Synthesis, X-ray crystal structure study and antitumoral evaluations of 5,6-disubstituted pyrimidine derivatives

Abstract

5,6-Disubstituted pyrimidine derivatives (3–20) were prepared by intramolecular cyclization reaction of α-(1-carbamyliminomethylene)-γ-butyrolactone (2) with sodium ethoxide and subsequent chemical transformation of 2-hydroxy group in C-5 side chain as well as lithiation reaction for introduction of acyclic side chain at C-6. All compounds were characterized by 1H NMR, 13C NMR and mass spectra. Structures of compounds 4, 7 and 14 were unambiguously confirmed by X-ray crystal structural analysis. Supramolecular structures of these three compounds differ significantly. Two N–H⋯O and one C–H⋯O hydrogen bonds in 4 form three-dimensional network. One O–H⋯N hydrogen bond and one π⋯π interaction self-assemble the molecules of 7 into sheets. In supramolecular aggregation of 14, only π⋯π stacking interactions participate, so forming chains. The compounds were evaluated for their cytostatic activities against human malignant cell lines. Of all tested compounds, 2,4-dimethoxy-5-methoxytritylethylpyrimidine (9) and 2,4-dichloro-5-chloroethylpyrimidine (14) exhibited the most prominent inhibitory effects. Furthermore, compound 14 showed marked activity against human colon carcinoma (IC50=0.4μM).