Introducing of acyclonucleoside analogues tethered 1,2,4-triazole as anticancer agents with dual epidermal growth factor receptor kinase and microtubule inhibitors

Abstract

This study reports an efficient and convenient regioselective synthesis of a novel series of S- and S,N-bis(acyclonucleoside) analogues carrying 5-(2-chlorophenyl)-2,4-dihydro-1,2,4-triazole-3-thione. A facile and straightforward synthesis of thiazolotriazole and triazolothiazines has also been reported. Structures of all newly synthesized compounds were well characterized by infrared IR, ¹H and ¹³C nuclear magnetic resonance (NMR) and mass (MS) spectra analyses. Cytotoxic screening was performed according to (3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide) tetrazolium (MTT) assay method using staurosporine as a reference drug against three different types: human liver cancer cell line (Hep G2), Michigan cancer foundation-7 (MCF-7) and human colorectal carcinoma cell line (HCT116). These data showed considerable anticancer activity for these newly synthesized compounds. Biological data for most of the S-acyclonucleoside analogues and S,N-bis(acyclonucleoside) analogues showed excellent activity with micromolar (µM) half maximal inhibitory concentration (IC₅₀) values against tumor cells. EGFR assay and tubulin inhibition assay analysis were performed for the most active compounds to get more details about their mechanism of action. In order to assess and explain their binding affinities, molecular docking simulation was studied against EGFR and tubulin binding sites. The results obtained from molecular docking study and those obtained from cytotoxic screening were correlated. Extensive structure activity relationship (SAR) analyses were also carried out.

Keywords: 1,2,4-triazoles; Acyclonucleoside analogues; Anticancer activity; EGFR kinases; Regioselectivity; Thiazolotriazole; Triazolothiazines; Tubulin polymerization.