Ruthenium anti-cancer drugs
Ruthenium complexes as anticancer drugs were originally designed to mimic platinum drugs for targeting DNA,[4] but emerging ruthenium compounds have shown a variety of mechanisms of actions, which include ROS generation, and as Endoplasmic reticulum stress agents.
[1][8][9] Its partially filled 4d sub-shell allows it to form complexes that are useful for a wide variety of applications including catalysis, electronics, photochemistry, biosensors and anticancer drugs.
The range of these exchange rates is around 10−2 to 10−4 s−1 which is on the scale of an average cell’s lifetime, giving the drug high kinetic stability and minimizing side reactions.
It is also possible through ligand variation to precisely tune the exchange kinetics, allowing a large degree of control over the complex’s stability.
When this is paired with the tendency of cancerous cells to contain higher levels of glutathione and a lower pH, a chemically reducing environment is created.
[1] The reduction is thought to occur by mitochondrial proteins or microsomal single electron transfer proteins, though it may also occur by trans-membrane electron transport systems which reside outside the cell – implying that entry to the cancerous cells may not be required for the drug to be effective.
[7] In theory it is also possible for the ruthenium compounds to be oxidized back to their inactive form if it leaves the cancerous environment.
This study showed that the Ru(III) oxidation state persists, and since BOLD-100 has significant biological effects within that 24-hour time point, this directly contradicts the "activation by reduction" mechanism.
[14] 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.
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.
[29] 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.
