TY - JOUR
T1 - Ferrocenylmethylation of estrone and estradiol
T2 - Structure, electrochemistry, and antiproliferative activity of new ferrocene–steroid conjugates
AU - Raičević, Vidak
AU - Radulović, Niko
AU - Jovanović, Ljiljana
AU - Rodić, Marko
AU - Kuzminac, Ivana
AU - Jakimov, Dimitar
AU - Wrodnigg, Tanja
AU - Knedel, Tim Oliver
AU - Janiak, Christoph
AU - Sakač, Marija
PY - 2020/10/1
Y1 - 2020/10/1
N2 - 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.
AB - 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.
KW - breast cancer
KW - cyclic voltammetry
KW - estrogens
KW - ferrocene
KW - X-ray crystallography
UR - http://www.scopus.com/inward/record.url?scp=85087436567&partnerID=8YFLogxK
U2 - 10.1002/aoc.5889
DO - 10.1002/aoc.5889
M3 - Article
AN - SCOPUS:85087436567
SN - 0268-2605
VL - 34
JO - Applied Organometallic Chemistry
JF - Applied Organometallic Chemistry
IS - 10
M1 - e5889
ER -