Dual inhibitors of P-glycoprotein and tumor cell growth: (re)discovering thioxanthones

Palmeira, Andreia; Vasconcelos, M. Helena; Paiva, Ana; Fernandes, Miguel X.; Pinto, Madalena; Sousa, Emília

http://hdl.handle.net/10400.13/5022

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Authors

Palmeira, Andreia

Vasconcelos, M. Helena

Abstract(s)

For many pathologies, there is a crescent effort to design multiple ligands that interact with a wide variety of targets. 1-Aminated thioxanthone derivatives were synthesized and assayed for their in vitro dual activity as antitumor agents and P-glycoprotein (P-gp) inhibitors. The approach was based on molecular hybridization of a thioxanthone scaffold, present in known antitumor drugs, and an amine, described as an important pharmacophoric feature for P-gp inhibition. A rational approach using homology modeling and docking was used, to select the molecules to be synthesized by conventional or microwave-assisted Ullmann C–N cross-coupling reaction. The obtained aminated thioxanthones were highly effective at inhibiting P-gp and/or causing growth inhibition in a chronic myelogenous leukemia cell line, K562. Six of the aminated thioxanthones had GI50 values in the K562 cell line below 10 mM and 1-{[2-(diethylamino)ethyl]amino}-4-propoxy-9H-thioxanthen-9-one (37) had a GI50 concentration (1.90 mM) 6-fold lower than doxorubicin (11.89 mM) in the K562Dox cell line. The best P-gp inhibitor found was 1-[2-(1H-benzimidazol-2-yl)ethanamine]-4-propoxy-9H-thioxanthen-9-one (45), which caused an accumulation rate of rhodamine-123 similar to that caused by verapamil in the K562Dox resistant cell line, and a decrease in ATP consumption by P-gp. At a concentration of 10 mM, compound 45 caused a decrease of 12.5-fold in the GI50 value of doxorubicin in the K562Dox cell line, being 2-fold more potent than verapamil. From the overall results, the aminated thioxanthones represent a new class of P-gp inhibitors with improved efficacy in sensitizing a resistant P-gp overexpressing cell line (K562Dox) to doxorubicin.

Keywords

Thioxanthones P-glycoprotein Multidrug resistance Anticancer Dual ligands . Faculdade de ciências Exatas e da Engenharia

URI

http://hdl.handle.net/10400.13/5022

Citation

Palmeira, A., Vasconcelos, M. H., Paiva, A., Fernandes, M. X., Pinto, M., & Sousa, E. (2012). Dual inhibitors of P-glycoprotein and tumor cell growth:(re) discovering thioxanthones. Biochemical pharmacology, 83(1), 57-68.