Synthesis, structural characterization, in vitro anti-proliferative effect and cell cycle analysis of N-(ferrocenyl)benzoyl dipeptide esters

N-ortho, meta and para-(ferrocenyl)benzoyl dipeptide esters 2–10 were prepared by coupling ferrocenyl benzoic acids 1(ortho, meta and para) to the dipeptide ethyl esters GlyAbu(OEt) 2–4, GlyNva(OEt) 5–7 and GlyNle(OEt) 8–10 in the presence of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole. The compounds were fully characterized by a range of NMR spectroscopic techniques, mass spectrometry and cyclic voltammetry. The cytotoxicity of 3, 6 and 9 versus H1299 lung cancer cells were 10.5 μM, 19.1 μM and 18.9 μM, respectively, whereas N-{meta-(ferrocenyl)-benzoyl}-glycine-l-alanine ethyl ester 11 and N-{para-(ferrocenyl)-benzoyl}-glycine-l-alanine ethyl ester 12 gave IC50 values of 4.0 and 6.6 μM, respectively. Therefore, an increase in alkyl chain length of the second amino acid also increases the IC50 values. Cell cycle analysis of N-{ortho-(ferrocenyl)-benzoyl}-glycine-l-alanine ethyl ester 13 suggests a block in the G2/M phase of the cell cycle.

Graphical abstractFerrocenyl benzoyl dipeptide esters 2–10 were prepared by conventional peptide chemistry using the EDC/HOBT protocol. Compounds 3, 6 and 9 exhibited cytotoxic effects versus H1299 lung cancer cells. Cell cycle analysis of N-{ortho-(ferrocenyl)-benzoyl}-glycine-l-alanine ethyl ester 13 suggests a block in the G2/M phase of the cell cycle.Figure optionsDownload full-size imageDownload as PowerPoint slide