Dual inhibitors of P-glycoprotein and tumor cell growth: (re)discovering thioxanthones
Autor(a) principal: | |
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Data de Publicação: | 2012 |
Outros Autores: | , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | http://hdl.handle.net/10400.13/5022 |
Resumo: | For many pathologies, there is a crescent effort to design multiple ligands that interact with a wide variety of targets. 1-Aminated thioxanthone derivatives were synthesized and assayed for their in vitro dual activity as antitumor agents and P-glycoprotein (P-gp) inhibitors. The approach was based on molecular hybridization of a thioxanthone scaffold, present in known antitumor drugs, and an amine, described as an important pharmacophoric feature for P-gp inhibition. A rational approach using homology modeling and docking was used, to select the molecules to be synthesized by conventional or microwave-assisted Ullmann C–N cross-coupling reaction. The obtained aminated thioxanthones were highly effective at inhibiting P-gp and/or causing growth inhibition in a chronic myelogenous leukemia cell line, K562. Six of the aminated thioxanthones had GI50 values in the K562 cell line below 10 mM and 1-{[2-(diethylamino)ethyl]amino}-4-propoxy-9H-thioxanthen-9-one (37) had a GI50 concentration (1.90 mM) 6-fold lower than doxorubicin (11.89 mM) in the K562Dox cell line. The best P-gp inhibitor found was 1-[2-(1H-benzimidazol-2-yl)ethanamine]-4-propoxy-9H-thioxanthen-9-one (45), which caused an accumulation rate of rhodamine-123 similar to that caused by verapamil in the K562Dox resistant cell line, and a decrease in ATP consumption by P-gp. At a concentration of 10 mM, compound 45 caused a decrease of 12.5-fold in the GI50 value of doxorubicin in the K562Dox cell line, being 2-fold more potent than verapamil. From the overall results, the aminated thioxanthones represent a new class of P-gp inhibitors with improved efficacy in sensitizing a resistant P-gp overexpressing cell line (K562Dox) to doxorubicin. |
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Dual inhibitors of P-glycoprotein and tumor cell growth: (re)discovering thioxanthonesThioxanthonesP-glycoproteinMultidrug resistanceAnticancerDual ligands.Faculdade de ciências Exatas e da EngenhariaFor many pathologies, there is a crescent effort to design multiple ligands that interact with a wide variety of targets. 1-Aminated thioxanthone derivatives were synthesized and assayed for their in vitro dual activity as antitumor agents and P-glycoprotein (P-gp) inhibitors. The approach was based on molecular hybridization of a thioxanthone scaffold, present in known antitumor drugs, and an amine, described as an important pharmacophoric feature for P-gp inhibition. A rational approach using homology modeling and docking was used, to select the molecules to be synthesized by conventional or microwave-assisted Ullmann C–N cross-coupling reaction. The obtained aminated thioxanthones were highly effective at inhibiting P-gp and/or causing growth inhibition in a chronic myelogenous leukemia cell line, K562. Six of the aminated thioxanthones had GI50 values in the K562 cell line below 10 mM and 1-{[2-(diethylamino)ethyl]amino}-4-propoxy-9H-thioxanthen-9-one (37) had a GI50 concentration (1.90 mM) 6-fold lower than doxorubicin (11.89 mM) in the K562Dox cell line. The best P-gp inhibitor found was 1-[2-(1H-benzimidazol-2-yl)ethanamine]-4-propoxy-9H-thioxanthen-9-one (45), which caused an accumulation rate of rhodamine-123 similar to that caused by verapamil in the K562Dox resistant cell line, and a decrease in ATP consumption by P-gp. At a concentration of 10 mM, compound 45 caused a decrease of 12.5-fold in the GI50 value of doxorubicin in the K562Dox cell line, being 2-fold more potent than verapamil. From the overall results, the aminated thioxanthones represent a new class of P-gp inhibitors with improved efficacy in sensitizing a resistant P-gp overexpressing cell line (K562Dox) to doxorubicin.ElsevierDigitUMaPalmeira, AndreiaVasconcelos, M. HelenaPaiva, AnaFernandes, Miguel X.Pinto, MadalenaSousa, Emília2023-02-09T14:44:55Z20122012-01-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10400.13/5022engPalmeira, A., Vasconcelos, M. H., Paiva, A., Fernandes, M. X., Pinto, M., & Sousa, E. (2012). Dual inhibitors of P-glycoprotein and tumor cell growth:(re) discovering thioxanthones. Biochemical pharmacology, 83(1), 57-68.10.1016/j.bcp.2011.10.004info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-02-12T03:31:10Zoai:digituma.uma.pt:10400.13/5022Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T16:46:29.906794Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
