title: The substitution pattern of anthocyanidins affects different cellular signaling cascades regulating cell proliferation.
abstract: The aglycons of the most abundant anthocyanins in food, cyanidin (cy) and delphinidin (del), represent potent inhibitors of the epidermal growth factor receptor (EGFR). Structure-activity studies show that the presence of vicinal hydroxy substituents at the phenyl ring at the 2-position (B-ring) is crucial for target interaction. The presence of a single hydroxy group or introduction of methoxy substituents at the B-ring results in a substantial loss of inhibitory properties. However, biological activity is not exclusively limited to compounds bearing vicinal hydroxy groups. A contradictory structure-activity relationship is observed for the inhibition of cAMP-specific phosphodiesterases (PDEs). Of the anthocyanidins tested, malvidin, bearing methoxy substituents in the 3'- and 5'-positions, most effectively inhibited cAMP hydrolysis. The absence of methoxy groups and/or replacement by hydroxy substituents was found to strongly diminish PDE-inhibitory properties. We found that either effective EGFR inhibition or effective PDE inhibition is required to achieve a shut-down of the central mitogen-activated protein kinase (MAPK) pathway, a signaling cascade crucial for the regulation of cell growth. This is consistent with the finding that efficient reduction of cell growth is limited to anthocyanidins that are potent EGFR- or PDE-inhibitors including cy and del or malvidin (mv), respectively. In summary, depending on the substitution pattern at the B-ring, anthocyanidins interfere with different signaling cascades involved in the regulation of cell growth.
authors.affiliation: Department of Chemistry, Division of Food Chemistry and Environmental Toxicology, University of Kaiserslautern, Kaiserslautern, Germany. marko@rhrk.uni-kl.de
authors.forename: Doris
authors.initials: D
authors.lastname: Marko
authors.forename: Nicole
authors.initials: N
authors.lastname: Puppel
authors.forename: Zeina
authors.initials: Z
authors.lastname: Tjaden
authors.forename: Sandra
authors.initials: S
authors.lastname: Jakobs
authors.forename: Gudrun
authors.initials: G
authors.lastname: Pahlke
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors; D000872:Anthocyanins / Q000737:chemistry* / Q000494:pharmacology*; D002455:Cell Division / Q000502:physiology*; D000242:Cyclic AMP / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D005260:Female; D006801:Humans; D006868:Hydrolysis; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D014846:Vulvar Neoplasms
chemical_list: D000872:Anthocyanins; D004791:Enzyme Inhibitors; C065861:malvidin; D000242:Cyclic AMP; D066246:ErbB Receptors; D015105:3',5'-Cyclic-AMP Phosphodiesterases