Discovery of Novel 2,4-Dianilinopyrimidine Derivatives Containing 4-(Morpholinomethyl)phenyl and <i>N</i>-Substituted Benzamides as Potential FAK Inhibitors and Anticancer Agents

Discovery of Novel 2,4-Dianilinopyrimidine Derivatives Containing 4-(Morpholinomethyl)phenyl and <i>N</i>-Substituted Benzamides as Potential FAK Inhibitors and Anticancer Agents

Focal adhesion kinase (FAK) is responsible for the development and progression of various malignancies. With the aim to explore novel FAK inhibitors as anticancer agents, a series of 2,4-dianilinopyrimidine derivatives <b>8a</b>–<b>8i</b> and <b>9a</b>–<b>9g...

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Main Authors: Chun Han, Kemin Shen, Shijun Wang, Zhijun Wang, Feng Su, Xi Wu, Xiaoqin Hu, Mengyao Li, Jing Han, Lintao Wu
Format: Article
Language:English
Published: MDPI AG 2021-07-01
Series:Molecules
Subjects:
FAK inhibitor
2,4-dianilinopyrimidine
4-(morpholinomethyl)phenyl
<i>N</i>-substituted benzamides
anticancer
molecular docking
Online Access:https://www.mdpi.com/1420-3049/26/14/4187
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spelling doaj-61bfedb07f5445c28a52932b8ec5d3952021-07-23T13:56:22ZengMDPI AGMolecules1420-30492021-07-01264187418710.3390/molecules26144187Discovery of Novel 2,4-Dianilinopyrimidine Derivatives Containing 4-(Morpholinomethyl)phenyl and <i>N</i>-Substituted Benzamides as Potential FAK Inhibitors and Anticancer AgentsChun Han0Kemin Shen1Shijun Wang2Zhijun Wang3Feng Su4Xi Wu5Xiaoqin Hu6Mengyao Li7Jing Han8Lintao Wu9Department of Chemistry, Changzhi University, Changzhi 046011, ChinaDepartment of Public Health and Preventive Medicine, Changzhi Medical College, Changzhi 046011, ChinaDepartment of Chemistry, Changzhi University, Changzhi 046011, ChinaDepartment of Chemistry, Changzhi University, Changzhi 046011, ChinaDepartment of Chemistry, Changzhi University, Changzhi 046011, ChinaDepartment of Chemistry, Changzhi University, Changzhi 046011, ChinaDepartment of Chemistry, Changzhi University, Changzhi 046011, ChinaDepartment of Chemistry, Changzhi University, Changzhi 046011, ChinaSchool of Chemistry and Materials Science, Jiangsu Normal University, Xuzhou 221116, ChinaDepartment of Chemistry, Changzhi University, Changzhi 046011, ChinaFocal adhesion kinase (FAK) is responsible for the development and progression of various malignancies. With the aim to explore novel FAK inhibitors as anticancer agents, a series of 2,4-dianilinopyrimidine derivatives <b>8a</b>–<b>8i</b> and <b>9a</b>–<b>9g</b> containing 4-(morpholinomethyl)phenyl and <i>N</i>-substituted benzamides have been designed and synthesized. Among them, compound <b>8a</b> displayed potent anti-FAK activity (IC<sub>50</sub> = 0.047 ± 0.006 μM) and selective antiproliferative effects against H1975 (IC<sub>50</sub> = 0.044 ± 0.011 μM) and A431 cells (IC<sub>50</sub> = 0.119 ± 0.036 μM). Furthermore, compound <b>8a</b> also induced apoptosis in a dose-dependent manner, arresting the cells in S/G2 phase and inhibiting the migration of H1975 cells, all of which were superior to those of TAE226. The docking analysis of compound <b>8a</b> was performed to elucidate its possible binding modes with FAK. These results established <b>8a</b> as our lead compound to be further investigated as a potential FAK inhibitor and anticancer agent.https://www.mdpi.com/1420-3049/26/14/4187FAK inhibitor2,4-dianilinopyrimidine4-(morpholinomethyl)phenyl<i>N</i>-substituted benzamidesanticancermolecular docking