dc.title.none.fl_str_mv |
Dual inhibitors of P-glycoprotein and tumor cell growth: (re)discovering thioxanthones |
title |
Dual inhibitors of P-glycoprotein and tumor cell growth: (re)discovering thioxanthones |
spellingShingle |
Dual inhibitors of P-glycoprotein and tumor cell growth: (re)discovering thioxanthones Palmeira, Andreia Thioxanthones P-glycoprotein Multidrug resistance Anticancer Dual ligands . Faculdade de ciências Exatas e da Engenharia |
title_short |
Dual inhibitors of P-glycoprotein and tumor cell growth: (re)discovering thioxanthones |
title_full |
Dual inhibitors of P-glycoprotein and tumor cell growth: (re)discovering thioxanthones |
title_fullStr |
Dual inhibitors of P-glycoprotein and tumor cell growth: (re)discovering thioxanthones |
title_full_unstemmed |
Dual inhibitors of P-glycoprotein and tumor cell growth: (re)discovering thioxanthones |
title_sort |
Dual inhibitors of P-glycoprotein and tumor cell growth: (re)discovering thioxanthones |
author |
Palmeira, Andreia |
author_facet |
Palmeira, Andreia Vasconcelos, M. Helena Paiva, Ana Fernandes, Miguel X. Pinto, Madalena Sousa, Emília |
author_role |
author |
author2 |
Vasconcelos, M. Helena Paiva, Ana Fernandes, Miguel X. Pinto, Madalena Sousa, Emília |
author2_role |
author author author author author |
dc.contributor.none.fl_str_mv |
DigitUMa |
dc.contributor.author.fl_str_mv |
Palmeira, Andreia Vasconcelos, M. Helena Paiva, Ana Fernandes, Miguel X. Pinto, Madalena Sousa, Emília |
dc.subject.por.fl_str_mv |
Thioxanthones P-glycoprotein Multidrug resistance Anticancer Dual ligands . Faculdade de ciências Exatas e da Engenharia |
topic |
Thioxanthones P-glycoprotein Multidrug resistance Anticancer Dual ligands . Faculdade de ciências Exatas e da Engenharia |
description |
For many pathologies, there is a crescent effort to design multiple ligands that interact with a wide variety of targets. 1-Aminated thioxanthone derivatives were synthesized and assayed for their in vitro dual activity as antitumor agents and P-glycoprotein (P-gp) inhibitors. The approach was based on molecular hybridization of a thioxanthone scaffold, present in known antitumor drugs, and an amine, described as an important pharmacophoric feature for P-gp inhibition. A rational approach using homology modeling and docking was used, to select the molecules to be synthesized by conventional or microwave-assisted Ullmann C–N cross-coupling reaction. The obtained aminated thioxanthones were highly effective at inhibiting P-gp and/or causing growth inhibition in a chronic myelogenous leukemia cell line, K562. Six of the aminated thioxanthones had GI50 values in the K562 cell line below 10 mM and 1-{[2-(diethylamino)ethyl]amino}-4-propoxy-9H-thioxanthen-9-one (37) had a GI50 concentration (1.90 mM) 6-fold lower than doxorubicin (11.89 mM) in the K562Dox cell line. The best P-gp inhibitor found was 1-[2-(1H-benzimidazol-2-yl)ethanamine]-4-propoxy-9H-thioxanthen-9-one (45), which caused an accumulation rate of rhodamine-123 similar to that caused by verapamil in the K562Dox resistant cell line, and a decrease in ATP consumption by P-gp. At a concentration of 10 mM, compound 45 caused a decrease of 12.5-fold in the GI50 value of doxorubicin in the K562Dox cell line, being 2-fold more potent than verapamil. From the overall results, the aminated thioxanthones represent a new class of P-gp inhibitors with improved efficacy in sensitizing a resistant P-gp overexpressing cell line (K562Dox) to doxorubicin. |
publishDate |
2012 |
dc.date.none.fl_str_mv |
2012 2012-01-01T00:00:00Z 2023-02-09T14:44:55Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/10400.13/5022 |
url |
http://hdl.handle.net/10400.13/5022 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
Palmeira, A., Vasconcelos, M. H., Paiva, A., Fernandes, M. X., Pinto, M., & Sousa, E. (2012). Dual inhibitors of P-glycoprotein and tumor cell growth:(re) discovering thioxanthones. Biochemical pharmacology, 83(1), 57-68. 10.1016/j.bcp.2011.10.004 |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
application/pdf |
dc.publisher.none.fl_str_mv |
Elsevier |
publisher.none.fl_str_mv |
Elsevier |
dc.source.none.fl_str_mv |
reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação instacron:RCAAP |
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Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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RCAAP |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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