Research Article

2,4-Disubstituted Quinazoline Derivatives Act as Inducers of Tubulin Polymerization: Synthesis and Cytotoxicity

Author(s):

Ebrahim S. Moghadam, Maryam H. Tehrani, René Csuk, Lucie Fischer, Mohammad Ali Faramarzi, Arezoo Rashidi, Iraj Javadi and Mohsen Amini*   Pages 1048 - 1057 ( 10 )

Abstract:

Background: During last recent years number of anti-tubulin agents were introduced for treatment of diverse kind of cancer. Despite of their potential in treatment of cancer, drug resistance and adverse toxicity such as peripheral neuropathy are some of the negative criteria of anti-tubulin agents.

Methods: Twenty seven quinazoline derivatives were synthesized using a multicomponent reaction. The cytotoxicity of compounds 1-27 was tested in SRB assays employing five different human tumor cell lines. Effect of two of active compounds on tubulin polymerization was also checked using a commercially available assay kit. Molecular modelling studies were also performed using autodock tools software.

Results: SRB assays showed that compounds 2, 9, 16 and 26, being highly cytotoxic with IC50 values ranging between 2.1 and 14.3µM. The possible mode of action of compounds, 2, 9, 16 and 26, and the taxol binding site of the protein tubulin, an important goal for antimitotic drugs, was also studied by molecular docking, which showed reasonable interactions with tubulin active site, followed by investigation of the effects of compounds 9 and 16 on the polymerization of tubulin. The results showed the tested compounds to be highly active as inducers of tubulin polymerization.

Conclusion: Altogether, with respect to obtained results, it is attractive and beneficial to further investigation on quinazoline scaffold as antimitotic agents.

Keywords:

Anti-cancer, quinazoline, synthesis, molecular docking, SRB assay, tubulin.

Affiliation:

Department of Medicinal Chemistry, Faculty of Pharmacy and Drug Design and Development Research Center, The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran 1417614411, Department of Medicinal Chemistry, Faculty of Pharmacy and Drug Design and Development Research Center, The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran 1417614411, Martin-Luther-University Halle-Wittenberg, Organic Chemistry, Kurt-Mothes-Str. 2, D-06120 Halle (Saale), Martin-Luther-University Halle-Wittenberg, Organic Chemistry, Kurt-Mothes-Str. 2, D-06120 Halle (Saale), Department of Pharmaceutical Biotechnology, Faculty of Pharmacy and Biotechnology Research Center, Tehran University of Medical Sciences, Tehran, Department of Pharmaceutical Biotechnology, Faculty of Pharmacy and Biotechnology Research Center, Tehran University of Medical Sciences, Tehran, Department of Toxicology, Faculty of Pharmacy, Shahreza Branch, Islamic Azad University, Shahreza, Department of Medicinal Chemistry, Faculty of Pharmacy and Drug Design and Development Research Center, The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran 1417614411

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