Synthesis, cytotoxic assessment, and molecular docking studies of 2,6-diaryl-substituted pyridine and 3,4- dihydropyrimidine-2(1H)-one scaffolds.

Ali RAMAZANI,Zahra Hosseinzadeh,Nima Razzaghi-Asl,Hamideh Aghahosseini

doi:10.3906/kim-1903-72

Ali RAMAZANI, Zahra Hosseinzadeh + Show 2 more

Open Access

https://doi.org/10.3906/kim-1903-72

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Abstract

Cancer is one of the main global health problems. In order to develop novel antitumor agents, we synthesized 3,4-dihydropyrimidine-2(1H)-one (DHPM) and 2,6-diaryl-substituted pyridine derivatives as potential antitumor structures and evaluated their cytotoxic effects against several cancer cell lines. An easy and convenient method is reported for the synthesis of these derivatives, employing cobalt ferrite (CoFe 2 O 4 @SiO 2 -SO 3 H) magnetic nanoparticles under microwave irradiation and solvent-free conditions. The structural characteristics of the prepared nanocatalyst were investigated by FTIR, XRD, SEM, and TGA techniques. In vitro cytotoxic effects of the synthesized products were assessed against the human breast adenocarcinoma cell line (MCF-7), gastric adenocarcinoma (AGS), and human embryonic kidney (HEK293) cells via MTT assay. The results indicated that compound 4r (DHPM derivative) was the most toxic molecule against the MCF-7 cell line (IC 50 of 0.17 μg/mL). Moreover, compounds 4j and 4r (DHPM derivatives) showed excellent cytotoxic activities against the AGS cell line, with an IC 50 of 4.90 and 4.97 μg/mL, respectively. Although they are pyridine derivatives, compounds 5g and 5m were more active against the MCF-7 cell line. Results showed that the candidate compounds exhibited low cytotoxicity against HEK293 cells. The kinesin Eg5 inhibitory potential of the candidate compounds was evaluated by molecular docking. The docking results showed that, among the pyridine derivatives, compound 5m had the most free energy of binding (–9.52 kcal/mol) and lowest Ki (0.105 μM), and among the pyrimidine derivatives, compound 4r had the most free energy of binding (–7.67 kcal/mol) and lowest Ki (2.39 μM). Ligand-enzyme affinity maps showed that compounds 4r and 5m had the potential to interact with the Eg5 binding site via H-bond interactions to GLU116 and GLY117 residues. The results of our study strongly suggest that DHPM and pyridine derivatives inhibit important tumorigenic features of breast and gastric cancer cells. Our results may be helpful in the further design of DHPMs and pyridine derivatives as potential anticancer agents.

Highlights

A common approach in cancer chemotherapy is the development of drugs that interrupt the mitosis phase of cell division
The mitotic spindle is an important target in cancer chemotherapy, and a fundamental spindle motor protein is kinesin Eg5, which is considered as an important therapeutic target due to its specific role during mitosis in assembly [1,2]
Since mitotic kinesins are exclusively involved in the formation of the mitotic spindle, the inhibition of Eg5 by DHPMs is considered an attractive approach to cancer treatment [3]

Summary

Introduction

A common approach in cancer chemotherapy is the development of drugs that interrupt the mitosis phase of cell division. Since mitotic kinesins are exclusively involved in the formation of the mitotic spindle, the inhibition of Eg5 by DHPMs is considered an attractive approach to cancer treatment [3]. It was reported that monastrol has an antitumor effect on various cancer cell types, such as breast, renal, and glioma cell lines. Unlike taxol, this compound, as an antimitotic agent, has not showed neuronal cytotoxicity [4,5]

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