What Are The Benefits Of Ruthenium Anticancer Drugs Biology Essay

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When mutations occur in the genes of a normal cell the outcome can usually be the development of cancer. These mutations that cause genes to become defective occur by exposure to environmental and chemical elements such as UV exposure ,unhealthy diet, excessive narcotic and depressants use exposure to radiation and prolonged chronic exposure to carcinogenic chemicals i.e. formaldehyde, benzene, etc. Cancer also may occur genetically as dormant genes that are passed down from parent to child, characterized by repeats and frameshift mutations within the genes base pairs of the effected individuals, these in some instances can be associated with the environmental a chemical causes. The genetic result of cancer is usually associated with a syndrome such as ataxia telangiectasia or Familial adenomatous polyposis.

No matter the cause of cancer the genes proliferation methods remain basically the same. These defective genes proliferate inside a cell that eventually lead to the replication of cancerous cells, these defective genes are passed down by daughter cells .During cell replication over time this can become a problem as daughter cells continually copy mutated copies of the gene till the overall accumulation speed up the proliferation of the cancerous cells to form structural changes producing a malignant tumor [3]. The chance of producing a malignant tumor is a co dependant system (two hit process) were a multiple of genetic mutations must occur in order to cause a carcinoma .These mutations have two different purposes, to keep oncogenes activated or deactivated and cause hypermethylation activation to create uncontrolled gene expression [1] and to disable tumor suppressor genes such as the p53 and apc genes that enable checkpoint control and apoptosis of a cancerous cell to occur[2].Research in these types of genes are invaluable as they can be use in targeted anticancer drugs. The outcome of chronic proliferation of carcinoma cells leads to death; fatalities in cancer are due to the shutdown of cellular process in effected tissues. The efficiency of mortality is that prominent if an individual acquiring making it one of the leading causes of death globally.

The main problem in cancer treatment is the tumors form secondary metastases carried through out the body by rouge cancer cells that find their way into the blood stream of the effected individual. While radiotherapy or surgery can be successful in dealing with primary cancer cells, the secondary metastases go on to affect different cell tissue through out the body eventually causing death. The best choice from a therapeutic stand point is the use of drug therapy to deliver specific antimetastic activity to the primary and secondary cancer cells[3]. The drug therapy that is of interest is coordinate metal complexes were different metals and ligands have been researched or are currently being researched in preclinical and clinical trials with promising degrees of effectiveness against malignant metastasis.

The metal elements that have been coordinated to ligand complexes (see fig. 1) are cobalt, gold and iron that show promising results in cancer control and gallium, titanium, ruthenium and platinum that have been evaluated to show effectiveness in phase I and II clinical trials [4]. In this paper the focus will be aimed at ruthenium complexes as anticancer drugs and discoveries made in the mechanisms of the drugs interact and deal with cancer

(Fig. 1) example of various metal coordinate complexes [4]

Through out history metals have always been used as a medicinal measure against a variety of ailments in a more or less sensible fashion, since the discovery of the platinum complex ,cisplatin by Rosenburg in 1965 [5]and its biological activity the potential of metal based anticancer agents had been realized and stringently researched. The discovery of this anticancer drug has an enormous impact on the chemotherapy. Its effectiveness in treatment of cancer (nearly 100% efficiency) makes it a popular choice for clinical use to this day against early diagnosed tumors and testicular, ovarian cancer. The problem with the platinum based drug is that its limited by the level of high systematic toxicity and the acquired resistance to it effects limiting its use clinically because of this years of research has been put in improving platinum drugs to improve these limitations. While some strived to improve other researchers used this knowledge and explored in using other metal elements in coordinated structure, ruthenium was one such choice.

