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

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.