Titanium and Cancer Treatment Overview

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Questions and Answers

What is the primary challenge that titanocenes face for clinical applications?

  • Limited availability of raw materials
  • High production costs
  • Poor aqueous solubility and instability in water (correct)
  • Toxicity to healthy cells

What strategy was used by McGowan and coworkers to enhance the properties of titanocenes?

  • Eliminating the titanium component
  • Introducing radioactive isotopes
  • Synthesis of ring-substituted cationic titanocene dichloride derivatives (correct)
  • Mixing with another class of antitumor agents

What type of cancer showed significant cytotoxic activity against the improved titanocenes?

  • Lung cancer
  • Breast cancer
  • Prostate cancer
  • Cisplatin-resistant ovarian cancer (correct)

How do substituted fulvenes contribute to the synthesis of titanocenes?

<p>They allow for the introduction of functional groups into titanocenes. (C)</p> Signup and view all the answers

What structural feature characterizes ansa-titanocenes?

<p>A carbon–carbon bridge between Cp rings (C)</p> Signup and view all the answers

What process leads to the formation of ansa-titanocenes from substituted fulvenes?

<p>Reductive dimerisation (A)</p> Signup and view all the answers

Which of the following best describes fulvenes?

<p>Organic molecules with a five-membered ring system (B)</p> Signup and view all the answers

The research by Tacke and coworkers primarily focused on developing what kind of methods?

<p>Novel synthetic methods starting from substituted fulvenes (C)</p> Signup and view all the answers

What is the significance of the hydroxyl group in the tamoxifen derivatives?

<p>It improves recognition by the oestrogen receptor. (B), It increases the RBA value of the derivative. (C)</p> Signup and view all the answers

Which derivative showed a higher cytotoxic effect against the MCF-7 cell line?

<p>Tamoxifen with R = OH at 4 μM. (A)</p> Signup and view all the answers

Why is the vectorization of DACH–Pt considered not beneficial as an SERM?

<p>There is no significant improvement over oxaliplatin. (C)</p> Signup and view all the answers

What was the unexpected result from the cytotoxicity tests of the titanocene-tamoxifen derivative?

<p>It showed a proliferative effect. (D)</p> Signup and view all the answers

What is the primary challenge associated with metal-based drugs like ferrocifen?

<p>Difficulty in finding suitable formulations. (B)</p> Signup and view all the answers

What is the observed RBA value of the titanocene-tamoxifen derivative?

<p>8.5% (B)</p> Signup and view all the answers

Which formulation method was NOT mentioned as being researched for drug delivery of ferrocifen?

<p>Microsphere technology. (B)</p> Signup and view all the answers

What effect did the titanium moiety have on the titanocene-tamoxifen derivative?

<p>It enhanced the estrogenic effect. (B)</p> Signup and view all the answers

What were substituted vanadocene dichlorides found to be when tested against renal cell cancer?

<p>Highly toxic compounds (B)</p> Signup and view all the answers

Which vanadium compound was evaluated as a potential treatment for Diabetes Mellitus?

<p>Sodium vanadate (A)</p> Signup and view all the answers

What was the main observed effect of sodium vanadate in patients with Diabetes Mellitus?

<p>Mild effects (B)</p> Signup and view all the answers

What type of studies are still needed for substituted vanadocenes after in vitro testing?

<p>Preclinical studies (A)</p> Signup and view all the answers

Which of the following statements is true regarding the toxicity of substituted vanadocenes compared to titanocene?

<p>Substituted vanadocenes are more potent and toxic than titanocene (A)</p> Signup and view all the answers

When were inorganic vanadium compounds evaluated for their potential treatment of Diabetes Mellitus?

<p>End of the nineteenth century (B)</p> Signup and view all the answers

What is a possible clinical application of substituted vanadocenes, based on the information provided?

<p>Treatment of renal cell cancer (B)</p> Signup and view all the answers

What does the compound sodium vanadate specifically target in patients with Diabetes Mellitus?

<p>Glucose levels in the blood (D)</p> Signup and view all the answers

What is a significant challenge in analyzing active vanadium compounds?

<p>Their paramagnetic character (D)</p> Signup and view all the answers

Which vanadium compound is noted for undergoing fast hydrolysis?

<p>Vanadocene dichloride (D)</p> Signup and view all the answers

What type of vanadium complexes were found to have cytotoxic activity against testicular cancer?

<p>Organometallic vanadium(+IV) complexes (B)</p> Signup and view all the answers

What did in vitro studies reveal about the substituted vanadocene compounds?

<p>They exhibit variable cytotoxic activity. (D)</p> Signup and view all the answers

How does the mode of action of vanadium-induced cytotoxicity differ from that of titanocene dichloride?

<p>It is not well understood and requires further study. (B)</p> Signup and view all the answers

What is a feature of the substituted vanadocene compounds being researched?

<p>They contain substituted cyclopentadienyl ligands. (C)</p> Signup and view all the answers

Which compound showed no cytotoxic effect in the studies conducted?

<p>Vanadyl(IV) sulfate (C)</p> Signup and view all the answers

What kind of research is being conducted alongside vanadocene analogues?