During the 1970s and 1980 research in ruthenium complexes carried out by Roper in 1972 examined ruthenium complexes found that they were highly nucleophilic assuming binding potential[6].M.J. Clarke and coworkers throughout the 1980's explored the binding nature of ruthenium complexes and had found properties of complexes that would localize to tumor sites[7].Observation made by these researches and other researches paved a forefront in the development of ruthenium anticancer drugs yielding a host of ruthenium anticancer compounds in the last two decades that show promising results .An example of two Ruthenium (III) octahedral complexes that have had success in stage I and currently in stage II clinical trials as antitumor agents[4] are NAMI-A and KP1019.

(Fig .2) anticancer agents currently in phase II trials [8]

Results of clinical test studies of the two octahedral complexes so far have shown good results, so a possibility of an alternative to cisplatin can be available in future. These results have shown so far that kP1019 showed promising results in a phase I clinical studies with evidence showing stability of the condition of five of six patients suffering solid tumors with mild side effects [9], stating future phase II trials. In phase I studies of NAMI-A reports have shown that patients also have experienced stability in cancer development after prolonged treatment using NAMI-I and that a determined maximum-tolerated dose had been found to exhibit mild side effects as of 2006.Phase II trials are currently in ongoing [10].

Even though that clinical trials of two ruthenium complexes are currently in progress, more research in biochemical mechanisms of ruthenium complexes are being researched in order to understand the interactions between ligand and protein interaction of the different classes of compounds to develop more specific targeting ruthenium complexes.

One example of a new field of interest in ruthenium drugs is using known attributes of NAMI-A to compare new ligand structures such as the RAPTA complexes (see fig.3) to investigate toxicity and effectiveness of the compounds on carcinoma. Research done in investigating this future drug application shows that RAPTA complexes exhibit less anticancer activity than NAMI-A, but have a lower toxicity (mouse model) giving potential for higher dose administration clinically[8][12].Other potential metal complex ruthenium strategies in future may be Selective estrogen receptor modulators(SERMs) co-ordinate to ruthenium also known as hydroxytamoxifen-Ru(see fig 4) , though this complex has no antimetastic properties the drug binds strongly to receptors of cancer cells and may be a useful radio imaging diagnostic tool for screening breast cancer using Ru isotopes, 97Ru and 103Ru[8][13].

Ruthenium Ketoconazole Complexes are another new class that has the potential to be used to enhance other methods of targeted therapeutic treatment [8]. Ruthenium-Based Protein Kinase Inhibitors are also a future option. The strategy in this method is using synthesized ruthenium compounds to mimic inhibitors as a delivery method advantaged by the compounds strong binding affinity. A ruthenium Pim-1mimic has been synthesized and has shown strong covalent binding seen in crystallization structures. These mimic protein ruthenium complex have the potential to become new types of organometallic targeting agents [8] [14].

Figure 3 : RAPTA-NAMI antimetastatic compound candidates [8]

Figure 4: example of Selective estrogen receptor modulators [8]

Ruthenium anticancer drugs as stated previously are chemotherapeutic agents used in cancer treatment. Another more accurate term for these agents is "target drugs" due to the fact that different types of ruthenium based drugs are developed to deal with specific mechanisms of cancerous cells. The advantage of targeting is that the drugs tend to have specificity and a more manageable toxicity profile. Examples of the types of growth factors and receptors that are good targets in cancers due to their presence throughout replication are epidermal growth factor receptors (EGFR), vascular endothelial growth factors (VEGF), and cyclin-dependent kinases (CDK) [15]. By targeting these growth factors it can be possible to inhibit replication of cancer tissue or to disable and terminate the cell altogether. In this lies a problem as the target drugs dont differentiate between healthy and malignant cells growth factors, so a balance must be maintained between dosage and toxicity. This tends to be an advantage in the use of ruthenium compounds as they tend to display fewer side effects than other metal complexed compounds. Ruthenium drugs are grouped as "classical" or "non classical". In this section the focus will be directed on the classical classes of drug classes and non classical classes such as NAMI and KP1019 that have been well researched due to their successful clinical nature [8]. Other examples of non classical drugs were previously mentioned i.e. RAPTA and SERMS.

