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Ferrocenylmethylation of estrone and estradiol: Structure, electrochemistry, and antiproliferative activity of new ferrocene–steroid conjugates
Author(s) -
Raičević Vidak,
Radulović Niko,
Jovanović Ljiljana,
Rodić Marko,
Kuzminac Ivana,
Jakimov Dimitar,
Wrodnigg Tanja,
Knedel TimOliver,
Janiak Christoph,
Sakač Marija
Publication year - 2020
Publication title -
applied organometallic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.53
H-Index - 71
eISSN - 1099-0739
pISSN - 0268-2605
DOI - 10.1002/aoc.5889
Subject(s) - chemistry , estrone , ferrocene , steroid , stereochemistry , dimethylformamide , conjugate , alkylation , cytotoxicity , iodide , combinatorial chemistry , electrochemistry , organic chemistry , in vitro , hormone , biochemistry , mathematical analysis , mathematics , electrode , solvent , catalysis
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 IC 50 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.