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Open AccessFeature PaperArticle

Chiral Thioxanthones as Modulators of P-glycoprotein: Synthesis and Enantioselectivity Studies

Laboratory of Organic and Pharmaceutical Chemistry, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, Rua Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal
REQUIMTE, Laboratory of Toxicology, Department of Biological Sciences, FFUP – Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal
Interdisciplinary Centre of Marine and Environmental Research, University of Porto, Terminal de Cruzeiros do Porto de Leixões, Av. General Norton de Matos s/n, 4450-208 Matosinhos, Portugal
Authors to whom correspondence should be addressed.
Molecules 2018, 23(3), 626;
Received: 7 February 2018 / Revised: 5 March 2018 / Accepted: 7 March 2018 / Published: 10 March 2018
(This article belongs to the Special Issue Chirality in Health and Environment: Recent developments)
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) 18, 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 18 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. View Full-Text
Keywords: P-glycoprotein; thioxanthones; enantioselectivity; expression; activation P-glycoprotein; thioxanthones; enantioselectivity; expression; activation
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MDPI and ACS Style

Lopes, A.; Martins, E.; Silva, R.; Pinto, M.M.M.; Remião, F.; Sousa, E.; Fernandes, C. Chiral Thioxanthones as Modulators of P-glycoprotein: Synthesis and Enantioselectivity Studies. Molecules 2018, 23, 626.

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