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.
Irina KuznetcovaFelix BacherSamah Mutasim AlfadulMax Jing Rui ThamWee Han AngMaria V BabakPeter RaptaVladimir B ArionPublished in: Inorganic chemistry (2022)
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 HL 1 - HL 4 and copper(II) complexes 1 - 4 . All compounds were characterized by spectroscopic methods ( 1 H and 13 C 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 1 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 HL 1 - HL 4 and 1 - 4 with those of structurally similar paullone-derived ( HL 5 - HL 7 and 5 - 7 ) and latonduine-derived scaffolds ( HL 8 - HL 11 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.
Keyphrases
- high resolution
- mass spectrometry
- ms ms
- endoplasmic reticulum stress
- magnetic resonance
- reactive oxygen species
- liquid chromatography
- induced apoptosis
- high performance liquid chromatography
- single molecule
- tandem mass spectrometry
- emergency department
- solid state
- molecular docking
- magnetic resonance imaging
- signaling pathway
- young adults
- gas chromatography
- adverse drug