A practical access to highly enantiomerically pure flavanones by catalytic asymmetric transfer hydrogenation.

A surprisingly selective, non-enzymatic kinetic resolution of readily available, racemic β-chiral ketones enabled the title process, which was applied to a rapid synthesis of several bioactive flavanones in virtually enantiopure form (see scheme; MOM=methoxymethyl, Ts=p-toluenesulfonyl).

Effects of the chemically synthesized flavanone 7-(O-prenyl)naringenin-4'-acetate on the estrogen signaling pathway in vivo and in vitro.

The flavanone naringenin is known to possess only weak estrogenic properties, but some of its derivatives such as 8-prenylnaringenin are potent phytoestrogens. The aim of this study was to further clarify structure-function relationships of flavanones regarding their estrogenic or antiestrogenic properties by characterizing the new chemically synthesized naringenin derivative 7-(O-prenyl)naringenin-4'-acetate (7-O-PN). A yeast based reporter gene assay and MVLN cells, a MCF-7-derived cell line that possesses a luciferase reporter gene under the control of a vitellogenin estrogen responsive element, were used to investigate estrogenic actions of 7-O-PN in vitro.

Naringenin-type flavonoids show different estrogenic effects in mammalian and teleost test systems.

The estrogenic activity of several intermediary plant compounds has raised concern about possible risks of unwanted interference with endocrine regulation, but on the other hand there are potential medical benefits, in particular in treatment of menopausal symptoms or cancer. In the present study, we compare the estrogenic effects of phytoestrogens naringenin, 8-prenylnaringenin, 6-(1,1-dimethylallyl)naringenin, and the synthetic 4'-acetyl-7-prenyloxynaringenin. Two mammalian in vitro systems and a fish in vivo system were used to study the estrogenic properties with reference to genistein, 17-beta-estradiol or ethynylestradiol.

Two major metabolites of 8-prenylnaringenin are estrogenic in vitro.

8-prenylnaringenin (8-PN) and preparations containing 8-prenylnaringenin have been suggested for use in medicinal and cosmetic applications like hormone replacement or bust enhancement. However, the safety of application is still under considerable debate. Recently it has been shown that human liver microsomes are converting 8-prenylnaringenin to 12 metabolites, with (E)-8-(4''-hydroxyisopentenyl)naringenin (8-PN-OH) and (E)-8-(4''-oxoisopentenyl)naringenin (8-PN=O) being among the most abundant.

Uterine effects of the phytoestrogen 6-(1,1-dimethylallyl)naringenin in rats.

Phytoestrogens are discussed as candidate substances to treat symptoms related to estrogen deficiency. In in vitro experiments, the naturally occurring flavonoid 6-(1,1-dimethylallyl)naringenin (6-DMAN) emerged as one of the most potent phytoestrogenic substances. 6-DMAN is not as well characterized as other flavonoids (8-prenylnaringenin) or isoflavones (genistein).

Toxicity and cell cycle effects of synthetic 8-prenylnaringenin and derivatives in human cells.

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.

Regulation of gene expression by 8-prenylnaringenin in uterus and liver of Wistar rats.

The potential estrogenic activity of 8-prenylnaringenin has been investigated using several in vitro test systems. 8-Prenylnaringenin is a natural secondary product of the female blossoms of hops. The aim of the present study was to characterize 8-prenylnaringenin for its estrogenic effects in vivo.

Metabolism of 8-prenylnaringenin, a potent phytoestrogen from hops (Humulus lupulus), by human liver microsomes.

The female flowers of hops are used throughout the world as a flavoring agent for beer. Recently, there has been increasing interest in the potential estrogenic properties of hop extracts. Among the possible estrogenic compounds in hops, 8-prenylnaringenin is perhaps most significant due to its high in vitro potency exceeding that of other known phytoestrogens.

Antiandrogenic activity of the phytoestrogens naringenin, 6-(1,1-dimethylallyl)naringenin and 8-prenylnaringenin.

Naturally occurring naringenin derivatives, known for their estrogenic activity, were tested in two independent (anti-)androgen screening assays. Using a yeast-based androgen receptor assay relatively strong antiandrogen activities were demonstrated for 6-(1,1-dimethylallyl)naringenin and 8-prenylnaringenin, while the parent compound naringenin did not show recognizable antiandrogen activity. In an androgen receptor activity assay based on the analysis of prostate specific antigen (PSA) concentrations in the supernatants of treated PC3(AR)2 cells the antiandrogenic activity of 6-(1,1-dimethylallyl)naringenin was detected at concentrations of 10 (-5) M.

Estrogenic activity of the phytoestrogens naringenin, 6-(1,1-dimethylallyl)naringenin and 8-prenylnaringenin.

Chemically synthesized naringenin derivatives, identical to natural occurring compounds, were tested for their estrogenic activity using two independent estrogen screening assays. Using a yeast based estrogen receptor assay, strong estrogenic activities were demonstrated for 6-(1,1-dimethylallyl)naringenin and 8-prenylnaringenin, while the parent compound naringenin did not show recognizable estrogenic activity. In MVLN cells, a bioluminescent MCF-7-derived cell line, the estrogenic activity of 8-prenylnaringenin and 6-(1,1-dimethylallyl)naringenin was detected at concentrations of 10(-6) M and 5 x 10(-6) M respectively.