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

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.

Newly Synthesized Oxygenated Xanthones as Potential P-Glycoprotein Activators: In Vitro, Ex Vivo, and In Silico Studies

“…The results obtained concerning the evaluation of the OXs’ effects on P-gp expression and activity further reinforce that this approach of evaluation of both parameters has an important impact on the evaluation of the modulatory potential of new compounds. Furthermore, the data is in accordance with other reports that also suggest that alterations in P-gp expression do not linearly translate into similar changes in P-gp transport activity (which could be due to an insufficient time to guarantee complete protein function or incomplete membrane targeting) and increases in P-gp activity may occur without changes in protein expression [21,26,27,39]. In fact, Silva et al observed in Caco-2 cells that the strong increases in P-gp expression levels after exposure to doxorubicin (Dox) (reaching 646% after 24 h of incubation with 100 μM Dox when compared to control cells (100%)) were not translated into proportional increases in P-gp transport activity (150% after a 24 h incubation period with 100 μM Dox, when compared to control cells (100%)) [21].…”

From Natural Products to New Synthetic Small Molecules: A Journey through the World of Xanthones

“…Therefore, these thioxanthones were shown to behave as P-gp activators, increasing the efflux of substrates without interfering with P-gp levels of expression. Moreover, ( R )-1-((1-hydroxypropan-2-yl)amino)-4-propoxy-9 H -thioxanthen-9-one ( 89 ), after 24 h of incubation, was also able to significantly increased P-gp expression (P-gp inducer) [ 181 ]. Concerning thioxanthones induction mechanism, one of the possibilities is the transcriptional activation of the MDR1 gene expression that involves the activation of the pregnane X receptor (PXR) [ 182 , 183 ].…”

“…Concerning thioxanthones induction mechanism, one of the possibilities is the transcriptional activation of the MDR1 gene expression that involves the activation of the pregnane X receptor (PXR) [ 182 , 183 ]. Furthermore, no significant differences were detected in the activity of the enantiomeric pairs towards P-gp [ 181 ]. Still concerning P-gp induction in other organisms, using high throughput RNA sequencing, the transcriptional response of the filamentous fungus Neurospora crassa to thioxanthone derivatives with antitumor activity ( 75 , 81 , and 86 ) revealed that there is an induction of ABC transporters in that fungus, particularly atrb and cdr4, which is a common consequence of the treatment with (thio)xanthones [ 94 ].…”

Similar Safety Profile of the Enantiomeric N-Aminoalkyl Derivatives of Trans-2-Aminocyclohexan-1-ol Demonstrating Anticonvulsant Activity

“…Therefore, it was demonstrated that both enantiomers possess P-gp inhibition ability, with R enantiomer being more potent. It was demonstrated previously that P-gp can interact in a different way with enantiomers [48,49,50]. When chiral drugs modulate P-gp, one enantiomer can increase the activity of the pump, while the other enantiomer can inhibit its activity [51,52].…”