Utilize este identificador para referenciar este registo:
https://hdl.handle.net/10216/120484
Autor(es): | Lopes A. Martins E. Silva R. Pinto M.M.M. Remião F. Sousa E. Fernandes C. |
Título: | Chiral Thioxanthones as Modulators of P-glycoprotein: Synthesis and Enantioselectivity Studies |
Editor: | MDPI |
Data de publicação: | 2018 |
Resumo: | Recently, thioxanthone derivatives were found to protect cells against toxic P-glycoprotein (P-gp) substrates, acting as potent inducers/activators of this efflux pump. The study of new P-gp chiral modulators produced from thioxanthone derivatives could clarify the enantioselectivity of this ABC transporter towards this new class of modulators. The aim of this study was to evaluate the P-gp modulatory ability of four enantiomeric pairs of new synthesized chiral aminated thioxanthones (ATxs) 1–8, studying the influence of the stereochemistry on P-gp induction/ activation in cultured Caco-2 cells. The data displayed that all the tested compounds (at 20 µM) significantly decreased the intracellular accumulation of a P-gp fluorescent substrate (rhodamine 123) when incubated simultaneously for 60 min, demonstrating an increased activity of the efflux, when compared to control cells. Additionally, all of them except ATx 3 (+), caused similar results when the accumulation of the P-gp fluorescent substrate was evaluated after pre-incubating cells with the test compounds for 24 h, significantly reducing the rhodamine 123 intracellular accumulation as a result of a significant increase in P-gp activity. However, ATx 2 (−) was the only derivative that, after 24 h of incubation, significantly increased P-gp expression. These results demonstrated a significantly increased P-gp activity, even without an increase in P-gp expression. Therefore, ATxs 1–8 were shown to behave as P-gp activators. Furthermore, no significant differences were detected in the activity of the protein when comparing the enantiomeric pairs. Nevertheless, ATx 2 (−) modulates P-gp expression differently from its enantiomer, ATx 1 (+). These results disclosed new activators and inducers of P-gp and highlight the existence of enantioselectivity in the induction mechanism. © 2018 by the authors. |
Assunto: | multidrug resistance protein 1 rhodamine 123 thioxanthene derivative thioxanthone xanthone derivative Caco-2 cell line chemical structure chemistry human metabolism synthesis upregulation ATP-Binding Cassette, Sub-Family B, Member 1 Caco-2 Cells Humans Molecular Structure Rhodamine 123 Thioxanthenes Up-Regulation Xanthones |
URI: | https://hdl.handle.net/10216/120484 |
Fonte: | Molecules, vol. 23(3):626 |
Informação Relacionada: | info:eu-repo/grantAgreement/FCT/5876/147268/PT |
Tipo de Documento: | Artigo em Revista Científica Internacional |
Condições de Acesso: | openAccess |
Aparece nas coleções: | CIIMAR - Artigo em Revista Científica Internacional |
Ficheiros deste registo:
Ficheiro | Descrição | Tamanho | Formato | |
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Lopes A_2018.pdf | 2.53 MB | Adobe PDF | Ver/Abrir |
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