Metallocene-Modified Uracils: Synthesis, Structure, and Biological Activity

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Abstract

A new family of metallocene–uracil conjugates, including [3-(N1-uracilyl)-1-(ferrocenyl)]propene (2c), [3-(N1-thyminyl)-1-(ferrocenyl)]propene (3c), [3-(N1-(5-fluorouracilyl))-1-(ferrocenyl)]propene (4c), and [3-(N1-uracilyl)-1-(ruthenocenyl)]propene (5c), was obtained in three steps from (3-chloropropionyl)ferrocene and (3-chloropropionyl)ruthenocene, respectively. The complexes 2c–5c and their intermediates 2a–5a and 2b–5b were characterized by NMR and infrared spectroscopy, mass spectrometry, and elemental analysis. The molecular structures of the intermediates 2b and 4a were determined by single-crystal X-ray structure analysis. In the solid state, two molecules of 2b or 4a form a dimeric structure, which is held together by strong hydrogen bonds. Compounds 2c–5c were also studied by cyclic voltammetry (CV). The ferrocenyl–uracil derivatives 2c–4c revealed reversible uncomplicated oxidations, whereas the cyclic voltammogram of the ruthenocenyl derivative 5c showed an irreversible oxidation. Compounds 2c–5c were tested for their antiproliferative activity against human MCF-7 breast adenocarcinoma and HT-29 colon carcinoma cells. Compounds 3c–5c were moderately active against MCF-7 cancerous cells. Atomic absorption spectroscopy measurements on compound 5c revealed that the ruthenocenyl derivative is taken up by HT-29 cells in a time-dependent manner. However, the ruthenium cellular level remains relatively low. Compounds 2a–5a were also tested against Gram-positive methicillin-sensitive Staphylococcus aureus (MSSA), methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Staphylococcus aureus (VRSA) and Staphylococcus epidermidis bacterial strains. Compound 4a showed significant antibacterial activity against all bacterial strains, while compounds 2a and 3b were only moderately active. No antibacterial activity was found for the ruthenocenyl derivative 5a.

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