collection DOAJ
language English
format Article
sources DOAJ
author Chun Han
Kemin Shen
Shijun Wang
Zhijun Wang
Feng Su
Xi Wu
Xiaoqin Hu
Mengyao Li
Jing Han
Lintao Wu
spellingShingle Chun Han
Kemin Shen
Shijun Wang
Zhijun Wang
Feng Su
Xi Wu
Xiaoqin Hu
Mengyao Li
Jing Han
Lintao Wu
Discovery of Novel 2,4-Dianilinopyrimidine Derivatives Containing 4-(Morpholinomethyl)phenyl and <i>N</i>-Substituted Benzamides as Potential FAK Inhibitors and Anticancer Agents
Molecules
FAK inhibitor
2,4-dianilinopyrimidine
4-(morpholinomethyl)phenyl
<i>N</i>-substituted benzamides
anticancer
molecular docking
author_facet Chun Han
Kemin Shen
Shijun Wang
Zhijun Wang
Feng Su
Xi Wu
Xiaoqin Hu
Mengyao Li
Jing Han
Lintao Wu
author_sort Chun Han
title Discovery of Novel 2,4-Dianilinopyrimidine Derivatives Containing 4-(Morpholinomethyl)phenyl and <i>N</i>-Substituted Benzamides as Potential FAK Inhibitors and Anticancer Agents
title_short Discovery of Novel 2,4-Dianilinopyrimidine Derivatives Containing 4-(Morpholinomethyl)phenyl and <i>N</i>-Substituted Benzamides as Potential FAK Inhibitors and Anticancer Agents
title_full Discovery of Novel 2,4-Dianilinopyrimidine Derivatives Containing 4-(Morpholinomethyl)phenyl and <i>N</i>-Substituted Benzamides as Potential FAK Inhibitors and Anticancer Agents
title_fullStr Discovery of Novel 2,4-Dianilinopyrimidine Derivatives Containing 4-(Morpholinomethyl)phenyl and <i>N</i>-Substituted Benzamides as Potential FAK Inhibitors and Anticancer Agents
title_full_unstemmed Discovery of Novel 2,4-Dianilinopyrimidine Derivatives Containing 4-(Morpholinomethyl)phenyl and <i>N</i>-Substituted Benzamides as Potential FAK Inhibitors and Anticancer Agents
title_sort discovery of novel 2,4-dianilinopyrimidine derivatives containing 4-(morpholinomethyl)phenyl and <i>n</i>-substituted benzamides as potential fak inhibitors and anticancer agents
publisher MDPI AG
series Molecules
issn 1420-3049
publishDate 2021-07-01
description Focal adhesion kinase (FAK) is responsible for the development and progression of various malignancies. With the aim to explore novel FAK inhibitors as anticancer agents, a series of 2,4-dianilinopyrimidine derivatives <b>8a</b>–<b>8i</b> and <b>9a</b>–<b>9g</b> containing 4-(morpholinomethyl)phenyl and <i>N</i>-substituted benzamides have been designed and synthesized. Among them, compound <b>8a</b> displayed potent anti-FAK activity (IC<sub>50</sub> = 0.047 ± 0.006 μM) and selective antiproliferative effects against H1975 (IC<sub>50</sub> = 0.044 ± 0.011 μM) and A431 cells (IC<sub>50</sub> = 0.119 ± 0.036 μM). Furthermore, compound <b>8a</b> also induced apoptosis in a dose-dependent manner, arresting the cells in S/G2 phase and inhibiting the migration of H1975 cells, all of which were superior to those of TAE226. The docking analysis of compound <b>8a</b> was performed to elucidate its possible binding modes with FAK. These results established <b>8a</b> as our lead compound to be further investigated as a potential FAK inhibitor and anticancer agent.
topic FAK inhibitor
2,4-dianilinopyrimidine
4-(morpholinomethyl)phenyl
<i>N</i>-substituted benzamides
anticancer
molecular docking
url https://www.mdpi.com/1420-3049/26/14/4187
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