KP1019
KP1019, or indazole trans-, is one of four ruthenium anti-cancer drugs to enter into phase I clinical trials, the others being BOLD-100, NAMI-A and TLD-1433. Research into ruthenium-based drugs has provided novel alternatives for platinum-based chemotherapeutics such as Cisplatin and its derivatives. KP1019 is useful for metastatic tumors and cis-platin resistant tumors. It exhibits potent cytotoxicity against primary tumors, particularly in colorectal cancer.
Structure and properties
KP1019 has an octahedral structure with two trans N-donor indazole and four chloride ligands in the equatorial plane. It has a low solubility in water, which makes it difficult to transport in the bloodstream. The Ru-Cl bonds are labile and KP1019 readily exchanges its chloro ligands in the presence of water.KP1019 derivatives
Due to its low solubility in water, KP1019 is often prepared as its sodium salt, the basis for KP-1339 and BOLD-100. By replacing the indazole rings with imidazole rings the derivative KP418 is formed. KP418 also exhibits anti-cancer activity, however it has not completed Phase I clinical testing. KP418 exhibits slower cellular uptake and slower protein binding. Similar to KP418, replacement of one of the imidazole ligands with DMSO yields NAMI-A. NAMI-A is considered to be one of two leading ruthenium-based anti-cancer drugs, along with BOLD-100. Both have entered clinical trials.Synthesis
KP1019 is synthesized by refluxing RuCl3-3H2O with HCl and ethanol. The ethanol is removed and indazole is allowed to react with the solution at 70 °C. The resulting solid is collected by filtration and its purity is evaluate by UV-visible spectroscopy, elemental analysis, and determination of reduction potential.Mechanism of action
Activation by reduction
The active form of KP1019 has Ru in its 2+ state. The hypoxic environment of cancer cell tissue facilitates this reduction and the specific action on cancer cells over healthy cells. The intracellular reducing agent is unknown, but glutathione is a good candidate as it reduces promiscuously and has a reduction potential on par with the transition of Ru from 3+ to 2+. This mechanism of action is favorable in terms of efficacy as well. An increase in Ru reduction potential positively correlates with the complex's antiproliferative activity.Reactivity with serum proteins
KP1019 binds transferrin, a 700 amino acid glycoprotein, in the pocket usually bound to 2 atoms of Fe3+. The transferrin protein binds to the transferrin receptor and is taken into the cell by endocytosis. This protein and its receptors are overexpressed in cancer cells owing to their increased demand for iron, and it is believed that Tf transport is the reason ruthenium compounds accumulate in tumors. CD and ESI-MS studies have shown that one molecule of Tf binds two ruthenium complexes via. The intracellular release requires a significant increase in pH due to the high binding affinity. Citric acid or adenosine 5’-triphosphate, which are both present in vivo, are capable of liberating KP1019.Human serum albumin, the most present protein in blood plasma, binds to KP1019 in a 1:4 protein:drug ratio. In plasma, it is almost exclusively bound to protein, up to 90%. It is possible that albumin serves to bind available Ru drugs until they are transported into the cell by Tf.