title: Structure-activity relationships of flavonoid-induced cytotoxicity on human leukemia cells.
abstract: The aim of this study was to identify structure elements in flavonoids that are associated with enhanced cytotoxic activity. We determined the cytotoxicity (EC(50)) of 23 different flavonoids, including O-methylated and glucuronidated metabolites, on the human leukemia cell line Jurkat E6-1 by analyzing cell death triggered after 24 and 48 h. By comparing the cytotoxicity of selected molecules that differ in only one structure element, we identified several structure-function relationships associated with enhanced cytotoxicity, including the presence of a 2-3 double bond, the presence of a 4-carbonyl group and ortho- compared to meta-hydroxylation in the B ring. Molecules with a 3-hydroxyl group exhibited significantly lower cytotoxicity than their non-hydroxylated counterparts. O-Methylation and glucuronidation were associated with a significant increase in cytotoxicity, suggesting that metabolites found in vivo are more active than unmodified flavonoids. We identified the solubility maximum of the tested flavonoids in culture medium and found a negative correlation between maximum solubility and cytotoxicity. The results of our study may help to identify novel flavonoid structures with optimized cytotoxic activity to be tested for anti-cancer treatment.
authors.affiliation: University of Wurzburg, Institute of Food Chemistry, Am Hubland, 97074 Wurzburg, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Plochmann
authors.forename: Gabriele
authors.initials: G
authors.lastname: Korte
authors.forename: Eleni
authors.initials: E
authors.lastname: Koutsilieri
authors.forename: Elke
authors.initials: E
authors.lastname: Richling
authors.forename: Peter
authors.initials: P
authors.lastname: Riederer
authors.forename: Axel
authors.initials: A
authors.lastname: Rethwilm
authors.forename: Peter
authors.initials: P
authors.lastname: Schreier
authors.forename: Carsten
authors.initials: C
authors.lastname: Scheller
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000627:therapeutic use / Q000633:toxicity*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D005419:Flavonoids / Q000737:chemistry* / Q000627:therapeutic use / Q000633:toxicity*; D006801:Humans; D006900:Hydroxylation; D019169:Jurkat Cells; D007938:Leukemia / Q000188:drug therapy; D012995:Solubility; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D005419:Flavonoids