Ferrocenylmethylation of estrone and estradiol: Structure,electrochemistry, and antiproliferative activity of new ferrocene–steroid conjugates |
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Authors: | Vidak Raičević Niko Radulović Ljiljana Jovanović Marko Rodić Ivana Kuzminac Dimitar Jakimov Tanja Wrodnigg Tim-Oliver Knedel Christoph Janiak Marija Sakač |
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Institution: | 1. Department of Chemistry, Biochemistry and Environmental Protection, Faculty of Sciences, University of Novi Sad, Trg Dositeja Obradovića 3, Novi Sad, 21000 Serbia;2. Department of Chemistry, Faculty of Sciences and Mathematics, University of Niš, Višegradska 33, Niš, 18000 Serbia;3. Oncology Institute of Vojvodina, Put doktora Goldmana 4, Sremska Kamenica, 21204 Serbia;4. Glycogroup, Institute of Chemistry and Technology of Biobased Systems, Graz University of Technology, Stremayrgasse 9, Graz, A-8010 Austria;5. Institute for Inorganic Chemistry and Structural Chemistry, Heinrich-Heine-Universität Düsseldorf, Universitätsstraße 1, Düsseldorf, D-40225 Germany |
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Abstract: | Conjugates of ferrocene with steroidal estrogens as selective antiproliferative agents against hormone-dependent breast cancer cells are believed to be limited by the inherent estrogenicity of the conjugates. Motivated by a significant cytotoxicity of the ester of ferrocenecarboxylic acid and the phenolic group of estradiol toward such a cell line, we decided to explore other a -ring-tethered ferrocene–estra-1,3,5(10)-triene conjugates; in this study, ferrocenylmethylation of estradiol and estrone with (ferrocenylmethyl)trimethylammonium iodide in the presence of potassium carbonate yielded five new compounds ( 1 – 5 ). In dimethylformamide, only O-alkylated products formed ( 1 and 3 ), while a mixture of O- and C-alkylated products was obtained when methanol was used ( 2 , 4 , and 5 in addition to 1 and 3 ). All compounds were characterized using 1D and 2D NMR, IR, UV–Vis, and high-resolution mass spectrometry. Two of the conjugates, a 3-O- and a 4-C-alkylated derivative of estrone ( 3 and 4 , respectively), were also analyzed using single-crystal X-ray diffraction. A cyclic voltammetric investigation of the electrochemical properties of 1 – 5 was performed. While some of the compounds were shown to have a slight-to-moderate antiproliferative activity against at least one of the six tested human tumor cell lines and were nontoxic to (the noncancerous) fetal human fibroblasts, compound 2 (4-(ferrocenylmethyl)estra-1,3,5(10)-triene-3,17β-diol) with an IC50 value of 0.34 μM was found to be more active against the hormone-dependent breast cancer cell line MCF-7 than doxorubicin. These results suggest that a -ring substitution of steroidal estrogens is a plausible strategy for preparing other ferrocene–steroid conjugates acting against tumor cells. |
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Keywords: | breast cancer cyclic voltammetry estrogens ferrocene X-ray crystallography |
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