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.

Abstract

Indolo[3,2-d][1]benzazepines (paullones), indolo[3,2-d][2]benzazepines, and indolo[2,3-d][2]benzazepines (latonduines) are isomeric scaffolds of current medicinal interest. Herein, we prepared a small library of novel indolo[3,2-d][2]benzazepine-derived ligands HL1–HL4 and copper(II) complexes 1–4. All compounds were characterized by spectroscopic methods (1H and 13C NMR, UV–vis, IR) and electrospray ionization (ESI) mass spectrometry, while complexes 2 and 3, 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 1H 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 HL1–HL4 and 1–4 with those of structurally similar paullone-derived (HL5–HL7 and 5–7) and latonduine-derived scaffolds (HL8–HL11 and 8–11). The high anticancer activity of the lead drug candidate 4 was linked to reactive oxygen species and endoplasmic reticulum stress induction, which were confirmed by fluorescent microscopy and Western blot analysis.