Marius Nagalo、Ronald A. Hill、Tatiana Efimova、Jean Fotie、Jean Christopher Chamcheu

  DOI：10.1111/cbdd.14418

  日期：2024.1

  Melanoma and nonmelanoma skin cancers are among the most prevalent and most lethal forms of skin cancers. To identify new lead compounds with potential anticancer properties for further optimization, in vitro assays combined with in‐silico target fishing and docking have been used to identify and further map out the antiproliferative and potential mode of action of molecules from a small library of compounds previously prepared in our laboratory. From screening these compounds in vitro against A375, SK‐MEL‐28, A431, and SCC‐12 skin cancer cell lines, 35 displayed antiproliferative activities at the micromolar level, with the majority being primarily potent against the A431 and SCC‐12 squamous carcinoma cell lines. The most active compounds 11 (A431: IC₅₀ = 5.0 μM, SCC‐12: IC₅₀ = 2.9 μM, SKMEL‐28: IC₅₀ = 4.9 μM, A375: IC₅₀ = 6.7 μM) and 13 (A431: IC₅₀ = 5.0 μM, SCC‐12: IC₅₀ = 3.3 μM, SKMEL‐28: IC₅₀ = 13.8 μM, A375: IC₅₀ = 17.1 μM), significantly and dose‐dependently induced apoptosis of SCC‐12 and SK‐MEL‐28 cells, as evidenced by the suppression of Bcl‐2 and upregulation of Bax, cleaved caspase‐3, caspase‐9, and PARP protein expression levels. Both agents significantly reduced scratch wound healing, colony formation, and expression levels of deregulated cancer molecular targets including RSK/Akt/ERK1/2 and S6K1. In silico target prediction and docking studies using the SwissTargetPrediction web‐based tool suggested that CDK8, CLK4, nuclear receptor ROR, tyrosine protein‐kinase Fyn/LCK, ROCK1/2, and PARP, all of which are dysregulated in skin cancers, might be prospective targets for the two most active compounds. Further validation of these targets by western blot analyses, revealed that ROCK/Fyn and its associated Hedgehog (Hh) pathways were downregulated or modulated by the two lead compounds. In aggregate, these results provide a strong framework for further validation of the observed activities and the development of a more comprehensive structure–activity relationship through the preparation and biological evaluation of analogs.

  摘要 黑色素瘤和非黑色素瘤皮肤癌是发病率最高、致死率最高的皮肤癌之一。为了鉴定具有潜在抗癌特性的新先导化合物并进行进一步优化，我们采用体外试验结合体内靶标捕获和对接的方法，从我们实验室以前制备的小型化合物库中鉴定并进一步绘制出分子的抗增殖作用和潜在作用模式图。通过对 A375、SK-MEL-28、A431 和 SCC-12 皮肤癌细胞系进行体外筛选，35 个化合物显示出微摩水平的抗增殖活性，其中大多数化合物主要对 A431 和 SCC-12 鳞癌细胞系有效。活性最强的化合物 11（A431：IC50 = 5.0 μM；SCC-12：IC50 = 2.9 μM；SKMEL-28：IC50 = 4.9 μM；A375：IC50 = 6.7 μM）和 13（A431：IC50 = 5.0 μM，SCC-12：IC50 = 3.3 μM，SKMEL-28：IC50 = 13.8 μM，A375：两种药物都能显著诱导 SCC-12 和 SK-MEL-28 细胞凋亡，且呈剂量依赖性，表现为抑制 Bcl-2，上调 Bax、裂解的 caspase-3、caspase-9 和 PARP 蛋白表达水平。这两种制剂都能明显降低划痕伤口愈合、集落形成以及包括 RSK/Akt/ERK1/2 和 S6K1 在内的失调癌症分子靶点的表达水平。利用 SwissTargetPrediction 网络工具进行的硅学靶点预测和对接研究表明，CDK8、CLK4、核受体 ROR、酪氨酸蛋白激酶 Fyn/LCK、ROCK1/2 和 PARP（所有这些靶点在皮肤癌中都失调）可能是这两种活性最强的化合物的潜在靶点。通过西部印迹分析对这些靶点的进一步验证表明，ROCK/Fyn 及其相关的刺猬（Hh）通路受到这两种先导化合物的下调或调节。总之，这些结果为进一步验证观察到的活性以及通过制备和生物评估类似物来发展更全面的结构-活性关系提供了一个强有力的框架。