chemistry

KP1019

KP1019 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 KP1019 rather than just read about it. In short: KP1019, or indazole trans-[tetrachlorobis(1H-indazole)ruthenate(III)], 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.

Key takeaways

KP1019 belongs to chemistry; place it in that map before memorising details.
Learn the definition first, then one example that makes the definition concrete.
Connect KP1019 to a quantity you can measure, compute or draw — that is where exam questions come from.
Reproduce the core statement of KP1019 from memory before moving on to harder problems.

Reference excerpt

KP1019, or indazole trans-[tetrachlorobis(1H-indazole)ruthenate(III)], 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 (III) reduction potential positively correlates with the complex's antiproliferative activity.

Reactivity with serum proteins KP1019 binds transferrin (Tf), 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.

Interaction with DNA Most metal-based anti-tumor compounds interact strongly with DNA. Binding assays of KP1019 with the four common nucleotide bases reveal a preference for guanosine 5’-monophosphate and adenosine 5’-monophosphate. KP1019 is able to untwist and bend DNA weakly. While Pt-based compounds also target purines, KP1019's DNA lesions may differ in quantity and strength. In tumor cells, the drug induces 15-fold lower interstrand DNA cross-linking efficiency than cisplatin. The interaction of KP1019 and its imidazole-containing analogue KP418 with DNA increases in the hypoxic environment that tumor cells are subject to. This correspondingly increased cytotoxicity as well.

Preclinical cancer efficacy KP1019 and KP1339 both induce apoptosis in colorectal tumor cell lines SW480 and HT29. This is induced predominantly by a loss of mitochondrial membrane potential in a high percentage of cells. DNA strand breaks are not believed to be the cause of the major damage. This is due to KP1019-induced death being independent of the cell's p53 status. Studies have shown oxidative stress to contribute towards KP1019-induced apoptosis. Furthermore, KP1019 has been shown to counteract tumor resistance to other metal-based drugs. KP1019 does not appear to be susceptible to the same cancer cell mechanism of acquiring drug resistance as other metal-based drugs, and remains potent in cell-lines known for their drug resistance. KP1019 has significant antineoplastic activity in chemically induced colorectal carcinoma in rats surpassing its in-vitro activity. The rat model of colorectal carcinoma is highly analogous to human colorectal carcinoma and presents a promising target for the drug. The yeast strain Saccharomyces cerevisiae serves as a cellular model for KP1019 and manifests induced DNA damage, cell cycle delay, and cell death.

Phase I clinical trials KP1019 was administered to patients twice weekly in doses ranging from 25 mg to 600 mg for three weeks. Patients had advanced solid tumors. Five out of six patients saw disease stabilization for up to 10 weeks. No serious side effects of KP1019 were reported.

References

Illustrations

Worked examples

Example 1 — a first encounter with KP1019

Start with the simplest possible case. Write down what KP1019 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 KP1019 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 KP1019 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 KP1019

In research: KP1019 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 KP1019 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: KP1019 is common in secondary-school and first-year university syllabi. It links to neighbouring topics Chloro complexes, Experimental cancer drugs, Indazoles, so understanding it makes those chapters shorter.
In everyday life: Look for KP1019 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 KP1019 in 20 minutes

Read the reference excerpt below once, without taking notes.
Close the page and write down what KP1019 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.
Explain KP1019 out loud to somebody else — or to Teacher Smith in the lgStudy chat.

Frequently asked questions

What is KP1019 in simple terms?

Why does KP1019 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 KP1019?

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 KP1019.