Vanadocenes

| Home | | Inorganic Pharmaceutical Chemistry |

Chapter: Essentials of Inorganic Chemistry : Organometallic Chemistry

Vanadium, with chemical symbol V and atomic number 23, is a member of the d-block metals and belongs to group 5 of the periodic table of elements.


Vanadocenes

Vanadium, with chemical symbol V and atomic number 23, is a member of the d-block metals and belongs to group 5 of the periodic table of elements (Figure 8.28).


Vanadium can be found in the earth’s crust in numerous minerals and is isolated from ores mostly as a by-product. Its main application is in the steel industry, where it is used as an alloy in combination with iron. Vanadium pentaoxide is also being used as a catalyst for the production of sulfuric acid. The metal vanadium has very similar properties to titanium. Therefore, it is not surprising that its metallocene, vanadium dichloride, was also subjected to research as a potential anticancer agent.

Vanadium is easily passivated by an oxide film, and the metal is insoluble in nonoxidising acids. Typical oxidation states are +II, +III, +IV and +V, whilst the biologically active oxidation states are +IV and +V. Vanadium reacts to vanadium halide by reacting the metal with the corresponding halogen under heating, whilst it also reacts with oxygen with the formation of V2O5. Vanadium (+V) oxides are amphoteric and, as a result, vanadates (VO43−) and dioxovanadium ions (VO2+) are formed in aqueous solutions depending on the pH (Figure 8.29) .


Vanadium is an essential trace metal in the human body, but still very little is known about its biological function. Vanadium is mainly found in its ionic state bound to proteins. As mentioned, the metal mostly occupies oxidation states +V and +IV in biological systems, resulting in electron configurations of [Ar]3d0 for V+5 and [Ar]3d1 for V+4. The chemical formula for the tetrahedral ion vanadate is written as VO43+; whereas the diatomic oxovanadium(+IV) ion, also called vanadyl, has the chemical formula VO2+ (Figure 8.30).

Vanadium compounds are well known for their toxicity. The most famous example is the poisonous mush-room toadstool, Amanita muscaria. A. muscaria contains the toxic compound amavadin, which is a toxic octahedral vanadium complex (see Figure 8.31) .


Vanadate and vanadyl are known to cause adverse effects in mammals, including loss of body weight, gas-trointestinal problems, reproductive toxicity and morbidity. However, their toxicity depends on a variety of factors such as the chemical form, oxidation state, route of administration and duration of exposure. Never-theless, toxic effects of vanadate or vanadyl are observed only at dose levels significantly greater than usual uptake through diet . Nevertheless, it is important to improve the understanding of the adverse and toxic effects of vanadium compounds before any compound can be successfully developed for clinical use.

 

Vanadocene dichloride as anticancer agents

Vanadocene dichloride [(η5-C5H5)2VCl2, dichloro bis( η5-cyclopentadienyl)vanadium(IV)] is structurally very similar to Cp2TiCl2. It also consists of a metal centre with an oxidation number of +IV, in this case vanadium, and two Cp and two chloride ligands. Vanadocene dichloride is a 17-electron complex containing an unpaired electron and is therefore paramagnetic (Figure 8.32).


Vanadocene dichloride has found application as a catalyst for polymerisation reactions, but was also intensively studied as an anticancer agent in parallel to Cp2TiCl2 because of their structural similarities. Vanadocene dichloride has proven to be even more effective than its titanium analogue as an antiproliferative agent against both animal and human cell lines in preclinical testing. The main problems are the difficult characterisation of the active vanadium compounds and their fast hydrolysis. Because of their paramagnetic character, it is difficult to apply standard classical analysis techniques such as NMR (nuclear magnetic resonance) to identify the antiproliferative vanadium species. Furthermore, vanadocene dichloride undergoes fast hydrolytic processes and is even more prone to hydrolysis than titanocene dichloride. This poses even more challenges for its potential clinical application .

In recent years, researchers have shown renewed interest in the use of substituted vanadocene dichlorides as potential anticancer agents. A selection of substituted vanadocenes have been synthesised and tested for their cytotoxic activity against testicular cancer. Examples of these compounds include vanadocenes con-taining substituted cyclopentadienyl ligands and/or replacement groups for the chloride ligands – similar to the research being undertaken for cisplatin analogues. Results of in vitro studies show that these com-pounds exhibit good but variable cytotoxic activity depending on the substitution pattern and induce apoptosis (cell-induced cell death). Interestingly, only organometallic vanadium(+IV) complexes showed cytotoxic activity against testicular cancer. When the purely inorganic compound vanadyl(IV) sulfate was tested in the same study, no cytotoxic effect was observed at the same concentrations. It is also important to note that titanocene dichloride and other metallocenes had no cytotoxic effect against testicular cancer. It was con-cluded that the mode of action of vanadium-induced cytotoxicity must be different from that of titanocene dichloride and other metallocenes (Figure 8.33) .


