chemistry

Ruthenium anti-cancer drugs

Ruthenium anti-cancer drugs is a chemistry topic covered in the lgStudy science library. This page brings together a partial reference excerpt, illustrations, worked examples, real-world applications and a short study plan, so you can understand Ruthenium anti-cancer drugs rather than just read about it. In short: 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.

Key takeaways

Ruthenium anti-cancer drugs belongs to chemistry; place it in that map before memorising details.
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Connect Ruthenium anti-cancer drugs to a quantity you can measure, compute or draw — that is where exam questions come from.
Reproduce the core statement of Ruthenium anti-cancer drugs from memory before moving on to harder problems.

Reference excerpt

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.

Properties of ruthenium complexes Ruthenium has numerous properties that qualify it as an antineoplastic drug contender.

Oxidation states and geometry Ruthenium complexes typically adopt oxidation states II and III The geometry assumed by most ruthenium complexes is octahedral, which differs from the square planar molecular geometry typical for platinum(II). The presence of six ligands allows for tuning of the complexes' electronic and steric properties. 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.

Ligand exchange rates The rate of ligand exchange for ruthenium complexes is relatively slow in comparison with other transition metal complexes. 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. This allows the Ru complex to remain intact as it approaches the target as well as remain viable throughout its interaction with the cells. It is also possible through ligand variation to precisely tune the exchange kinetics, allowing a large degree of control over the complex's stability.

Activation The theory of "activation by reduction" is based on the understanding that Ru(II) complexes are generally more reactive than Ru(III) complexes. As cancer cells are generally growing and multiplying much more rapidly than normal healthy cells, this creates an environment that is less oxygen-rich due to the raised metabolic rate. 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. This theoretically allows for ruthenium complexes to be administered as much less active, non-toxic Ru(III) compounds (as a prodrug), which can be activated solely at the site of the cancerous cells. 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. 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 phenomenon remains a theory, and has been primarily demonstrated in vitro. Although this theory is attractive, convenient, and grounded in fundamental ruthenium chemistry, this theory falls apart when investigated under in vivo. A direct contradiction of this theory was proven using XANES and BOLD-100. This study examined several tissues (tumor included) of SW480-bearing mice for 24 hours after administration of BOLD-100. 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.

Biological transportation

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-[tetrachlorobis (1H-indazole)ruthenate(III)], 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

NAMI {Na[trans-RuCl4](DMSO)(imida)]} and NAMI-A {H2Im[trans-RuCl4(DMSO)HIm[imidH] 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, trans-tetrachlorobis(indazole)ruthenate(III), 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. KP1019 reacts with proteins and other N-donors. 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-[3.3.1.1]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 lowers the side-effects associated with chemotherapy.

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Illustrations

Worked examples

Example 1 — a first encounter with Ruthenium anti-cancer drugs

Start with the simplest possible case. Write down what Ruthenium anti-cancer drugs claims or describes in one sentence, then invent the smallest concrete situation in which that sentence is true. In chemistry, the smallest case is usually a single object, a single equation or a single measurement. Check that every symbol or term in your sentence has a meaning in that case.

Example 2 — changing one variable

Take the situation from Example 1 and change exactly one quantity: double it, halve it, or set it to zero. Predict what should happen to Ruthenium anti-cancer drugs before you calculate. Comparing your prediction with the result is the fastest way to find out whether you understand the idea or only the words.

Example 3 — an exam-style question

Typical questions about Ruthenium anti-cancer drugs ask you to (a) state it precisely, (b) apply it to given data, and (c) explain a limitation. Practise writing all three answers in under five minutes; the third part is what separates a full-mark answer from an average one.

Applications of Ruthenium anti-cancer drugs

In research: Ruthenium anti-cancer drugs appears in chemistry research whenever the underlying quantities have to be modelled precisely. Papers usually cite it as a starting assumption and then explore where it breaks down.
In technology and industry: Engineering practice reuses Ruthenium anti-cancer drugs in design rules, simulations and safety margins. Knowing the idea lets you read a specification sheet and understand why the numbers look the way they do.
In the classroom: Ruthenium anti-cancer drugs is common in secondary-school and first-year university syllabi. It links to neighbouring topics Experimental cancer drugs, Ruthenium-based antineoplastic agents, Ruthenium compounds, so understanding it makes those chapters shorter.
In everyday life: Look for Ruthenium anti-cancer drugs outside the textbook — in sport, cooking, traffic, electronics or the sky above you. An example you found yourself is remembered far longer than one you were given.

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How to study Ruthenium anti-cancer drugs in 20 minutes

Read the reference excerpt below once, without taking notes.
Close the page and write down what Ruthenium anti-cancer drugs means in your own words.
Compare your version with the excerpt and mark what you missed.
Work through the three examples above with pen and paper.
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Frequently asked questions

What is Ruthenium anti-cancer drugs in simple terms?

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.

Why does Ruthenium anti-cancer drugs matter?

Because it connects several chemistry ideas at once: it gives you a definition you can apply, a quantity you can calculate, and a way to check whether a result is plausible.

How should I study Ruthenium anti-cancer drugs?

Read the excerpt, restate it from memory, then work through the examples and applications listed on this page. The five-step study plan above takes about twenty minutes.

What does this page cover?

It gives you a compact reference excerpt plus original lgStudy explanations, examples, applications and study material on Ruthenium anti-cancer drugs.