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

Mei Huang,Wengui Duan,Xiu Wang,Naiyuan Chen,Guishan Lin

doi:10.3389/fchem.2021.815531

Abstract

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 in vitro antitumor activity was tested by standard methyl thiazolytetrazolium assay and showed that 4i, 4g, 4s, and 4m are the best compounds with IC50 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 4i, 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 4i might inhibit Hela cells through inhibit PI3K/Akt/mTOR signaling pathway. The binding modes and the binding sites interactions between compound 4i and the target proteins were predicted preliminarily by the molecular docking method.

Highlights

Cancer is a life-threatening disease with a high mortality rate and a major public health problem worldwide (Siegel et al, 2018)
Network pharmacology prediction showed that compound 4i might against Hela cells through regulating the expression and activation of the core targets, Epidermal growth factor receptor (EGFR), HRAS, Mitogen-activated protein kinase 1 (MAPK1), and Akt2
In Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, PI3K/Akt signaling pathway was evaluated as the first pathway for compound 4i against Hela cells

Summary

Introduction

Cancer is a life-threatening disease with a high mortality rate and a major public health problem worldwide (Siegel et al, 2018). Many new significant therapeutic methods were developed during the past decades, chemotherapy remains the main method for cancer treatment (Bukowski et al, 2020). The development of new drugs to overcome the resistance is still an important mission for medicinal chemists. PI3K/Akt/mTOR pathway has been reported as an important cell growth signaling pathway. This pathway is excessively activated in many tumor cells and facilitates the cancer cells resistance to chemotherapy (Chen et al, 2010; Zhang and Yang, 2020). There is evidence that the sensitivity of tumor cells to therapeutic drugs could be restored by inhibiting PI3K/Akt/mTOR pathway, which prompts the apoptosis of tumor cells (Papadimitrakopoulo, 2012). Many small molecule inhibitors against PI3K/ Akt/mTOR signaling pathway have been studied for antitumor use (Alzahrani, 2019)

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