Synthesis and Antitumor Evaluation of Menthone-Derived Pyrimidine-Urea Compounds as Potential PI3K/Akt/mTOR Signaling Pathway Inhibitor.

A series of novel menthone derivatives bearing pyrimidine and urea moieties was designed and synthesized to explore more potent natural product-derived antitumor agents. The structures of the target compounds were confirmed by FTIR, NMR, and HRMS. The antitumor activity was tested by standard methyl thiazolytetrazolium assay and showed that , , , and are the best compounds with IC values of 6.04 ± 0.62µM, 3.21 ± 0.67µM, 19.09 ± 0.49µM, and 18.68 ± 1.53µM, against Hela, MGC-803, MCF-7, and A549, respectively. The results of the preliminary action mechanism studies showed that compound , the representative compound, could induce cell apoptosis in Hela cells in a dose-dependent manner and might arrest the cell cycle in the G2/M phase. Furthermore, the results of network pharmacology prediction and Western blot experiments indicated that compound might inhibit Hela cells through inhibit PI3K/Akt/mTOR signaling pathway. The binding modes and the binding sites interactions between compound and the target proteins were predicted preliminarily by the molecular docking method.