The synthesis, structure, electrochemistry and in vitro anticancer activity studies of ferrocenyl-thymine conjugates

We report the synthesis of two ferrocenyl-thymine conjugates; acyclonucleoside 11d and its precursor 11c. The key step of our synthetic approach relied on a Michael addition reaction of acryloylferrocene and thymine. We also report herein on synthesis of novel W(CO)5-2,5-dimethylazaferrocene derivatives. The structures of acyclonucleoside and azaferrocene derivatives were determined by single-crystal X-ray analysis. All newly synthesized compounds were investigated by cyclic voltammetry (CV). Ferrocenyl-thymine complexes revealed reversible uncomplicated oxidation whereas azaferrocenes were found to exhibit reversible uncomplicated first oxidation followed by an irreversible second oxidation at considerably higher potential. The anticancer activities of ferrocenyl-thymine derivatives 11c, 11d, azaferrocenes 12a, 12b, acryloylferrocene 11b and 3-chloropropionylferrocene 11a against estrogen receptor-responsive MCF-7 and estrogen receptor-negative MDA-MB-231 mammary carcinoma cells, ovarian carcinoma cells SKOV-3 and T lymphoblastoid CCRF-CEM cell lines were studied in vitro. Noteworthy antiproliferative activities against all four cell lines have been found for 11a, 12a and 12b compounds. Acryloylferrocene 11b showed activity against three cell lines (MCF-7, MDA-MB-231 and CCRF-CEM). The ferrocenyl-thymine conjugate 11c was active against MCF-7 and CCRF-CEM cells while complex 11d showed no activity.

Synthesis and characterization of ferrocenyl-thymine conjugates and W(CO)5-2,5 -dimethylazaferrocene derivatives is described. Antiproliferative activity of obtained complexes were tested on four human cancerous cell lines. The most significant anticancer properties exhibit acryloylazaferrocene 12b.Figure optionsDownload as PowerPoint slideHighlights
► Synthesis of ferrocenyl-thymine conjugate via Michael addition reaction.
► Synthesis of azaferrocenes bearing acryloyl and 3-chloropropionyl groups.
► Cytotoxicity of obtained compounds and two known ferrocenes against cancer cell lines.
► The lowest IC50 of 11.6±0.8 has been found for the acryloylazaferrocene.