Indazolium trans-[tetrachlorobis(1H-indazole)ruthenate(III)], or KP1019, has been shown to reduce tumor size in rats and trigger apoptosis in vitro. In a limited clinical trial, no dose limiting toxicity was found for the drug. Although the drug itself is effective in killing cancer cells, the details of its mechanism are not well understood. KP1019 is thought to undergo activation by reduction of the ruthenium center once inside the cell. One of the reducing agents often found in excess in cancer cells is glutathione, which could potentially interact with the ruthenium center and activate the drug. This study has examined this interaction using NMR spectroscopy looking specifically at the peak changes in the aromatic region that correspond to the bound indazole ligands in the reduced form. Unfortunately, the indazolium counterion also has peaks in this region making analysis more difficult. To better elucidate this interaction, KP1339, a sodium salt of KP1019 with a higher aqueous solubility, was synthesized and reacted with glutathione. Since KP1339 does not have the indazolium counterion, changes in the bound indazole peaks could be more easily analyzed. These results show the shifting of the bound ligand peaks upon reduction, and further changes over time provide insight into the mechanism of ligand exchange in the reduced species.

Reduction of KP1019/KP1339 using glutathione

255th National Meeting (2018)

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