Bioactive xanthones with effect on P-glycoprotein and prediction of intestinal absorption

• Type: Article in International Scientific Journal
• Date: 2013

Authors

Emilia Sousa (Author) FFUP; Andreia Palmeira (Author) Other; Ana Sara Cordeiro (Author) Other; Bruno Sarmento (Author) Other; Domingos Ferreira (Author) FFUP; Raquel T Lima (Author) Other; Helena Vasconcelos, MH (Author) FFUP; Madalena Pinto (Author) FFUP

Journal

Title: Medicinal Chemistry Research

Vol. 22

Pages: 2115-2123

ISSN: 1054-2523

Publisher: Springer Nature

Indexing

ISI Proceedings

ISI Web of Knowledge - 17 Citations

Scopus - 17 Citations

Scientific classification

FOS: Medical and Health sciences > Basic medicine

Other information

Authenticus ID: P-005-1E4

DOI: 10.1007/s00044-012-0203-y

Abstract (EN): Our research group has been focusing in the discovery of potential antitumor small molecules based on the xanthone scaffold. However, a serious obstacle in the field of cancer therapy is the multidrug resistance (MDR) phenotype, most often caused by the overexpression of P-glycoprotein (P-gp). Another limitation to development of such drug candidates is the reduced information available about the bioavailability of these compounds. We have previously identified four interesting compounds as inhibitors of tumor cell growth namely two dihydroxyxanthones, a xanthonolignoid and a pyranoxanthone. Based on these considerations, it was our aim to: (i) investigate their effect on the P-gp activity; and (ii) estimate their intestinal absorption using Caco-2 cell monolayers as an intestinal model. An HPLC analysis from the in vitro permeation assay with Caco-2 cells monolayer was performed to predict the intestinal permeability of xanthonic derivatives. A rhodamine (Rh123) accumulation assay using P-gp overexpressing leukemia cells, K562Dox, incubated with the four xanthonic derivatives, was performed to investigate their P-gp inhibitory activity. A luminescence-based ATPase assay was performed to differentiate between competitive and noncompetitive P-gp inhibitors. The xanthonolignoid and the pyranoxanthone were found to increase the accumulation of Rh123 in K562Dox cell line, and both were acting by a noncompetitive P-gp inhibitory mechanism. Transport of the four xanthones occurred in the absorptive direction (P-app, 0.012-2.8 nm/s). The behavior of the xanthonolignoid and the pyranoxanthone as P-gp inhibitors and their high apparent permeability coefficients make them promising hit compounds to pursue with further studies.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 9