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

• Tipo: Artigo em Revista Científica Internacional
• Data: 2012

Autores

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

Revista

Título: Biochemical Pharmacology

Vol. 83

Páginas: 57-68

ISSN: 0006-2952

Editora: Elsevier

Indexação

ISI Proceedings

ISI Web of Knowledge - 89 Citações

Scopus - 93 Citações

Classificação Científica

FOS: Ciências médicas e da saúde > Medicina básica

Outras Informações

ID Authenticus: 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.

Idioma: Inglês

Tipo (Avaliação Docente): Científica

Nº de páginas: 12