Chiral Thioxanthones as Modulators of P-glycoprotein: Synthesis and Enantioselectivity Studies
AbstractRecently, 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. View Full-Text
Share & Cite This Article
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.
Lopes A, Martins E, Silva R, Pinto MMM, Remião F, Sousa E, Fernandes C. Chiral Thioxanthones as Modulators of P-glycoprotein: Synthesis and Enantioselectivity Studies. Molecules. 2018; 23(3):626.Chicago/Turabian Style
Lopes, Ana; Martins, Eva; Silva, Renata; Pinto, Madalena M.M.; Remião, Fernando; Sousa, Emília; Fernandes, Carla. 2018. "Chiral Thioxanthones as Modulators of P-glycoprotein: Synthesis and Enantioselectivity Studies." Molecules 23, no. 3: 626.
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.