title: Dual inhibitors of P-glycoprotein and tumor cell growth: (re)discovering thioxanthones.
abstract: 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-9H-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-(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 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.
authors: Departamento de Química, Laboratório de Química Orgânica e Farmacêutica, Faculdade de Farmácia, Universidade do Porto, Portugal. apalmeira@ff.up.pt
authors: Andreia
authors: A
authors: Palmeira
authors: M Helena
authors: MH
authors: Vasconcelos
authors: Ana
authors: A
authors: Paiva
authors: Miguel X
authors: MX
authors: Fernandes
authors: Madalena
authors: M
authors: Pinto
authors: Emília
authors: E
authors: Sousa
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000502:physiology; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D055808:Drug Discovery / Q000639:trends*; D006131:Growth Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D020014:K562 Cells; D013892:Thioxanthenes / Q000737:chemistry / Q000494:pharmacology; D044004:Xanthones / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D006131:Growth Inhibitors; D013892:Thioxanthenes; D044004:Xanthones; C484911:thioxanthone