Design, synthesis and application of fluorescent 2,1,3-benzothiadiazole-triazole-linked biologically active lapachone derivatives

Abstract

Two new benzothiadiazole-triazole-linked lapachone derivatives were designed, synthesized and characterized by 1D and 2D NMR spectroscopy. Their photophysical properties were also investigated. Theoretical calculations (DFT), based on the molecular design of the new compounds, allowed a better understanding of the derivatives' stability and behaviour, especially in the excited state. This manuscript also describes a discussion on the molecular architecture which is based on two substitutions at positions 4- and 7- of the important 2,1,3-benzothiadiazole (BTD) core. One side is replaced by a group capable of performing an ESIPT (excited-state intramolecular proton transfer) stabilizing process, and the other side is substituted by a triazole-containing group. This triazole ring acts as the linker between the BTD core and a group of known antitumoral activity i.e. a nor-β-lapachone derivative. These novel fluorescent compounds had their biological activities evaluated against twenty cancer cell lines and three normal cells with promising results. Finally, due to their interesting photophysical properties and good fluorescence, bioimaging experiments were conducted, and these dyes were tested as fluorescent cell-imaging probes, thus showing their preferable cellular location in MDA-MB-231 cancer cells (a breast-invasive cancer-cell lineage).