Design, Synthesis and Biological Evaluation of 1,3,5-Triazine Derivatives Targeting hA1 and hA3 Adenosine Receptor

Sujin Park; Yujin Ahn; Yongchan Kim; Eun Joo Roh; Yoonji Lee; Chaebin Han; Hee Min Yoo; Jinha Yu

doi:10.3390/molecules27134016

Design, Synthesis and Biological Evaluation of 1,3,5-Triazine Derivatives Targeting hA1 and hA3 Adenosine Receptor

Sujin Park, Yujin Ahn, Yongchan Kim, Eun Joo Roh, Yoonji Lee, Chaebin Han, Hee Min Yoo, Jinha Yu

Department of Pharmaceutical Sciences

Research output: Contribution to journal › Article › peer-review

3 Scopus citations

Abstract

Adenosine mediates various physiological activities in the body. Adenosine receptors (ARs) are widely expressed in tumors and the tumor microenvironment (TME), and they induce tumor proliferation and suppress immune cell function. There are four types of human adenosine receptor (hARs): hA1, hA2A, hA2B, and hA3. Both hA1 and hA3 AR play an important role in tumor proliferation. We designed and synthesized novel 1,3,5-triazine derivatives through amination and Suzuki coupling, and evaluated them for binding affinities to each hAR subtype. Compounds 9a and 11b showed good binding affinity to both hA1 and hA3 AR, while 9c showed the highest binding affinity to hA1 AR. In this study, we discovered that 9c inhibits cell viability, leading to cell death in lung cancer cell lines. Flow cytometry analysis revealed that 9c caused an increase in intracellular reactive oxygen species (ROS) and a depolarization of the mitochondrial membrane potential. The binding mode of 1,3,5-triazine derivatives to hA1 and hA3 AR were predicted by a molecular docking study.

Original language	English
Article number	4016
Journal	Molecules
Volume	27
Issue number	13
DOIs	https://doi.org/10.3390/molecules27134016
State	Published - 1 Jul 2022

Bibliographical note

Funding Information:
Funding: This research was supported by the Ministry of Science and ICT (MSIT), National Research Foundation of Korea (NRF-2022R1C1C1004804 and 2020R1A4A4079494) and the Korea Institute of Science and Technology (KIST) to J.Y. In addition, this work was also supported by the “Establishment of measurement standards for Chemistry and Radiation”, grant number KRISS-2022-GP2022-0003 funded by the Korea Research Institute of Standards and Science and Ministry of Science and ICT (MSIT), National Research Foundation of Korea (NRF-2021M3C1C3097638) to H.M.Y.

Publisher Copyright:
© 2022 by the authors. Licensee MDPI, Basel, Switzerland.

Keywords

1,3,5-triazine
adenosine receptor
antitumor agents
dual ligand
molecular docking

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10.3390/molecules27134016

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title = "Design, Synthesis and Biological Evaluation of 1,3,5-Triazine Derivatives Targeting hA1 and hA3 Adenosine Receptor",

abstract = "Adenosine mediates various physiological activities in the body. Adenosine receptors (ARs) are widely expressed in tumors and the tumor microenvironment (TME), and they induce tumor proliferation and suppress immune cell function. There are four types of human adenosine receptor (hARs): hA1, hA2A, hA2B, and hA3. Both hA1 and hA3 AR play an important role in tumor proliferation. We designed and synthesized novel 1,3,5-triazine derivatives through amination and Suzuki coupling, and evaluated them for binding affinities to each hAR subtype. Compounds 9a and 11b showed good binding affinity to both hA1 and hA3 AR, while 9c showed the highest binding affinity to hA1 AR. In this study, we discovered that 9c inhibits cell viability, leading to cell death in lung cancer cell lines. Flow cytometry analysis revealed that 9c caused an increase in intracellular reactive oxygen species (ROS) and a depolarization of the mitochondrial membrane potential. The binding mode of 1,3,5-triazine derivatives to hA1 and hA3 AR were predicted by a molecular docking study.",

keywords = "1,3,5-triazine, adenosine receptor, antitumor agents, dual ligand, molecular docking",

author = "Sujin Park and Yujin Ahn and Yongchan Kim and Roh, {Eun Joo} and Yoonji Lee and Chaebin Han and Yoo, {Hee Min} and Jinha Yu",

note = "Funding Information: Funding: This research was supported by the Ministry of Science and ICT (MSIT), National Research Foundation of Korea (NRF-2022R1C1C1004804 and 2020R1A4A4079494) and the Korea Institute of Science and Technology (KIST) to J.Y. In addition, this work was also supported by the “Establishment of measurement standards for Chemistry and Radiation”, grant number KRISS-2022-GP2022-0003 funded by the Korea Research Institute of Standards and Science and Ministry of Science and ICT (MSIT), National Research Foundation of Korea (NRF-2021M3C1C3097638) to H.M.Y. Publisher Copyright: {\textcopyright} 2022 by the authors. Licensee MDPI, Basel, Switzerland.",

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AU - Roh, Eun Joo

AU - Lee, Yoonji

AU - Han, Chaebin

AU - Yoo, Hee Min

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N2 - Adenosine mediates various physiological activities in the body. Adenosine receptors (ARs) are widely expressed in tumors and the tumor microenvironment (TME), and they induce tumor proliferation and suppress immune cell function. There are four types of human adenosine receptor (hARs): hA1, hA2A, hA2B, and hA3. Both hA1 and hA3 AR play an important role in tumor proliferation. We designed and synthesized novel 1,3,5-triazine derivatives through amination and Suzuki coupling, and evaluated them for binding affinities to each hAR subtype. Compounds 9a and 11b showed good binding affinity to both hA1 and hA3 AR, while 9c showed the highest binding affinity to hA1 AR. In this study, we discovered that 9c inhibits cell viability, leading to cell death in lung cancer cell lines. Flow cytometry analysis revealed that 9c caused an increase in intracellular reactive oxygen species (ROS) and a depolarization of the mitochondrial membrane potential. The binding mode of 1,3,5-triazine derivatives to hA1 and hA3 AR were predicted by a molecular docking study.

AB - Adenosine mediates various physiological activities in the body. Adenosine receptors (ARs) are widely expressed in tumors and the tumor microenvironment (TME), and they induce tumor proliferation and suppress immune cell function. There are four types of human adenosine receptor (hARs): hA1, hA2A, hA2B, and hA3. Both hA1 and hA3 AR play an important role in tumor proliferation. We designed and synthesized novel 1,3,5-triazine derivatives through amination and Suzuki coupling, and evaluated them for binding affinities to each hAR subtype. Compounds 9a and 11b showed good binding affinity to both hA1 and hA3 AR, while 9c showed the highest binding affinity to hA1 AR. In this study, we discovered that 9c inhibits cell viability, leading to cell death in lung cancer cell lines. Flow cytometry analysis revealed that 9c caused an increase in intracellular reactive oxygen species (ROS) and a depolarization of the mitochondrial membrane potential. The binding mode of 1,3,5-triazine derivatives to hA1 and hA3 AR were predicted by a molecular docking study.

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ER -

Design, Synthesis and Biological Evaluation of 1,3,5-Triazine Derivatives Targeting hA1 and hA3 Adenosine Receptor

Abstract

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Keywords

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