In parallel to the research undertaken with substituted titanocene dichlorides as potential chemotherapeutic agents, some of their vanadocene analogues have been synthesised. Some examples include the hydrolithiation of fulvenes and subsequent transmetallation with vanadium tetrachloride. 

The resulting substituted vanadocene dichlorides were found to be highly toxic compounds when tested in vitro against a model of renal cell cancer and more potent than the corresponding titanocene. Further preclinical studies are still needed (Figure 8.34) .


 

Further vanadium-based drugs: insulin mimetics

Towards the end of the nineteenth century, inorganic vanadium compounds were under evaluation as potential treatment options for Diabetes Mellitus (DM) as so-called insulin mimetics. Sodium vanadate (Na3V(+V)O4) was tested for its ability to lower glucose levels in the blood of candidates with and without DM. The inor-ganic vanadium compound showed mild effects in some of the patients suffering from DM, whilst no severe side effects were reported for the dose applied. 

However, research focused more on the less toxic inorganic vanadium compounds, such as vanadyl sulfate (V(+IV)OSO4) which is significantly less toxic than sodium vanadate. Nevertheless, with the development of insulin in 1922, the interest in vanadium compounds as antidiabetic drugs diminished (Figure 8.35) .


In more recent years, metal complexes have become of interest for a variety of clinical applications. This also renewed the interest for vanadium complexes to be examined for the treatment of diabetes. The vanadium complexes bis(maltolato)oxovanadium (BMOV) and bis(ethylmaltolato)oxovanadium (BEOV) have shown to be unique insulin mimetics when tested in diabetic rats [9, 17]. An increase in uptake and tolerability compared to the inorganic form was noted. Studies have also shown that there is a difference in distribution between the inorganic and the complexed form of vanadyl in in vivo experiments, which might relate to the differences in uptake and tolerability. Animal experiments with vanadyl sulfate have shown accumulation of vanadium mainly in the kidneys and liver, whilst experiments with the vanadyl complexes BMOV and BEOV resulted in a high accumulation on the bones followed by kidneys (Figure 8.36) [14, 18].

BMOV has proven itself as a successful antidiabetic agent when tested in animal models. Nevertheless, only very little is known about its mode of action. It is believed that BMOV acts as a competitive and reversible inhibitor of the enzyme protein tyrosine phosphatase (PTP). Other vanadium complexes are also known to inhibit PTP, but mostly inhibiting it irreversibly .

PTPs belong a family of enzymes that remove phosphate groups from phosphorylated tyrosine residues on proteins. Its member protein tyrosine phosphatase 1B (PTP1B), which is located in the cytosol, has been iden-tified as a negative regulator of insulin signal transduction. Resistance to insulin can be observed in different tissues such as muscles, liver and fat, which are all crucial for the homeostasis of glucose levels in the human body. In the healthy human body, the transport of glucose into the cell occurs through the activation of the insulin receptor including the phosphorylation of the tyrosine residue. As a result, the so-called insulin recep-tor substrate (IRS) is recruited, followed by the activation of several enzymes. Finally, the glucose transporter GLUT4 is translocated, which mediates the transport of glucose into the cell.

PTP1B seems to be a key regulator for the activity of the insulin receptor, including all downstream sig-nalling processes . It works by the dephosphorylation of the phosphotyrosine residues at the activated insulin receptor kinase and therefore ultimately hinders the uptake of glucose. PTP1B has been identified as a promising target for new drugs treating DM Type 2. Blocking the PTP1B-mediated dephosphorylation of insulin receptor kinase by an inhibitor of PTB1B is believed to lead to an increase in insulin sensitivity.

As previously mentioned, BMOV is believed to be a potent and competitive inhibitor of the PTP1B activity and additionally seem to support the autophosphorylation of the insulin receptor leading to an increased sensi-tivity towards insulin. Research has shown that varying the organic ligand has an influence on the effectiveness and bioavailability of the resulting vanadium compound. It is believed that factors such as absorption, tissue uptake and distribution are affected most. Interestingly enough, X-ray crystal data of PTP1B soaked with BMOV showed only vanadate [V(+V)O43−] at the active site. This would emphasise that the organic lig-ands are only carriers of the active compound and play no role in the enzyme inhibition itself. Furthermore, in aqueous solution, V(IV) is rapidly and reversibly oxidised to V(V), supporting the possible formation of vanadate.

BEOV entered clinical trials and successfully finished phase IIa trials for the treatment of DM Type 2. In phase I trials, doses of 10–90 mg were given to healthy nondiabetic volunteers and no adverse side effects were seen. In the phase IIa clinical trial, seven diabetic patients were treated with 20 mg/day of BEOV and showed a reduction of around 15% of their blood glucose levels. Two patients were treated with a placebo, and no reduction in blood glucose levels was observed. It was also interesting to note that the glucose level reduction lasted for 1 week after finishing the treatment . 

Contact Us, Privacy Policy, Terms and Compliant, DMCA Policy and Compliant

TH 2019 - 2022 pharmacy180.com; Developed by Therithal info.