Study of the anticancer effect of new quinazolinone hydrazine derivatives as receptor tyrosine kinase inhibitors
The advent of novel receptor tyrosine kinase inhibitors has provided an important therapeutic tool for cancer patients. In this study, a series of quinazolinone hydrazide triazole derivatives were designed and synthesized as novel MET (c-MET) receptor tyrosine kinase inhibitors. The antiproliferativ...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-11-01
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| Series: | Frontiers in Chemistry |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fchem.2022.969559/full |
| _version_ | 1811224463684927488 |
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| author | Motahareh Mortazavi Masoumeh Divar Tahereh Damghani Fatemeh Moosavi Luciano Saso Somayeh Pirhadi Mehdi Khoshneviszadeh Mehdi Khoshneviszadeh Najmeh Edraki Omidreza Firuzi |
| author_facet | Motahareh Mortazavi Masoumeh Divar Tahereh Damghani Fatemeh Moosavi Luciano Saso Somayeh Pirhadi Mehdi Khoshneviszadeh Mehdi Khoshneviszadeh Najmeh Edraki Omidreza Firuzi |
| author_sort | Motahareh Mortazavi |
| collection | DOAJ |
| description | The advent of novel receptor tyrosine kinase inhibitors has provided an important therapeutic tool for cancer patients. In this study, a series of quinazolinone hydrazide triazole derivatives were designed and synthesized as novel MET (c-MET) receptor tyrosine kinase inhibitors. The antiproliferative effect of the synthesized compounds was examined against EBC-1, A549, HT-29 and U-87MG cells by MTT assay. MET kinase inhibitory effect was tested by a Homogenous Time Resolved Fluorescence (HTRF) assay. The antiproliferative effect of compounds in a three-dimensional spheroid culture was studied by acid phosphatase (APH) assay, while apoptosis induction was examined by Hoechst 33258 staining. We found that compound CM9 bearing p-bromo benzyl pendant inhibited MET kinase activity at the concentrations of 10–50 μM (% Inhibition = 37.1–66.3%). Compound CM9 showed antiproliferative effect against cancer cells, in particular lung cancer cells with MET amplification (EBC-1) with an IC50 value of 8.6 μM. Moreover, this derivative inhibited cell growth in spheroid cultures in a dose-dependent manner and induced apoptosis in cancer cells. Assessment of inhibitory effect of CM9 against a panel of 18 different protein kinases demonstrated that this compound also inhibits ALK, AXL, FGFR1, FLT1 (VEGFR1) and FLT4 (VEGFR3) more than 50% at 25 μM. Finally, molecular docking and dynamics simulation corroborated the experimental findings and showed critical structural features for the interactions between CM9 and target kinases. The findings of this study present quinazolinone hydrazide triazole derivatives as kinase inhibitors with considerable anticancer effects. |
| first_indexed | 2024-04-12T08:49:50Z |
| format | Article |
| id | doaj.art-cf100fbfe3654206af7467a5ea561e43 |
| institution | Directory Open Access Journal |
| issn | 2296-2646 |
| language | English |
| last_indexed | 2024-04-12T08:49:50Z |
| publishDate | 2022-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Chemistry |
| spelling | doaj.art-cf100fbfe3654206af7467a5ea561e432022-12-22T03:39:36ZengFrontiers Media S.A.Frontiers in Chemistry2296-26462022-11-011010.3389/fchem.2022.969559969559Study of the anticancer effect of new quinazolinone hydrazine derivatives as receptor tyrosine kinase inhibitorsMotahareh Mortazavi0Masoumeh Divar1Tahereh Damghani2Fatemeh Moosavi3Luciano Saso4Somayeh Pirhadi5Mehdi Khoshneviszadeh6Mehdi Khoshneviszadeh7Najmeh Edraki8Omidreza Firuzi9Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, IranMedicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, IranMedicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, IranMedicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, IranDepartment of Physiology and Pharmacology “Vittorio Erspamer”, Sapienza University of Rome, Rome, ItalyMedicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, IranMedicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, IranDepartment of Medicinal Chemistry, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, IranMedicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, IranMedicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, IranThe advent of novel receptor tyrosine kinase inhibitors has provided an important therapeutic tool for cancer patients. In this study, a series of quinazolinone hydrazide triazole derivatives were designed and synthesized as novel MET (c-MET) receptor tyrosine kinase inhibitors. The antiproliferative effect of the synthesized compounds was examined against EBC-1, A549, HT-29 and U-87MG cells by MTT assay. MET kinase inhibitory effect was tested by a Homogenous Time Resolved Fluorescence (HTRF) assay. The antiproliferative effect of compounds in a three-dimensional spheroid culture was studied by acid phosphatase (APH) assay, while apoptosis induction was examined by Hoechst 33258 staining. We found that compound CM9 bearing p-bromo benzyl pendant inhibited MET kinase activity at the concentrations of 10–50 μM (% Inhibition = 37.1–66.3%). Compound CM9 showed antiproliferative effect against cancer cells, in particular lung cancer cells with MET amplification (EBC-1) with an IC50 value of 8.6 μM. Moreover, this derivative inhibited cell growth in spheroid cultures in a dose-dependent manner and induced apoptosis in cancer cells. Assessment of inhibitory effect of CM9 against a panel of 18 different protein kinases demonstrated that this compound also inhibits ALK, AXL, FGFR1, FLT1 (VEGFR1) and FLT4 (VEGFR3) more than 50% at 25 μM. Finally, molecular docking and dynamics simulation corroborated the experimental findings and showed critical structural features for the interactions between CM9 and target kinases. The findings of this study present quinazolinone hydrazide triazole derivatives as kinase inhibitors with considerable anticancer effects.https://www.frontiersin.org/articles/10.3389/fchem.2022.969559/fullanticancer agentskinase inhibitorsmultitargeted compoundsdrug designthree-dimensional culture |
| spellingShingle | Motahareh Mortazavi Masoumeh Divar Tahereh Damghani Fatemeh Moosavi Luciano Saso Somayeh Pirhadi Mehdi Khoshneviszadeh Mehdi Khoshneviszadeh Najmeh Edraki Omidreza Firuzi Study of the anticancer effect of new quinazolinone hydrazine derivatives as receptor tyrosine kinase inhibitors Frontiers in Chemistry anticancer agents kinase inhibitors multitargeted compounds drug design three-dimensional culture |
| title | Study of the anticancer effect of new quinazolinone hydrazine derivatives as receptor tyrosine kinase inhibitors |
| title_full | Study of the anticancer effect of new quinazolinone hydrazine derivatives as receptor tyrosine kinase inhibitors |
| title_fullStr | Study of the anticancer effect of new quinazolinone hydrazine derivatives as receptor tyrosine kinase inhibitors |
| title_full_unstemmed | Study of the anticancer effect of new quinazolinone hydrazine derivatives as receptor tyrosine kinase inhibitors |
| title_short | Study of the anticancer effect of new quinazolinone hydrazine derivatives as receptor tyrosine kinase inhibitors |
| title_sort | study of the anticancer effect of new quinazolinone hydrazine derivatives as receptor tyrosine kinase inhibitors |
| topic | anticancer agents kinase inhibitors multitargeted compounds drug design three-dimensional culture |
| url | https://www.frontiersin.org/articles/10.3389/fchem.2022.969559/full |
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