New 3rd Generation of Casiopeinas Family Compounds with Indomethacin as a Secondary Ligand: Synthesis, Characterization, Antiproliferative Activity, and Nanoencapsulation ^†

The search for new molecules with greater antitumor activity as well as new forms of administration of chemotherapeutic drugs are the task of this work.

Synthesis of new seven copper coordination compounds with a general structure of [Cu(NN)(Indo)]NO₃ was carried out, where NN represents bidentate binders of the diimine 1,10-phenanthroline or 2,2’-bipyridine type, with methyl substituents at different positions of the aromatic rings, and Indo represents the indomethacin drug deprotonated.

The characterization of green powders obtained confirms the presence of both ligands and shows compounds with a Cu(II) center with square-based pyramid C_4v. The redox behavior of the Cu (II)/Cu (I) process shows quasi-reversible systems in which the electronic transfer is carried out slowly.

The antiproliferative activity of the compounds was evaluated in vitro against a cervical cancer cell line (HeLa). It was observed that the incorporation of indomethacin to Cu-diimine coordination compounds allows obtaining compounds with antitumor activity with values of mean inhibitory concentration (IC 50) in a range between 0.67 and 25.2 μM. The compound [Cu(4,7-dimethyl-phen)(Indo)]NO₃ is one of the most active in the cell line evaluated (0.72 ± 0.10 μM), so it was selected as a model drug to carry out the design of a nanogel sensitive to the stimuli of increased temperature and acid pH, which will allow controlling the release of the compound in conditions similar to those found in the tumor zone

Synthesis and characterization of a nanogel composed by chitosan and NIPAAm were carried out. The release of the compound by the nanogel under different values of pH (5.00 and 7.4) is presented. The results showed that the system could be useful for the release of the compound in the tumor microenvironment.