Imidazopyridine hydrazone derivatives exert antiproliferative effect on lung and pancreatic cancer cells and potentially inhibit receptor tyrosine kinases including c-Met

Abstract Aberrant activation of c-Met signalling plays a prominent role in cancer development and progression. A series of 12 imidazo [1,2-α] pyridine derivatives bearing 1,2,3-triazole moiety were designed, synthesized and evaluated for c-Met inhibitory potential and anticancer effect. The inhibito...

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Autores principales:	Tahereh Damghani, Fatemeh Moosavi, Mehdi Khoshneviszadeh, Motahareh Mortazavi, Somayeh Pirhadi, Zahra Kayani, Luciano Saso, Najmeh Edraki, Omidreza Firuzi
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/e84ba50f01d64642a71fc85adbc1b611
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spelling	oai:doaj.org-article:e84ba50f01d64642a71fc85adbc1b6112021-12-02T14:11:31ZImidazopyridine hydrazone derivatives exert antiproliferative effect on lung and pancreatic cancer cells and potentially inhibit receptor tyrosine kinases including c-Met10.1038/s41598-021-83069-42045-2322https://doaj.org/article/e84ba50f01d64642a71fc85adbc1b6112021-02-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-83069-4https://doaj.org/toc/2045-2322Abstract Aberrant activation of c-Met signalling plays a prominent role in cancer development and progression. A series of 12 imidazo [1,2-α] pyridine derivatives bearing 1,2,3-triazole moiety were designed, synthesized and evaluated for c-Met inhibitory potential and anticancer effect. The inhibitory activity of all synthesized compounds against c-Met kinase was evaluated by a homogeneous time-resolved fluorescence (HTRF) assay at the concentration range of 5–25 µM. Derivatives 6d, 6e and 6f bearing methyl, tertiary butyl and dichloro-phenyl moieties on the triazole ring, respectively, were the compounds with the highest potential. They significantly inhibited c-Met by 55.3, 53.0 and 51.3%, respectively, at the concentration of 25 µM. Synthetic compounds showed antiproliferative effects against lung (EBC-1) and pancreatic cancer cells (AsPc-1, Suit-2 and Mia-PaCa-2) expressing different levels of c-Met, with IC50 values as low as 3.0 µM measured by sulforhodamine B assay. Active derivatives significantly blocked c-Met phosphorylation, inhibited cell growth in three-dimensional spheroid cultures and also induced apoptosis as revealed by Annexin V/propidium iodide flow cytometric assay in AsPc-1 cells. They also inhibited PDGFRA and FLT3 at 25 µM among a panel of 16 kinases. Molecular docking and dynamics simulation studies corroborated the experimental findings and revealed possible binding modes of the select derivatives with target receptor tyrosine kinases. The results of this study show that some imidazopyridine derivatives bearing 1,2,3-triazole moiety could be promising molecularly targeted anticancer agents against lung and pancreatic cancers.Tahereh DamghaniFatemeh MoosaviMehdi KhoshneviszadehMotahareh MortazaviSomayeh PirhadiZahra KayaniLuciano SasoNajmeh EdrakiOmidreza FiruziNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-20 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Tahereh Damghani Fatemeh Moosavi Mehdi Khoshneviszadeh Motahareh Mortazavi Somayeh Pirhadi Zahra Kayani Luciano Saso Najmeh Edraki Omidreza Firuzi Imidazopyridine hydrazone derivatives exert antiproliferative effect on lung and pancreatic cancer cells and potentially inhibit receptor tyrosine kinases including c-Met
description	Abstract Aberrant activation of c-Met signalling plays a prominent role in cancer development and progression. A series of 12 imidazo [1,2-α] pyridine derivatives bearing 1,2,3-triazole moiety were designed, synthesized and evaluated for c-Met inhibitory potential and anticancer effect. The inhibitory activity of all synthesized compounds against c-Met kinase was evaluated by a homogeneous time-resolved fluorescence (HTRF) assay at the concentration range of 5–25 µM. Derivatives 6d, 6e and 6f bearing methyl, tertiary butyl and dichloro-phenyl moieties on the triazole ring, respectively, were the compounds with the highest potential. They significantly inhibited c-Met by 55.3, 53.0 and 51.3%, respectively, at the concentration of 25 µM. Synthetic compounds showed antiproliferative effects against lung (EBC-1) and pancreatic cancer cells (AsPc-1, Suit-2 and Mia-PaCa-2) expressing different levels of c-Met, with IC50 values as low as 3.0 µM measured by sulforhodamine B assay. Active derivatives significantly blocked c-Met phosphorylation, inhibited cell growth in three-dimensional spheroid cultures and also induced apoptosis as revealed by Annexin V/propidium iodide flow cytometric assay in AsPc-1 cells. They also inhibited PDGFRA and FLT3 at 25 µM among a panel of 16 kinases. Molecular docking and dynamics simulation studies corroborated the experimental findings and revealed possible binding modes of the select derivatives with target receptor tyrosine kinases. The results of this study show that some imidazopyridine derivatives bearing 1,2,3-triazole moiety could be promising molecularly targeted anticancer agents against lung and pancreatic cancers.
format	article
author	Tahereh Damghani Fatemeh Moosavi Mehdi Khoshneviszadeh Motahareh Mortazavi Somayeh Pirhadi Zahra Kayani Luciano Saso Najmeh Edraki Omidreza Firuzi
author_facet	Tahereh Damghani Fatemeh Moosavi Mehdi Khoshneviszadeh Motahareh Mortazavi Somayeh Pirhadi Zahra Kayani Luciano Saso Najmeh Edraki Omidreza Firuzi
author_sort	Tahereh Damghani
title	Imidazopyridine hydrazone derivatives exert antiproliferative effect on lung and pancreatic cancer cells and potentially inhibit receptor tyrosine kinases including c-Met
title_short	Imidazopyridine hydrazone derivatives exert antiproliferative effect on lung and pancreatic cancer cells and potentially inhibit receptor tyrosine kinases including c-Met
title_full	Imidazopyridine hydrazone derivatives exert antiproliferative effect on lung and pancreatic cancer cells and potentially inhibit receptor tyrosine kinases including c-Met
title_fullStr	Imidazopyridine hydrazone derivatives exert antiproliferative effect on lung and pancreatic cancer cells and potentially inhibit receptor tyrosine kinases including c-Met
title_full_unstemmed	Imidazopyridine hydrazone derivatives exert antiproliferative effect on lung and pancreatic cancer cells and potentially inhibit receptor tyrosine kinases including c-Met
title_sort	imidazopyridine hydrazone derivatives exert antiproliferative effect on lung and pancreatic cancer cells and potentially inhibit receptor tyrosine kinases including c-met
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/e84ba50f01d64642a71fc85adbc1b611
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Imidazopyridine hydrazone derivatives exert antiproliferative effect on lung and pancreatic cancer cells and potentially inhibit receptor tyrosine kinases including c-Met

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