Elucidation of Structure-Activity Relationships in Indolobenzazepine-Derived Ligands and Their Copper(II) Complexes: the Role of Key Structural Components and Insight into the Mechanism of Action.

Indolo[3,2-][1]benzazepines (paullones), indolo[3,2-][2]benzazepines, and indolo[2,3-][2]benzazepines (latonduines) are isomeric scaffolds of current medicinal interest. Herein, we prepared a small library of novel indolo[3,2-][2]benzazepine-derived ligands - and copper(II) complexes -. All compounds were characterized by spectroscopic methods (H and C NMR, UV-vis, IR) and electrospray ionization (ESI) mass spectrometry, while complexes and , in addition, by X-ray crystallography. Their purity was confirmed by HPLC coupled with high-resolution ESI mass spectrometry and/or elemental analysis. The stability of compounds in aqueous solutions in the presence of DMSO was confirmed by H NMR and UV-vis spectroscopy measurements. The compounds revealed high antiproliferative activity in vitro in the breast cancer cell line MDA-MB-231 and hepatocellular carcinoma cell line LM3 in the low micromolar to nanomolar concentration range. Important structure-activity relationships were deduced from the comparison of anticancer activities of - and - with those of structurally similar paullone-derived (- and -) and latonduine-derived scaffolds (- and -). The high anticancer activity of the lead drug candidate was linked to reactive oxygen species and endoplasmic reticulum stress induction, which were confirmed by fluorescent microscopy and Western blot analysis.