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Design and development of ICCA as a dual inhibitor of GPIIb/IIIa and P-selectin receptors

BACKGROUND: The impact of upregulation of platelet membrane glycoprotein (GP)IIb/IIIa and P-selectin on the onset of arterial thrombosis, venous thrombosis, and cancer encourages to hypothesize that dual inhibitor of GPIIb/IIIa and P-selectin receptors should simultaneously inhibit arterial thrombos...

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Autores principales: Chen, Haiyan, Lu, An, Zhang, Xiaoyi, Gui, Lin, Wang, Yaonan, Wu, Jianhui, Feng, Hua, Peng, Shiqi, Zhao, Ming
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Dove Medical Press 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6042529/
https://www.ncbi.nlm.nih.gov/pubmed/30022809
http://dx.doi.org/10.2147/DDDT.S169238
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author Chen, Haiyan
Lu, An
Zhang, Xiaoyi
Gui, Lin
Wang, Yaonan
Wu, Jianhui
Feng, Hua
Peng, Shiqi
Zhao, Ming
author_facet Chen, Haiyan
Lu, An
Zhang, Xiaoyi
Gui, Lin
Wang, Yaonan
Wu, Jianhui
Feng, Hua
Peng, Shiqi
Zhao, Ming
author_sort Chen, Haiyan
collection PubMed
description BACKGROUND: The impact of upregulation of platelet membrane glycoprotein (GP)IIb/IIIa and P-selectin on the onset of arterial thrombosis, venous thrombosis, and cancer encourages to hypothesize that dual inhibitor of GPIIb/IIIa and P-selectin receptors should simultaneously inhibit arterial thrombosis, block venous thrombosis, and slow tumor growth. METHODS: For this reason, the structural characteristics and the CDOCKER interaction energies of 12 carbolines were analyzed. This led to the design of 1-(4-isopropyl-phenyl)-β-carboline-3-carboxylic acid (ICCA) as a promising inhibitor of GPIIb/IIIa and P-selectin receptors. RESULTS: The synthetic route provided ICCA in 48% total yield and 99.6% high-performance liquid chromatography purity. In vivo 5 μmol/kg oral ICCA downregulated GPIIb/IIIa and P-selectin expression thereby inhibited arterial thrombosis, blocked venous thrombosis, and slowed down tumor growth, but did not damage the kidney and the liver. CONCLUSION: Therefore, ICCA could be a promising candidate capable of downregulating GPIIb/IIIa and P-selectin receptors, inhibiting arterial thrombosis, blocking venous thrombosis, and slowing down tumor growth.
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spelling pubmed-60425292018-07-18 Design and development of ICCA as a dual inhibitor of GPIIb/IIIa and P-selectin receptors Chen, Haiyan Lu, An Zhang, Xiaoyi Gui, Lin Wang, Yaonan Wu, Jianhui Feng, Hua Peng, Shiqi Zhao, Ming Drug Des Devel Ther Original Research BACKGROUND: The impact of upregulation of platelet membrane glycoprotein (GP)IIb/IIIa and P-selectin on the onset of arterial thrombosis, venous thrombosis, and cancer encourages to hypothesize that dual inhibitor of GPIIb/IIIa and P-selectin receptors should simultaneously inhibit arterial thrombosis, block venous thrombosis, and slow tumor growth. METHODS: For this reason, the structural characteristics and the CDOCKER interaction energies of 12 carbolines were analyzed. This led to the design of 1-(4-isopropyl-phenyl)-β-carboline-3-carboxylic acid (ICCA) as a promising inhibitor of GPIIb/IIIa and P-selectin receptors. RESULTS: The synthetic route provided ICCA in 48% total yield and 99.6% high-performance liquid chromatography purity. In vivo 5 μmol/kg oral ICCA downregulated GPIIb/IIIa and P-selectin expression thereby inhibited arterial thrombosis, blocked venous thrombosis, and slowed down tumor growth, but did not damage the kidney and the liver. CONCLUSION: Therefore, ICCA could be a promising candidate capable of downregulating GPIIb/IIIa and P-selectin receptors, inhibiting arterial thrombosis, blocking venous thrombosis, and slowing down tumor growth. Dove Medical Press 2018-07-09 /pmc/articles/PMC6042529/ /pubmed/30022809 http://dx.doi.org/10.2147/DDDT.S169238 Text en © 2018 Chen et al. This work is published and licensed by Dove Medical Press Limited The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.
spellingShingle Original Research
Chen, Haiyan
Lu, An
Zhang, Xiaoyi
Gui, Lin
Wang, Yaonan
Wu, Jianhui
Feng, Hua
Peng, Shiqi
Zhao, Ming
Design and development of ICCA as a dual inhibitor of GPIIb/IIIa and P-selectin receptors
title Design and development of ICCA as a dual inhibitor of GPIIb/IIIa and P-selectin receptors
title_full Design and development of ICCA as a dual inhibitor of GPIIb/IIIa and P-selectin receptors
title_fullStr Design and development of ICCA as a dual inhibitor of GPIIb/IIIa and P-selectin receptors
title_full_unstemmed Design and development of ICCA as a dual inhibitor of GPIIb/IIIa and P-selectin receptors
title_short Design and development of ICCA as a dual inhibitor of GPIIb/IIIa and P-selectin receptors
title_sort design and development of icca as a dual inhibitor of gpiib/iiia and p-selectin receptors
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6042529/
https://www.ncbi.nlm.nih.gov/pubmed/30022809
http://dx.doi.org/10.2147/DDDT.S169238
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