Synthesis and biological evaluation of novel ethyl 2-amino-6-ferrocenyl-1,6-dihydropyrimidine-5-carboxylates and ethyl 2-amino-6-ferrocenylpyrimidine-5-carboxylates

Reactions of ethyl 2-acyl-3-ferrocenylacrylates (acyl = acetyl, benzoyl, p-nitrobenzoyl) with guanidine and 1,1-dimethylguanidine furnish ethyl 2-amino-6-ferrocenyl-4-methyl(aryl)-1,6-dihydropyrimidine-5-carboxylates. Their oxidative dehydrogenation with PhI(OAc)2 results in the corresponding ethyl 2-amino-6-ferrocenyl-4-methyl(aryl)pyrimidine-5-carboxylates. The structures of the synthesized compounds were established on the basis of the data from 1H and 13C NMR spectroscopy and confirmed by X-ray diffraction analysis. All compounds were tested in vitro against six human tumor cell lines U-251, PC-3,K-562, HCT-15, MCF-7 and SKLU-1 to assess their in vitro antitumor activity. The results suggest biological specificity towards PC-3 and K-562 cells for compounds 4a–c at doses 50 μM, which are lower than cis-platin IC50's in the two cell lines. Additionally, peritoneal mouse macrophages (M∅) were also evaluated for compounds 4a–f and 5a–f.

Graphical abstractReactions of ethyl 2-acyl-3-ferrocenylacrylates with guanidines furnish ethyl 2-amino-6-ferrocenyl-4-methyl(aryl)-1,6-dihydropyrimidine-5-carboxylates and ethyl 2-amino-6-ferrocenyl-4-methyl(aryl)pyrimidine-5-carboxylates. All compounds were tested in vitro against six human tumor cell lines U251, PC-3,K-562, HCT-15, MCF-7 and SKLU-1 to assess their in vitro antitumor activity.Figure optionsDownload full-size imageDownload as PowerPoint slideHighlights► Synthesis of novel ferrocenyl(dihydro)pyrimidines and aromatic pyrimidines. ► Ethyl 2-amino-6-ferrocenyl-1,6-dihydropyrimidine-5-carboxylates. ► Ethyl 2-amino-6-ferrocenylpyrimidine-5-carboxylates. ► Determination of antitumoral activity of ferrocenylpyrimidines.