Insights into the In Vitro Antitumor Mechanism of Action of a New Pyranoxanthone

• Type: Article in International Scientific Journal
• Date: 2010

Authors

Andreia Palmeira (Author) Other; Ana Paiva (Author) Other; Emilia Sousa (Author) FFUP; Hugo Seca (Author) Other; Gabriela M Almeida (Author) Other; Raquel T Lima (Author) Other; Miguel X Fernandes (Author) Other; Madalena Pinto (Author) FFUP; Helena H Vasconcelos (Author) FFUP

Journal

Title: Chemical Biology and Drug Design

Vol. 76

Pages: 43-58

ISSN: 1747-0277

Publisher: Wiley-Blackwell

Indexing

ISI Proceedings

ISI Web of Knowledge - 40 Citations

Scopus - 40 Citations

Scientific classification

FOS: Medical and Health sciences > Basic medicine

Other information

Authenticus ID: P-003-53N

DOI: 10.1111/j.1747-0285.2010.00978.x

Abstract (EN): Naturally occurring xanthones have been documented as having antitumor properties, with some of them presently undergoing clinical trials. In an attempt to improve the biological activities of dihydroxyxanthones, prenylation and other molecular modifications were performed. All the compounds reduced viable cell number in a leukemia cell line K-562, with the fused xanthone 3,4-dihydro-12-hydroxy-2,2-dimethyl-2H,6H-pyrano[3,2-b]xanthen-6-one (5) being the most potent. The pyranoxanthone 5 was particularly effective in additional leukemia cell lines (HL-60 and BV-173). Furthermore, the pyranoxanthone 5 decreased cellular proliferation and induced an S-phase cell cycle arrest. In vitro, the pyranoxanthone 5 increased the percentage of apoptotic cells which was confirmed by an appropriate response at the protein level (e.g., PARP cleavage). Using a computer screening strategy based on the structure of several anti- and pro-apoptotic proteins, it was verified that the pyranoxanthone 5 may block the binding of anti-apoptotic Bcl-xL to pro-apoptotic Bad and Bim. The structure-based screening revealed the pyranoxanthone 5 as a new scaffold that may guide the design of small molecules with better affinity profile for Bcl-xL.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 16