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KP1019 is an example on a ruthenium based anticancer drug. It was one of the two first of its kind transferred into clinical trials.

Structure, properties and synthesises.
KP1019 (trans-tetrachlorobis(indazole)ruthenate(III)) has an octahedral structure with two trans N-donor indazole and four chloride ligands in the equatorial plan. The structure was proved by X-ray characterization in 1999.

The octahedral geometry facilitates a change in the oxidation state without great geometrically differences. This is different from the formerly known platinum based drugs.

KP1019 is a red/brown powder, which is stable in solid state.

It has a low solubility in water, which makes it difficult to transport in the bloodstream. Instead KP1039 is used as a preparation of KP1019 in clinical trials, since it has a better solubility as a sodium salt.

To synthesise KP1019, RuCl3*H2O is refluxed through a mixture of ethanol and HCl, followed by a treatment with excess of indazole.

Mechanism of action

Proteins and other N-donors are good binding partners for KP1019 in the bloodstream via ligand substitution of a chloride ligand. , Especially transferrin and albumin are good binding partners, which leads to the action of the anticancer effect. The overall mechanism of action for KP1019 needs to be supported further, but there is good hypothesis of how the mechanism takes place.

Tumor cells have a high requirement of iron, which results in a large number of transferrin molecules. Ru(III) complexes will bind to transferrin in a 2:1 ratio, and the Ru(III) complexes will be transported into the cell in favour of the required iron.

It is possible to reduce the Ru(III) complex in the bloodstream in principle, but UV/Vis studies show that this will not occur. Thus Ru(III) complexes is not reduced and therefore not activated outside the tumor cells.

However, the Ru(III) complexes is reduces in tumor tissues, where the environment is more reductive than the environment of a normal cell. This is due to an insufficient formation of new blood vessels and therefore a lower oxygen level coursed by the rapid growth of tumor cells.

It is not clear which reducing agent reduces Ru(III), but most research indicates gluthathione could have a role in the reduction. However it has also been shown that gluthathione has an inhibitor effect on the binding between DNA and Ru(II) complex, which leads to a contradiction because it is not favourable to have a activation agent that also inhibits the reaction.

DNA is one of the targets of KP1019. It is shown in an electrophoresis analysis that KP1019 can untwist and bend DNA, which can lead to apoptosis.

Target and side affects

The main target of KP1019 is colorectal cancer, but result from the clinical trial phase 1 shows that KP1019 might have an affect in other cancer cells as weel.

Through the clinical trials no severe side affects has been discovered. The low toxicity of KP1019 might be due to the fact that KP1019 is transferred into the cell and then reduced to its active form. Thus KP1019 is not present it its active form in the bloodstream and is not reduced in normal cells, because only the environment in the tumor cells is highly reductive.