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