<p>Synthesis of substituted titanocene dichlorides. (B)</p> Signup and view all the answers

What type of reaction allows access to benzyl-bridged titanocenes?

<p>Hydridolithiation reaction (D)</p> Signup and view all the answers

Which titanocene has been reported as the most intensively studied in relation to anticancer activity?

<p>Titanocene Y (A)</p> Signup and view all the answers

What is a potential disadvantage of using carbolithiation to obtain titanocenes?

<p>It introduces additional stereocentres. (B)</p> Signup and view all the answers

What compound is utilized during the hydridolithiation reaction for creating titanocenes?

<p>Superhydride (LiBEt3 H) (C)</p> Signup and view all the answers

What characteristic is shared by the titanocenes synthesized through hydridolithiation and carbolithiation?

<p>Both exhibit moderate cytotoxic activity. (D)</p> Signup and view all the answers

What is one advantage of incorporating functional groups into titanocenes?

<p>It improves water solubility. (C)</p> Signup and view all the answers

What type of cancer was specifically mentioned in the studies relating to titanocene activity?

<p>Renal cell cancer (B)</p> Signup and view all the answers

How does substituent variation in titanocenes generally affect their properties?

<p>It potentially alters their solubility. (C)</p> Signup and view all the answers

What is the primary purpose of the transmetallation step in the synthesis of substituted titanocenes?

<p>To introduce titanium into the compound. (D)</p> Signup and view all the answers

What property did titanocenes demonstrate in in vitro experiments?

<p>Moderate cytotoxic activity (D)</p> Signup and view all the answers

What was identified as the dose-limiting side effect of the treatment?

<p>Cardiac arrhythmia (C)</p> Signup and view all the answers

What were the main issues faced during the clinical trials of the titanium-based compounds?

<p>Poor water solubility and fast hydrolysis (C)</p> Signup and view all the answers

Which of the following compounds is associated with the synthesis described?

<p>[Ti(bzac)2 (OEt)2] (D)</p> Signup and view all the answers

What aspect of the formulation led to the discontinuation of clinical trials?

<p>The existence of isomers (D)</p> Signup and view all the answers

Which isomer of budotitane is classified as trans,trans,trans-?

<p>trans,trans,trans-[Ti(bzac)2(OEt)2] (B)</p> Signup and view all the answers

What is the main characteristic of titanocene or titanium-based compounds that limits their effectiveness as anticancer agents?

<p>Poor water solubility and fast hydrolysis (D)</p> Signup and view all the answers

What chemical reaction is represented in the synthesis of budotitane?

<p>Ligand substitution reaction (D)</p> Signup and view all the answers

What is a potential consequence of the fast hydrolysis of titanium-based compounds?

<p>Reduced therapeutic efficacy (D)</p> Signup and view all the answers

Flashcards

Cardiac arrhythmia

A problem with the heartbeat's rhythm.

2Hbzac + TiCl4

Reactants in the synthesis of budotitane.

Budotitane

A titanium compound, potentially a drug.

Isomers of budotitane

Different molecular structures with the same chemical formula.

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Formulation problems

Difficulties in preparing the drug for use.

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Clinical trials discontinuation

Stopping the testing of a drug in humans.

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Poor water solubility

A drug does not dissolve well in water.

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Fast hydrolysis

A drug quickly breaks down in water.

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4-hydroxytamoxifen

A chemical compound with a hydroxyl group, used in research for breast cancer treatment.

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Oxaliplatin

A cytotoxic drug that has shown effectiveness against breast cancer cells.

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Cytotoxic effect

The ability of a substance to kill or damage cells.

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RBA (Relative Binding Affinity)

A measure of how strongly a drug binds to a specific receptor.

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IC50 value

The concentration of a drug required to inhibit 50% of a biological process, like cell growth.

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Estrogen Receptor

A receptor protein that binds to estrogen and regulates gene expression.

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Titanocene-tamoxifen derivative

A tamoxifen derivative containing titanium, showing estrogenic activity.

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OH-ferrocifen

A ferrocifen derivative with a hydroxyl group, subjected to clinical trials

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Titanocenes

Organotitanium compounds with two cyclopentadienyl rings attached to titanium.

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Aqueous Solubility

The ability of a substance to dissolve in water.

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Cationic Titanocenes

Titanocenes with a positive charge, which improves water solubility.

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Cisplatin-resistant ovarian cancer

A type of ovarian cancer that is not affected by cisplatin treatment.

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Substituted Fulvenes

Fulvenes with added chemical groups, used to make titanocenes.

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Ansa-Titanocenes

Titanocenes with a carbon-carbon bridge between the cyclopentadienyl rings, often catalysts.

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Reductive Dimerisation

A chemical reaction where two molecules combine by losing electrons.

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Cyclopentadienyl (Cp) rings

Five-membered carbon ring systems, key part of titanocenes.

