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.
Highlights
P-glycoprotein (P-gp) is the best characterized efflux transporter belonging to the superfamily of ATP-binding cassette (ABC) transporters [1,2,3,4]
The new chiral aminated thioxanthones (ATxs) 1–8 were synthesized by copper-catalyzed Ullmann cross-coupling reactions between the thioxanthone derivative 1-chloro-4-propoxy-9H-thioxanthen-9-one (Tx) and reactions between the thioxanthone derivative (Tx) and eight enantiomerically pure amino alcohols
In order to accomplish the main aim of this study, four enantiomeric pairs of thioxanthones were synthesized through a copper catalyzed Ullman asymmetric coupling reaction that provided the desired chiral thioxanthones with an e.e. > 99%
Summary
P-glycoprotein (P-gp) is the best characterized efflux transporter belonging to the superfamily of ATP-binding cassette (ABC) transporters [1,2,3,4]. Molecules 2018, 23, 626; doi:10.3390/molecules23030626 www.mdpi.com/journal/molecules (TMD), formed of six membrane-spanning α helices (TMHs), and a nucleotide binding domain (NBD), located at the cytoplasmic side of the membrane [4,8,9,10] This 170 kDa protein, known as ABCB1, is encoded in humans by the multidrug resistance (MDR) genes MDR1 (ABCB1) and MDR3 (ABCB4), being the multidrug resistance (MDR) phenotype associated with the ABCB1 isoform. Using the energy from ATP hydrolysis, the P-gp promotes the outward transport of a large range of structurally unconnected compounds [4,7,13] It plays important physiological functions, being its primary function to protect the cells against toxic xenobiotics and endogenous metabolites [1,7]. When a drug that is a P-gp substrate is co-administrated with another drug, a P-gp inducer, activator or inhibitor, the pharmacokinetics and bioavailability of the P-gp substrate may be substantially altered [16,18]
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