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

• Published in: Biochemical pharmacology Vol. 83; no. 1; pp. 57 - 68
• Main Authors: Palmeira, Andreia, Vasconcelos, M. Helena, Paiva, Ana, Fernandes, Miguel X., Pinto, Madalena, Sousa, Emília
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Inc 2012; Elsevier
• Subjects: antagonists & inhibitors; Anticancer; anticarcinogenic activity; Antineoplastic Agents; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP-Binding Cassette, Sub-Family B, Member 1 - antagonists & inhibitors; ATP-Binding Cassette, Sub-Family B, Member 1 - physiology; Biological and medical sciences; cell growth; chemistry; doxorubicin; Drug Discovery; Drug Discovery - trends; Dual ligands; Growth Inhibitors; Growth Inhibitors - chemistry; Growth Inhibitors - pharmacology; growth retardation; Humans; K562 Cells; leukemia; Medical sciences; microwave treatment; Multidrug resistance; P-glycoprotein; pharmacology; Pharmacology. Drug treatments; physiology; Thioxanthenes; Thioxanthenes - chemistry; Thioxanthenes - pharmacology; Thioxanthones; trends; verapamil; Xanthones; Xanthones - chemistry; Xanthones - pharmacology; ABC; SRB; P-gp; Multidrug resistance; MRP; MW; RMSD; TMD; MRP-1; Thioxanthones; Rh123; P-glycoprotein; MFI; NBD; SE; GI 50; DNA; Dual ligands; TM; MDR; RLU; Anticancer; ATP; BLAST; Antineoplastic agent; Cell proliferation; Treatment resistance; Ligand; P Glycoprotein; Malignant tumor; Tumor growth; Multiple resistance; Inhibitor; Tumor cell; Cancer
• ISSN: 0006-2952; 1873-2968; 1873-2968
• DOI: 10.1016/j.bcp.2011.10.004

1-Aminated thioxanthones are dual inhibitors of P-glycoprotein and tumor cell growth. 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 GI 50 values in the K562 cell line below 10 μM and 1-{[2-(diethylamino)ethyl]amino}-4-propoxy-9 H-thioxanthen-9-one ( 37) had a GI 50 concentration (1.90 μM) 6-fold lower than doxorubicin (11.89 μM) in the K562Dox cell line. The best P-gp inhibitor found was 1-[2-(1 H-benzimidazol-2-yl)ethanamine]-4-propoxy-9 H-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 μM, compound 45 caused a decrease of 12.5-fold in the GI 50 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.