title: Insights into the in vitro antitumor mechanism of action of a new pyranoxanthone.
abstract: 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.
authors.affiliation: Department of Chemistry, Laboratory of Organic and Pharmaceutical Chemistry, Faculty of Pharmacy, University of Porto, 4050-047 Porto, Portugal.
authors.forename: Andreia
authors.initials: A
authors.lastname: Palmeira
authors.forename: Ana
authors.initials: A
authors.lastname: Paiva
authors.forename: Emília
authors.initials: E
authors.lastname: Sousa
authors.forename: Hugo
authors.initials: H
authors.lastname: Seca
authors.forename: Gabriela M
authors.initials: GM
authors.lastname: Almeida
authors.forename: Raquel T
authors.initials: RT
authors.lastname: Lima
authors.forename: Miguel X
authors.initials: MX
authors.lastname: Fernandes
authors.forename: Madalena
authors.initials: M
authors.lastname: Pinto
authors.forename: M Helena
authors.initials: MH
authors.lastname: Vasconcelos
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007938:Leukemia / Q000188:drug therapy*; D008958:Models, Molecular; D044004:Xanthones / Q000737:chemistry* / Q000494:pharmacology*; D051020:bcl-X Protein / Q000737:chemistry / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D044004:Xanthones; D051020:bcl-X Protein