Ruthenium anti-cancer drugs

Ruthenium anti-cancer drugs are coordination complexes of ruthenium complexes that have anticancer properties. They promise to provide alternatives to platinum-based drugs for anticancer therapy. No ruthenium anti-cancer drug has been commercialized.

Since 1979, when Cisplatin entered clinical trials, there has been continuing interest in alternative metal-based drugs. The leading ruthenium-based candidates are BOLD-100 and TLD-1433. Other ruthenium based therapeutics that have been tested clinically include NAMI-A and KP1019. The first ruthenium-based drug to enter clinical trials was NAMI-A. More ruthenium drugs are still under development. Ruthenium complexes as anticancer drugs were originally designed to mimic platinum drugs for targeting DNA, but emerging ruthenium compounds have shown a variety of mechanisms of actions, which include ROS generation, and as Endoplasmic reticulum stress agents.

3D rendering of human serum albumin (HSA)

The ruthenium complex BOLD-100 binds to serum albumin as established by X-ray crystallography. This adduct is proposed to facilitate uptake. The levels of serum albumin in these cancerous cells are greatly increased, which may contribute to the lower toxicity associated to the ruthenium drugs in comparison to platinum.

Prospective ruthenium anti-cancer drugs

BOLD-100

BOLD-100, or sodium trans-, is the most clinically advanced ruthenium-based therapeutic. As of November 2021, BOLD-100 was being tested in a Phase 1b clinical trial in patients with advanced gastrointestinal cancers in combination with the chemotherapy regimen FOLFOX.

NAMI

Chemical structure of sodium trans- (BOLD-100)

NAMI {Na(DMSO)(imida)]} and NAMI-A {H2Im are salts that were investigated as anti-cancer drugs. NAMI-A is considered a pro-drug and is inactive at physiological pH of 7.4. Cancer cells generally contain a lower oxygen concentration as well as higher levels of glutathione and a lower pH than normal tissues creating a reducing environment. Upon entering cancer cells NAMI-A is activated by the reduction of Ru(III) to Ru(II) to form the active anti-cancer agent.

KP1019

KP1019, a salt of trans-tetrachlorobis(indazole)ruthenate(III) were investigated as drugs. 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. Instead KP1339 is used as a preparation of KP1019 in clinical trials, since it has a better solubility as a sodium salt.

Proteins and other N-donors are good binding partners for KP1019.

Especially transferrin and albumin are good binding partners. The overall method of action for KP1019 needs to be supported further.

Tumor cells have a high requirement of iron, which results in a large concentration of transferrin. Ru(III) complexes bind to transferrin and are proposed to interfere with iron uptake.

RAPTA

RAPTA compounds are ruthenium–arene complexes bearing the 1,3,5-triaza-7-phosphatricyclo-decane ligand. The complex has a piano stool geometry. The PTA ligand confers water solubility, and the two chloride ligands are labile. RAPTA compounds have low general toxicity that apparently reduces the side-effects associated with chemotherapy.

RAED

Ruthenium diamine complexes have been investigated as potential anticancer drugs. RAED compounds are ruthenium–arene complexes bearing the 1,2-ethylenediamine ligand.

The ruthenium diamine complexes form adducts with guanine. Methylation or substitution on en-NH, which prevent the hydrogen bonding, can lead to the loss of cytotoxic activity of the complex toward cancer cell. The ethylenediamine ligand suppresses reactions of the complex with amino acid residues. The Ru(II) complexes have a higher affinity to DNA in the presence of protein than the Ru(III) compounds, such as NAMI-A.

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