The chromene derivative 4 reacts with acetic anhydride, phenylisothiocyanate and ethyl orthoformate to afford the N-acetyl derivative 6, the chromenopyrimidine 8 and the formimidate 9, respectively. 2-(1H-Indol-3-ylmethylene)-malononitrile 10b reacts with 1,3-cyclohexanedione and dimedone 11a, b to afford the 4(3-indolyl)-chromene derivatives 12a, b respectively, and with the pyrazolone derivatives 13a-d to afford the arylidene exchange derivatives 14a-c and the pyranopyrazole derivative 15, respectively. The arylidene derivatives 10a, b react also with indane-1,3-dione 16 to afford the arylidene exchange derivatives 18a, b. The molluscicidal activity of the synthesized compounds towards Biomphalaria alexandrina snails, the intermediate host of Schistosoma mansoni, was investigated and most of them showed weak to moderate activity.
2-(3-Hydroxy-5,5-dimethylcyclohexylidene)malononitrile 5 undergoes an azo coupling reaction with aryldiazonium salts to afford 3-amino-2-aryl-6,6-dimethyl-8-oxo-2,6,7,8-tetrahydrocinnoline-4-carbonitriles 7. Upon reflux in acetic acid, these compounds were acetylated to give the cinnoline derivatives 9. The pyrazolones 10a, b react with 3-furfurylidene- and 3-thienylidene-malononitrile derivatives 11a, b to afford the pyrano[2,3-c]pyrazole derivatives 13a-d. These newly synthesized compounds show generally a moderate molluscicidal activity to Biomphalaria alexandrina snails.
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. Naringenin demonstrated estrogenic activity but only at a concentration of 10(-5) M. These estrogenic effects are mediated by the ER, as the antiestrogen 4-hydroxytamoxifen inhibited these activities. In summary, this study provides the further confirmation that 8-prenylnaringenin demonstrates high estrogenic activity, and demonstrated for the first time for 6-(1,1-dimethylallyl)naringenin a reasonable high estrogenic activity, while naringenin exhibit low or no estrogenic activity.
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ABSTRACT: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. Since data regarding the pharmacokinetic properties of this compound are lacking, we investigated the in vitro metabolism of 8-prenylnaringenin by human liver microsomes. A total of 12 metabolites were identified, and biotransformation occurred on the prenyl group and the flavanone skeleton. The major site of oxidation was on the terminal methyl groups, and of the two possible isomers, the trans isomer was more abundant. The double bond on the prenyl group was also oxidized to an epoxide that was opened by intramolecular reaction with the neighboring hydroxyl group. On the flavanone skeleton, the major site of oxidation was at 3 position on the B ring. Other metabolites included oxidation at carbon-3 as well as desaturation of the C ring to produce 8-prenylapigenin. An unusual hydroxy quinone product formed by ipso hydroxylation of the B ring of 8-prenylnaringenin was also detected. This product was probably an intermediate for the B ring cleavage product, 8-prenylchromone.
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