title: Toxicity and cell cycle effects of synthetic 8-prenylnaringenin and derivatives in human cells.
abstract: The estrogenic flavanone rac-8-prenylnaringenin (8-PN) and 3 derivatives (rac-7-(O-prenyl)naringenin-4'-acetate (7-O-PN), rac-5-(O-prenyl)naringenin-4',7-diacetate (5-O-PN), and rac-6-(1,1-dimethylallyl)naringenin (6-DMAN) were prepared by chemical synthesis and analyzed with respect to their toxicity and possible cell cycle effects in human acute myeloid leukemia (HL-60) cells. With the exception of 5-O-PN, all the other naringenins showed only weak toxic effects at concentrations below 50 micromol/l. A cell cycle analysis over several cell generations up to 4 days was carried out using the fluorescent dye carboxyfluorescein diacetate N-succinimidyl ester (CFSE) followed by propidium iodide (PI) staining at the end of the experiment. The well-studied flavonol quercetin was included in the analysis as a reference substance. All flavonoids affected cell proliferation, but the extent and the resulting changes in the proliferation pattern were specific for each substance. In contrast to the radical scavenging activity of quercetin, the tested flavanones showed no anti-oxidative properties using several different test systems. Similarly, the mitochondrial membrane potential (DeltaPsim) was hardly effected by these compounds, while both menadione and quercetin strongly reduced the potential after 1 h of treatment. The reported chemical modification of interesting lead substances (like the strongly estrogenic 8-PN) presents a promising approach to modulate the properties of a relevant substance in a pharmacologically desirable way. The low toxicity and weak cytostatic properties of the tested naringenin derivatives is encouraging for further studies on known naringenin target molecules.
authors.affiliation: Institut für Zoologie, TU Dresden, Dresden, Germany. Herwig.Gutzeit@mailbox.tu-dresden.de
authors.forename: Sergey V
authors.initials: SV
authors.lastname: Tokalov
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Henker
authors.forename: Pia
authors.initials: P
authors.lastname: Schwab
authors.forename: Peter
authors.initials: P
authors.lastname: Metz
authors.forename: Herwig O
authors.initials: HO
authors.lastname: Gutzeit
mesh_terms: D001562:Benzimidazoles / Q000494:pharmacology; D001943:Breast Neoplasms / Q000473:pathology; D002232:Carbocyanines / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects*; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D044950:Flavanones / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity*; D005456:Fluorescent Dyes / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000737:chemistry / Q000494:pharmacology; D005859:Germany, East; D018922:HL-60 Cells; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D011794:Quercetin / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors; D013997:Time Factors; D024483:Vitamin K 3 / Q000494:pharmacology
chemical_list: C488178:5-(O-prenyl)naringenin-4',7-diacetate; C488177:7-(O-prenyl)naringenin; C119737:8-prenylnaringenin; D001562:Benzimidazoles; D002232:Carbocyanines; D044950:Flavanones; D005456:Fluorescent Dyes; D016166:Free Radical Scavengers; D017382:Reactive Oxygen Species; C068624:5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolocarbocyanine; D024483:Vitamin K 3; D011794:Quercetin; C005273:naringenin