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Molecular Requirements for the Expression of Antiplatelet Effects by Synthetic Structural Optimized Analogues of the Anticancer Drugs Imatinib and Nilotinib
BACKGROUND: Platelets play important roles in cancer progression and metastasis, as well as in cancer-associated thrombosis (CAT). Tyrosine kinases are implicated in several intracellular signaling pathways involved in tumor biology, thus tyrosine kinase inhibitors (TKIs) represent an important clas...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Dove
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6913343/ https://www.ncbi.nlm.nih.gov/pubmed/31849454 http://dx.doi.org/10.2147/DDDT.S211907 |
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author | Pantazi, Despoina Ntemou, Nikoleta Brentas, Alexios Alivertis, Dimitrios Skobridis, Konstantinos Tselepis, Alexandros D |
author_facet | Pantazi, Despoina Ntemou, Nikoleta Brentas, Alexios Alivertis, Dimitrios Skobridis, Konstantinos Tselepis, Alexandros D |
author_sort | Pantazi, Despoina |
collection | PubMed |
description | BACKGROUND: Platelets play important roles in cancer progression and metastasis, as well as in cancer-associated thrombosis (CAT). Tyrosine kinases are implicated in several intracellular signaling pathways involved in tumor biology, thus tyrosine kinase inhibitors (TKIs) represent an important class of anticancer drugs, based on the concept of targeted therapy. PURPOSE: The objective of this study is the design and synthesis of analogues of the TKIs imatinib and nilotinib in order to develop tyrosine kinase inhibitors, by investigating their molecular requirements, which would express antiplatelet properties. METHODS: Based on a recently described by us improved approach in the preparation of imatinib and/or nilotinib analogues, we designed and synthesized in five-step reaction sequences, 8 analogues of imatinib (I–IV), nilotinib (V, VI) and imatinib/nilotinib (VII, VIII). Their inhibitory effects on platelet aggregation and P-selectin membrane expression induced by arachidonic acid (AA), adenosine diphosphate (ADP) and thrombin receptor activating peptide-6 (TRAP-6), in vitro, were studied. Molecular docking studies and calculations were also performed. RESULTS: The novel analogues V–VIII were well established with the aid of spectroscopic methods. Imatinib and nilotinib inhibited AA-induced platelet aggregation, exhibiting IC(50) values of 13.30 μΜ and 3.91 μΜ, respectively. Analogues I and II exhibited an improved inhibitory activity compared with imatinib. Among the nilotinib analogues, V exhibited a 9-fold higher activity than nilotinib. All compounds were less efficient in inhibiting platelet aggregation towards ADP and TRAP-6. Similar results were obtained for the membrane expression of P-selectin. Molecular docking studies showed that the improved antiplatelet activity of nilotinib analogue V is primarily attributed to the number and the strength of hydrogen bonds. CONCLUSION: Our results show that there is considerable potential to develop synthetic analogues of imatinib and nilotinib, as TKIs with antiplatelet properties and therefore being suitable to target cancer progression and metastasis, as well as CAT by inhibiting platelet activation. |
format | Online Article Text |
id | pubmed-6913343 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Dove |
record_format | MEDLINE/PubMed |
spelling | pubmed-69133432019-12-17 Molecular Requirements for the Expression of Antiplatelet Effects by Synthetic Structural Optimized Analogues of the Anticancer Drugs Imatinib and Nilotinib Pantazi, Despoina Ntemou, Nikoleta Brentas, Alexios Alivertis, Dimitrios Skobridis, Konstantinos Tselepis, Alexandros D Drug Des Devel Ther Original Research BACKGROUND: Platelets play important roles in cancer progression and metastasis, as well as in cancer-associated thrombosis (CAT). Tyrosine kinases are implicated in several intracellular signaling pathways involved in tumor biology, thus tyrosine kinase inhibitors (TKIs) represent an important class of anticancer drugs, based on the concept of targeted therapy. PURPOSE: The objective of this study is the design and synthesis of analogues of the TKIs imatinib and nilotinib in order to develop tyrosine kinase inhibitors, by investigating their molecular requirements, which would express antiplatelet properties. METHODS: Based on a recently described by us improved approach in the preparation of imatinib and/or nilotinib analogues, we designed and synthesized in five-step reaction sequences, 8 analogues of imatinib (I–IV), nilotinib (V, VI) and imatinib/nilotinib (VII, VIII). Their inhibitory effects on platelet aggregation and P-selectin membrane expression induced by arachidonic acid (AA), adenosine diphosphate (ADP) and thrombin receptor activating peptide-6 (TRAP-6), in vitro, were studied. Molecular docking studies and calculations were also performed. RESULTS: The novel analogues V–VIII were well established with the aid of spectroscopic methods. Imatinib and nilotinib inhibited AA-induced platelet aggregation, exhibiting IC(50) values of 13.30 μΜ and 3.91 μΜ, respectively. Analogues I and II exhibited an improved inhibitory activity compared with imatinib. Among the nilotinib analogues, V exhibited a 9-fold higher activity than nilotinib. All compounds were less efficient in inhibiting platelet aggregation towards ADP and TRAP-6. Similar results were obtained for the membrane expression of P-selectin. Molecular docking studies showed that the improved antiplatelet activity of nilotinib analogue V is primarily attributed to the number and the strength of hydrogen bonds. CONCLUSION: Our results show that there is considerable potential to develop synthetic analogues of imatinib and nilotinib, as TKIs with antiplatelet properties and therefore being suitable to target cancer progression and metastasis, as well as CAT by inhibiting platelet activation. Dove 2019-12-12 /pmc/articles/PMC6913343/ /pubmed/31849454 http://dx.doi.org/10.2147/DDDT.S211907 Text en © 2019 Pantazi et al. http://creativecommons.org/licenses/by-nc/3.0/ 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. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). |
spellingShingle | Original Research Pantazi, Despoina Ntemou, Nikoleta Brentas, Alexios Alivertis, Dimitrios Skobridis, Konstantinos Tselepis, Alexandros D Molecular Requirements for the Expression of Antiplatelet Effects by Synthetic Structural Optimized Analogues of the Anticancer Drugs Imatinib and Nilotinib |
title | Molecular Requirements for the Expression of Antiplatelet Effects by Synthetic Structural Optimized Analogues of the Anticancer Drugs Imatinib and Nilotinib |
title_full | Molecular Requirements for the Expression of Antiplatelet Effects by Synthetic Structural Optimized Analogues of the Anticancer Drugs Imatinib and Nilotinib |
title_fullStr | Molecular Requirements for the Expression of Antiplatelet Effects by Synthetic Structural Optimized Analogues of the Anticancer Drugs Imatinib and Nilotinib |
title_full_unstemmed | Molecular Requirements for the Expression of Antiplatelet Effects by Synthetic Structural Optimized Analogues of the Anticancer Drugs Imatinib and Nilotinib |
title_short | Molecular Requirements for the Expression of Antiplatelet Effects by Synthetic Structural Optimized Analogues of the Anticancer Drugs Imatinib and Nilotinib |
title_sort | molecular requirements for the expression of antiplatelet effects by synthetic structural optimized analogues of the anticancer drugs imatinib and nilotinib |
topic | Original Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6913343/ https://www.ncbi.nlm.nih.gov/pubmed/31849454 http://dx.doi.org/10.2147/DDDT.S211907 |
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