The synthesis, structural characterization and in vitro anti-cancer activity of novel N-(3-ferrocenyl-2-naphthoyl) dipeptide ethyl esters and novel N-(6-ferrocenyl-2-naphthoyl) dipeptide ethyl esters

N-(3-ferrocenyl-2-naphthoyl) dipeptide esters (5–7) and N-(6-ferrocenyl-2-naphthoyl) dipeptide esters (8–10) were prepared by coupling either 3-ferrocenylnaphthalene-2-carboxylic acid 2 or 6-ferrocenylnaphthalene-2-carboxylic acid 4 to the dipeptide ethyl esters GlyAla(OEt) (5, 8), AlaGly(OEt) (6, 9), and AlaAla(OEt) (7, 10) 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). In vitro, the cytotoxic effects of compounds 5–10 show improvements over the corresponding N-(ferrocenyl)benzoyl derivatives, with IC50 values against the H1299 lung cancer cells ranging from 1.2 μM to 8.0 μM. N-(6-ferrocenyl-2-naphthoyl)-glycine-l-alanine ethyl ester 8 was found to be the most active derivative of the naphthoyl series so far, displaying an IC50 value of 1.3 ± 0.1 μM. This value is slightly lower than that found for the clinically employed anti-cancer drug cisplatin (IC50 = 1.5 ± 0.1 μM against H1299).

N-(3-ferrocenyl-2-naphthoyl) dipeptide esters (5–7) and N-(6-ferrocenyl-2-naphthoyl) dipeptide esters (8–10) were prepared by conventional peptide chemistry using the EDC/HOBT protocol. Compounds 5–10 exhibited cytotoxic effects on the human lung carcinoma cell line H1299; the most active derivative being N-(6-ferrocenyl-2-naphthoyl)-glycine-l-alanine ethyl ester 8 (IC50 = 1.3 ± 0.1 μM).Figure optionsDownload as PowerPoint slide