The synthesis, structural characterization and in vitro anti-cancer activity of novel 1-alkyl-1′-N-para-(ferrocenyl) benzoyl dipeptide esters

•1-Alkyl-1′-N-para-(ferrocenyl) benzoyl dipeptide ester derivatives were prepared.•They exhibited cytotoxicity on the human lung carcinoma cell line H1299.•Alkylation of the cyclopentadiene ring increases the cytotoxicity.•The cytotoxicity decreases with an increase of the size of the alkyl group.

1-Alkyl-1′-N-para-(ferrocenyl) benzoyl dipeptide esters 4–12 were prepared by coupling the alkyl ferrocenyl benzoic acids 1–3 to the dipeptide ethyl esters Gly-L-Ala(OEt), Gly-L-Leu(OEt) and Gly-L-Phe(OEt) using the standard N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride (EDC), 1-hydroxybenzotriazole (HOBt) protocol. All the compounds were fully characterized using a combination of 1H NMR, 13C NMR, DEPT-135 and 1H–13C COSY (HMQC) spectroscopy, electrospray ionization mass spectrometry (ESI-MS) and cyclic voltammetry (CV). Selected compounds showed micromolar activity in the H1299 NSCLC cell line, with IC50 values in the range of 4.5–6.6 μM.

Graphical abstract1-Alkyl-1′-N-para-(ferrocenyl) benzoyl dipeptide ethyl esters 4–12 were prepared by conventional peptide chemistry using the EDC/HOBT protocol. Compounds 4–12 exhibited cytotoxic effects on the human lung carcinoma cell line H1299, the most active derivative being 1-methyl-1′-N-{para-(ferrocenyl)-benzoyl}-glycine-l-alanine ethyl ester 4 (IC50 = 4.5 μM).Figure optionsDownload full-size imageDownload as PowerPoint slide