Antiestrogenic Activity and Possible Mode of Action of Certain New Nonsteroidal Coumarin-4-acetamides

The preparation of certain 2-(2-oxo-2H-chromen-4-yl)-N-substituted acetamides IIIa–h was planned as a step in the development of new modified nonsteroidal antiestrogens. The purity of target compounds IIIa–h was checked by thin-layer chromatography (TLC), and their structures were confirmed using various spectroscopic tools including IR, 1H-NMR, 13C-NMR, and MS spectroscopy. Viability tests were applied using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay to evaluate the cytotoxic effect of the synthesized compounds against two breast cancer cell lines, MCF-7 and MDA-MB-231. Compound IIIb proved the most active against MCF-7 cells, with an IC50 value of 0.32 μM. The results of an analysis of in vitro antiestrogenic activity indicated that only compound IIIb exhibited antiestrogenic activity; its IC50 value of 29.49 μM was about twice as potent as that of the reference compound, MIBP. The aromatase activity was evaluated for the synthesized target compounds IIIa–g and the intermediates Ib and IIa. A significant aromatase inhibition was observed for the intermediate Ib and compound IIIe, with IC50 values of 14.5 and 17.4 μM, respectively. Compound IIIb, namely 7-methoxy-4-(2-oxo-2-(piperidin-1-yl)ethyl)-2H-chromen-2-one, could be used as an antiestrogen and/or cytotoxic agent with selective activity against tumor cells.

Microbiological degradation of bile acids. The preparation of hexahydroindane derivatives as substrates for studying cholic acid degradation

Relatively large amounts of 3-(3aalpha-hexahydro-7abeta-methyl-1,5-dioxoindan-4alpha-yl)propionic acid (IIb), which is believed to be one of the intermediates involved in the degradation of cholic acid (I), were needed to identify is further degradation products. A simple method for the preparation of this compound was then investigated. Arthrobacter simplex could degrade-3-oxoandrost-4-ene-17beta-carboxylic acid (IIIa) to 3-(1beta-carboxy-3aalpha-hexahydro-7abeta-methyl-5-oxoindan-4alpha-yl)propionic acid (IVa) in good yield, the structure of which was established by partial synthesis. It was therefore expected that, if a similar degradation by this organism occurred with 17alpha-hydroxy-3-oxoandrost-4-ene-17beta-carboxylic acid (IIIb), which is easily obtained by chemical oxidation of commercially availabe 17alpha-hydroxydeoxycorticosterone, the resulting product, 3-(1beta-carboxy-3aalpha-hexahydro-1alpha-hydroxy-7abeta-methyl-5-oxoindan-4alpha-yl)propionic acid (IVb), could be readily converted chemically into the required dioxocarboxylic acid, (IIb). Exposure of compound (IIIb) to A. simplex produced, as expected, compound (IVb) which was then oxidized with NaBiO3 to give a reasonable yield of compound (IIb).