Co-Culture Based Screening Revealed Selective Cytostatic Effects of Pyrazol-Azepinoindoles.

Abstract

This work focuses on the search for new small molecules for anticancer therapy using the Fluorescent Cells Co-Cultivation Test (FCCT). This method allows the control of the specificity of the action of compounds from the earliest stages of drug development. For the FCCT, labelled MCF7' breast cancer cells and non-cancerous breast MCF10A cells were co-cultured. Screening of 2025 compounds in the above system and previously developed co-culture of A549' with VA-13 yielded 16 selectively cytotoxic molecules. The results were confirmed by MTT assay for 7 of these molecules. Few are known as potential antitumor agents: angelicin, coumarin, and colchicine derivatives. However, the structures of macrocycle 1, pyrazole-azepinoindole derivative 2, and complex heterocyclic derivative 3 were not described as anticancer compounds according to the PubChem and SciFinder databases. Structure-activity relationships were investigated for 2, and its derivatives. The indole with a caprolactam ring (tetrahydro-azepinoindolone core) together with the pyrazolyl at the 3-position are the key elements of the pharmacophore. The optimized pyrazole-azepinoindole derivative 23 showed SI=18 for HCT116 vs VA-13 on the expanded array of cell lines. I.