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

Emília Sousa*, Andreia Palmeira, Ana Sara Cordeiro, Bruno Sarmento, Domingos Ferreira, Raquel T. Lima, M. Helena Vasconcelos, Madalena Pinto

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

16 Citations (Scopus)


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 (Papp, 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.

Original languageEnglish
Pages (from-to)2115-2123
Number of pages9
JournalMedicinal Chemistry Research
Issue number5
Publication statusPublished - 01 May 2013
Externally publishedYes


  • Antitumor
  • P-glycoprotein
  • Permeability
  • Xanthones

ASJC Scopus subject areas

  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Organic Chemistry


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