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Cytotoxic activity

The ability of a substance to kill or damage cells

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Hydridolithiation

Reaction of substituted fulvenes with superhydride

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Carbolithiation

Reaction with organolithium compounds

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Transmetallation

Transfer of a metal from one compound to another

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Titanocenes

Titanium compounds with a specific ring structure

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Renal cell cancer

Cancer of the kidney cells

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In vitro testing

Testing performed in a laboratory setting, not in a living organism

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Benzyl-bridged titanocenes

Titanocenes with a benzyl group connecting the titanium rings

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Water solubility

Ability of a substance to dissolve in water

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Anticancer activity

Ability of a substance to fight or prevent cancer

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Vanadium compounds hydrolysis

Vanadium compounds break down quickly in water.

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Paramagnetic character

A property making it hard to analyze vanadium compounds with standard methods, like NMR.

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Vanadocene dichloride

An organometallic compound prone to hydrolysis, potentially useful in cancer treatment.

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Cytotoxic activity

The ability of a compound to kill or damage cells.

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Organometallic vanadium(+IV) complexes

Metal-containing vanadium compounds that showed anti-cancer activity.

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Substituted vanadocenes

Vanadocene compounds with modified structures, studied for anti-cancer potential.

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Apoptosis induction

Triggering programmed cell death (apoptosis).

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In vitro studies

Experiments performed in a laboratory container instead of a living organism.

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Vanadocene dichloride structure

A chemical structure with vanadium, chlorine, and cyclopentadienyl rings.

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Substituted vanadocenes toxicity

Certain substituted vanadocene dichlorides are highly toxic to renal cancer cells, stronger than titanocenes.

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Insulin mimetics

Inorganic vanadium compounds tested to regulate blood glucose levels like insulin.

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Sodium vanadate

An inorganic vanadium compound initially evaluated as an anti-diabetes treatment.

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In vitro testing

Testing a compound's effect on cells in a lab, not in a whole organism.

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Preclinical studies

Testing a treatment before human trials. Needed before human testing.

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Diabetes Mellitus (DM)

A disease where the body can't regulate blood sugar.

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Organometallic compounds

Compounds containing metal-carbon bonds, like the vanadocene.

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Study Notes

4-Hydroxytamoxifen and Ferrocifen

  • 4-hydroxytamoxifen and ferrocifen are derivatives used in cancer treatment.
  • 4-hydroxytamoxifen showed cytotoxic effect of 6.3 µM on MCF-7 breast cancer cells.
  • Tamoxifen-vectorized derivatives also showed anti-proliferative effect.
  • The hydroxyl group in the active metabolite of tamoxifen is important in oestrogen receptor recognition.
  • Titanocene-tamoxifen derivative has an estrogenic effect comparable to that of oestrogen.
  • Proliferative effect observed with the titanocene-tamoxifen derivative.

Titanocenes

  • Titanium (Ti) is a group 4 d-block metal.
  • It has no known native role in the human body, despite its high abundance in the earth's crust.
  • Titanium complexes are known for catalytic properties and interactions with biomolecules.
  • Titanium dioxide (TiO2) is a white solid with low aqueous solubility, used as a white pigment.
  • Research into titanium complexes as anticancer agents focuses on complexes containing functional groups that can interact with biomolecules.
  • Pharmaceutical approaches include nanoparticles, cyclodextrins, and lipid nanocapsules.

History of Titanium-Based Anticancer Agents

  • The success of cisplatin led to research into metal-based anticancer drugs.
  • Titanocene dichloride (Cp2TiCl2) and budotitane were identified as promising drug candidates.
  • Both compounds contain labile groups analogous to cisplatin.
  • Hydrolysis in titanium compounds is faster than in cisplatin, leading to formation of hydroxo-bridges and insoluble TiO2.
  • Cp2TiCl2 is red crystalline solid with Ti(IV) center coordinated by two n-Cp ligands and two chlorine ligands.
  • The planar cyclopentadienyl ligands are coordinated to the titanium center in a bent sandwich configuration.
  • Cp2TiCl2 has only 16 VEs: six electrons from each Cp ligand, two from each Cl.
  • Titanium will accumulate near phosphorus-rich areas, indicating a titanium-DNA interaction.
  • Crystallographic studies suggest that Cp groups sterically prevent DNA cross-linking in Cp2TiCl2.
  • In cells, Ti(IV) may bind DNA backbone, which is not very strong.
  • Preclinical tests showed promising results.
  • Hydrolytic instability (loss of chlorides at low pH) is a significant challenge for clinical use.
  • Formulation as lyophilised powder or water-soluble powder is required for clinical trials.

Vanadium Compounds (Vanadocenes)

  • Vanadium is a Group 5 d-block metal.
  • Vanadium compounds are also researched for anticancer properties.
  • Vanadium compounds are very similar in their properties to titanium.
  • Vanadium(IV) complexes exist as octahedral, tetrahedral, and diatomic oxovanadium ions.
  • Some vanadium compounds are toxic.
  • Vanadocene dichloride is structurally similar to Cp2TiCl2, but is even more prone to hydrolysis.
  • The compounds have shown some cytotoxic activity, especially against testicular cancer.
  • Vanadium compounds have exhibited potential as insulin mimetics.

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