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Author(s): Lopes A.
Martins E.
Silva R.
Pinto M.M.M.
Remião F.
Sousa E.
Fernandes C.
Title: Chiral Thioxanthones as Modulators of P-glycoprotein: Synthesis and Enantioselectivity Studies
Publisher: MDPI
Issue Date: 2018
Abstract: 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.
Subject: multidrug resistance protein 1
rhodamine 123
thioxanthene derivative
xanthone derivative
Caco-2 cell line
chemical structure
ATP-Binding Cassette, Sub-Family B, Member 1
Caco-2 Cells
Molecular Structure
Rhodamine 123
Source: Molecules, vol. 23(3):626
Related Information: info:eu-repo/grantAgreement/FCT/5876/147268/PT
Document Type: Artigo em Revista Científica Internacional
Rights: openAccess
Appears in Collections:CIIMAR - Artigo em Revista Científica Internacional

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