Synthesis, antiproliferative activity, 3D-QSAR and molecular docking studies of novel L-carvone-derived pyrimidine-urea compounds

Abstract

Abstract In order to explore novel antiproliferative compounds, twenty L-carvone-derived pyrimidine-urea compounds 4a – 4t were synthesized through the multi-step reaction of L-carvone, and structurally characterized by FT-IR, 1H-NMR, 13C-NMR, and HRMS. Besides, the in vitro antiproliferative activities of the target compounds against HepG2, Hela, and MCF-7 cells were evaluated by MTT assay. According to the results, the target compounds showed certain inhibitory activities against the tested cancer cell lines, and five compounds (4b, 4h, 4k, 4l, and 4t) exhibited better inhibition activities against Hela cell than the positive control (5-FU). Among them, compound 4b held significant antiproliferative activities against Hela and HepG2 cells, and thus deserved further study as a leading compound of new anticancer drugs. In addition, an effective and reasonable 3D-QSAR model was built by CoMFA method to analyze the relationship between the structures of the target compounds and their antiproliferative activities (expressed as pIC50) against Hela cell, and proven to have good predictive ability. Molecular docking was carried out to study the binding modes of compound 4b and Survivin which can enter the butt pocket like potential Survivin inhibitor GDP366, forming hydrogen bonding and hydrophobic interactions similar to each other.