Ferrocenylmethylation of estrone and estradiol: Structure, electrochemistry, and antiproliferative activity of new ferrocene–steroid conjugates

Vidak Raičević*, Niko Radulović, Ljiljana Jovanović, Marko Rodić, Ivana Kuzminac, Dimitar Jakimov, Tanja Wrodnigg, Tim Oliver Knedel, Christoph Janiak, Marija Sakač

*Corresponding author for this work

Research output: Contribution to journalArticle

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.

Original languageEnglish
Article numbere5889
JournalApplied Organometallic Chemistry
Volume34
Issue number10
DOIs
Publication statusPublished - 1 Oct 2020

Keywords

  • breast cancer
  • cyclic voltammetry
  • estrogens
  • ferrocene
  • X-ray crystallography

ASJC Scopus subject areas

  • Chemistry(all)
  • Inorganic Chemistry

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