# Studies on the Complexation of Platinum(II) by Some 4-Nitroisothiazoles and the Cytotoxic Activity of the Resulting Complexes

## TL;DR

This study explores new platinum complexes with isothiazoles and finds some are as effective as cisplatin in killing cancer cells.

## Contribution

The paper introduces novel platinum(II) complexes and evaluates their cytotoxicity and structural properties.

## Key findings

- Some platinum complexes showed cytotoxic activity comparable to cisplatin against breast and ovarian cancer cells.
- The trans complex C2 was more toxic to healthy cells than to certain cancer cells.
- Theoretical calculations suggest nitrogen, not sulfur, coordinates platinum in complexation.

## Abstract

Five novel platinum(II) complexes C1–C5 were synthesized in the reaction of the appropriate substituted 4-nitroisothiazoles with K2PtCl4 and characterized with elemental analysis, ESI MS spectrometry, NMR spectroscopy, and IR spectroscopy. Also, a new methyl 3-methyl-4-nitroisothiazole-5-carboxylate (L2) was obtained. The structures of trans complex C4 and the new isothiazole derivative L2 were additionally confirmed by X-ray diffraction (XRD) method. The cytotoxicity of the investigated complexes was examined in vitro on three human cancer cell lines (MCF-7 breast, ES-2 ovarian, and A549 lung adenocarcinomas) in both normoxic and hypoxic conditions. The tested complexes, except for the most polar cis
C5, which appeared to be the least active, showed cytotoxic activity comparable to that of the reference cisplatin. cis-complex C1, trans
C2, and trans
C3 showed slightly better cytotoxic activity than cisplatin against the MCF-7 cell line. The complexes had the weakest effect on the A549 cell line. No differences in the cytotoxic activity of the complexes were observed between normoxic and hypoxic conditions, except for the A549 cell line, where all the complexes, except for C2, were inactive in hypoxia. However, most complexes, including the reference cisplatin, were equally toxic to healthy BALB/3T3 cells and cancer cells. The trans complex C2 (isomeric to cis
C1) showed even greater toxicity to healthy cells than to MCF-7 and A549 cancer cells. Some complexes were tested for stability against glutathione (GSH) solution to gain additional information that may facilitate the explanation of the pharmacological activity of the tested compounds. Additionally, some theoretical calculations on the thermochemistry of the complexation process were performed using quantum density functional theory (DFT), which indicate that complexation should occur through the coordination of the platinum cation by the nitrogen rather than the sulfur atom of the isothiazole ring.