Casiopeinas® third generation, with indomethacin: synthesis, characterization, DFT studies, antiproliferative activity, and nanoencapsulation

Abstract

Seven new Casiopeinas® were synthesized and properly characterized. These novel compounds have a general formula [Cu(N–N)(Indo)]NO₃, where Indo is deprotonated indomethacin and N–N is either bipyridine or phenanthroline with some methyl-substituted derivatives, belonging to the third generation of Casiopeinas®. Spectroscopic characterization suggests a square-based pyramid geometry and voltammetry experiments indicate that the redox potential is strongly dependent on the N–N ligand. All the presented compounds show high cytotoxic efficiency, and most of them exhibit higher efficacy compared to the well-known cisplatin drug and acetylacetonate analogs of the first generation. Computational calculations show that antiproliferative behavior can be directly related to the volume of the molecules. Besides, a chitosan (CS)–polyacrylamide (PNIPAAm) nanogel was synthesized and characterized to examine the encapsulation and release properties of the [Cu(4,7-dimethyl-1,10-phenanthroline)(Indo)]NO₃ compound. The results show good encapsulation performance in acidic conditions and a higher kinetic drug release in acidic media than at neutral pH. This result can be described by the Peppas–Sahlin model and indicates a release mechanism predominantly by Fick diffusion.