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

Abstract

P-glycoprotein (P-gp) plays a crucial role in the protection of susceptible organs, by significantly decreasing the absorption/distribution of harmful xenobiotics and, consequently, their toxicity. Therefore, P-gp has been proposed as a potential antidotal pathway, when activated and/or induced. Knowing that xanthones are known to interact with P-gp, the main goal was to study P-gp induction or/and activation by six new oxygenated xanthones (OX 1-6). Furthermore, the potential protection of Caco-2 cells against paraquat cytotoxicity was also assessed. The most promising compound was further tested for its ability to increase P-gp activity ex vivo, using everted intestinal sacs from adult Wistar-Han rats. The oxygenated xanthones interacted with P-gp in vitro, increasing P-gp expression and/or activity 24 h after exposure. Additionally, after a short-incubation period, several xanthones were identified as P-gp activators, as they immediately increased P-gp activity. Moreover, some xanthones decreased PQ cytotoxicity towards Caco-2 cells, an effect prevented under P-gp inhibition. Ex vivo, a significant increase in P-gp activity was observed in the presence of OX6, which was selectively blocked by a model P-gp inhibitor, zosuquidar, confirming the in vitro results. Docking simulations between a validated P-gp model and the tested xanthones predicted these interactions, and these compounds also fitted onto previously described P-gp induction and activation pharmacophores. In conclusion, the in vitro, ex vivo, and in silico results suggest the potential of some of the oxygenated xanthones in the modulation of P-gp, disclosing new perspectives in the therapeutics of intoxications by P-gp substrates.

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

“…This chemical collection of pure xanthones (>95%) was submitted to several screenings to discover their biological activities which allowed to build quantitative structure–activity relationship [(Q)SAR] models and to establish pharmacophores for antitumor [ 48 ], antioxidant [ 49 ], hepatoprotection [ 50 ], antifungal [ 29 , 51 ], antibacterial [ 52 , 53 ], antiobesity [ 54 ], antifouling [ 55 ] activities and/or targets such as monoaminoxidase (MAO) [ 56 ], P-glycoprotein (P-gp) [ 57 , 58 ], protein kinase C (PKC) [ 59 , 60 ], tyrosinase [ 61 ], over these two last decades. Moreover, from these studies several simple oxygenated ( Figure 4 ) or more complex hit compounds emerged that were additionally investigated in many directions, namely for further molecular modifications [ 62 ], for their cellular and molecular mechanism of actions [ 63 , 64 ], for their ADMET properties [ 65 , 66 , 67 ], for chromatographic applications [ 68 , 69 ] and for their incorporation in nanoformulations [ 70 , 71 ].…”

“…While showing favourable permeability parameters, the ability of dihydroxylated xanthones for P-gp activation was disclosed with 3,6-dihydroxyxanthone ( 8 ) being the most active. Further studies pointed their putative application as antidotes of paraquat, by protection against the cytotoxicity induced by this pesticide P-gp substrate [ 57 , 58 , 74 ].…”

Synthesis, Biological Evaluation, and In Silico Studies of Novel Aminated Xanthones as Potential p53-Activating Agents

“…Subsequent intramolecular nucleophilic aromatic substitution followed by elimination of methanol under basic conditions and microwave (MW) irradiation provided the 3,4-dimethoxy-1-methyl-9 H -xanthen-9-one ( 27 ) in good yield quantity. This two-step methodology for the construction of xanthone analogues of 27 has been previously described in the literature [32,41,42,43]. With the application of MW methodology in the basic cyclization of 26 instead of the conventional heating employed in the synthesis of 23 , the reaction time was reduced from 48 h to 6 h. Furthermore, xanthone 27 was obtained in higher reaction yield under MW irradiation (63% yield ( 27 ) vs. 38% yield ( 23 )).…”

Novel Intrinsic Mechanisms of Active Drug Extrusion at the Blood-Brain Barrier: Potential Targets for Enhancing Drug Delivery to the Brain?

“…In addition to transcriptional, posttranscriptional, and traditional posttranslational mechanisms that increase Pgp expression in the apical plasma membrane of BCECs, a new class of compounds has recently been identified (and designated as Pgp activators) that immediately increase Pgp activity without increasing its protein expression [ 20 , 57 , 58 ]. Such compounds act by binding to a specific ligand-binding site, inducing a conformational change in Pgp that stimulates the efflux of a substrate bound on another ligand-binding site.…”