Discovery of triaromatic flexible agents bearing 1,2,3-Triazole with selective and potent anti-breast cancer activity and CDK9 inhibition supported by molecular dynamics

This study reports an efficient and convenient click synthesis of novel series of chromene scaffold linked to 1,2,3 triazole ring and terminal lipophilic fragments. Structures of all newly synthesized compounds were well characterized by IR, 1H NMR, 13C NMR and elemental analyses. In vitro MTT cytotoxic screening was performed using staurosporine as a reference drug against three different types: aggressive and invasive human breast cancer cell line (MDA-MB 231), Michigan cancer foundation-7 (MCF-7) and human colorectal carcinoma cell line (HCT116). These screening data showed considerable anticancer activity for these newly synthesized compounds compared to reference staurosporine drug with high degree of cell line selectivity and excellent activity with micromolar (µM) half maximal inhibitory concentration (IC50) values against tumor cells. In addition, Cyclin-Dependent Kinase1 and 9 (CDK1 and 9) assays 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 CDK9 site. The results obtained from molecular docking study and those obtained from cytotoxic screening and enzyme inhibition were correlated. One of the most prominent analogs is 34 that showed high selective cytotoxicity profile against single breast cancer cell line MCF-7 and MDA-MB 231 with IC50 3.4 µM and 1.4 uM respectively. Molecular dynamics (MD) simulation of the CDK9 complex by Desmond revealed stability during 100 ns with RMSD of CDK9 complex converged at 2.1 Å after 20 ns. During MD, the interaction fractions confirmed multiple interactions of 34 with Cys106, a crucial residue for inhibition of CDK9 activity. A novel 34 triazole compound was introduced for drug design works as potent and selective hit for treatment of breast cancers after processing of optimization steps.