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.

Scheme 1. The seven heteroleptic complexes of Cu^II under study.

Fig. 1. Cyclic voltammogram of 0.001 mol L⁻¹ [Cu(4,4′-dimethyl-2,2′-bipyridine)(Indo)]NO₃, 0.1 mol L⁻¹ TBAPF₆ in DMSO, v = 0.1 V s⁻¹.

Fig. 2. Antiproliferative activity and molar volume relations.

Scheme 2. Scheme of CS–NIPAAm synthesis.

Fig. 3. Micrographs for the nanogel at pH: 5.0 (left) and 7.4 (right).

Fig. 4. Percentage of in vitro cumulative [Cu(4,7-dimethyl-1,10-phenanthroline)(Indo)]NO₃ released as a time function.