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

• Type: Article in International Scientific Journal
• Date: 2012

Authors

Andreia Palmeira (Author) Other; Helena H Vasconcelos (Author) FFUP; Ana Paiva (Author) Other; Miguel X Fernandes (Author) Other; Madalena Pinto (Author) FFUP; Emilia Sousa (Author) FFUP

Journal

Title: Biochemical Pharmacology

Vol. 83

Pages: 57-68

ISSN: 0006-2952

Publisher: Elsevier

Indexing

ISI Proceedings

ISI Web of Knowledge - 89 Citations

Scopus - 93 Citations

Scientific classification

FOS: Medical and Health sciences > Basic medicine

Other information

Authenticus ID: P-002-HGZ

DOI: 10.1016/j.bcp.2011.10.004

Abstract (EN): 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 1(562 cell line below 10 mu M and 1-{[2-(diethylamino)ethyl]amino}-4-propoxy-9H-thioxanthen-9-one (37) had a GI(50) concentration (1.90 mu M) 6-fold lower than doxorubicin (11.89 mu M) 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 mu M, 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.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 12