The one characteristic that all classes of ruthenium drugs have in regards to the Quantitative structure-activity relationship is the dependency of conformation of the ligand complex. The anticancer activity is dependant on a coordinated ligands isometric form (Trans, cis, mer). Throughout the different classes isomers show a range of binding strengths to DNA, the stronger the bond the better the anticancer effect the compound has. These forms of isomers can be used to target protein side chains of DNA to create drugs that have customized bonding or intercalating activity to and between major and minor grooves on DNA strands (see fig 5). The outcome of this occurring destabilizes protein structure and stops a cancer gene from functioning.

Figure 5: Polypyridyl-Ru complex binding to DNA [25]

The classification of ruthenium based drugs is classified by the ligands that form complexes that are coordinated to ruthenium ions. These classes exist as Polypyridyl-Ru, Ru-Polyaminocarboxylate, Ruthenium Arylazopyridine, Organometallic Arene-Ruthenium and Dimethyl Sulfoxide-Ru complexes.

Polypyridyl-Ru complexes are complexes that have rigid, large multidentate Polypyridyl ligands coordinated to ruthenium ions. The characteristic shape and chirality of the Polypyridyl-Ru complexes have properties that can be customized to intercalate to DNA at different binding sites. Examples of some commercially available polypyridy ligands (see fig.6) that form stable complexes with ruthenium and show some anti -cancer activity are 1, 10-phenanthroline (phen), 2,2_:6_2__-terpyridine (terpy) and 2,2_-bipyridine (bpy)[8].Examples of the QSAR activity of some these complexes made using these class of ligands is the example of the complex mer-[Ru(terpy)Cl3] ability to interstrand crosslink between DNA chains were a similar complex cis-[Ru(bpy)2Cl2] showed no activity[17] exhibiting evidence that isomer conformation is necessary for activity..

Figure 6: Examples of polypyridyl-Ru complexes [8]

Arylazopyridine ruthenium (II) complexes are complexes that have the ligand 2-phenylazopyridine coordinated to a ruthenium ion .The anticancer property of these complexes is highly dependant on the isomeric forms of the ligand structure adopts. There are five different conformations that have been synthesized and have proven to have significant anticancer activity, α, β and γ isomers [8] [16]. An example of synthesized complex that has efficient activity, Ru(azpy)2Cl2 and the isolated active isomers using x ray chromatography can be seen in figure below(figure 7).These Ru(azpy)2Cl2 isomers are a good example of QSAR of the azol class of drugs in selection of useful anticancer agents. The complexes α -[Ru(azpy)2Cl2] and trans-γ-[Ru(azpy)2Cl2] show a high cytotoxicity while cytotoxicity of the cis-β-[Ru(azpy)2Cl2] isomer is much lower[16].

Figure 7: α, β and γ isomeric arylazopyridine ruthenium (II) complexes [8]

Ru-Polyaminocarboxylate complexes are complexes that contain ligands that exhibit strong binding with metal centers and have similar carboxylate and amino binding entities found in biological systems[8][11].These ligand systems tend to have rather specific in their activity when bonded with DNA .These reactions can cleave and alter DNA effectively making then good inhibitors of cancerous cells.

Figure .8; Examples of Ru-pac complexes [8]

Organometallic ruthenium complexes are complexes that have η6-arene

Ligands Organometallic Ruthenium complexes containing Arene ligands make up some of the more modern anticancer agents. η6-arene ligand are known to stabilize ruthenium(II), in the last decade a number of these organometallic ruthenium (II) complexes have been synthesized and biologically tested for possible anticancer activity. Complexes such as [Ru(η6-C6H6)(dmso)Cl2] and its derivatives(see fig.9) show that the ligand slows down topoisomerase II activity by cleavage complex formation[18]and interacts with DNA and forms cross-links with topoisomerase II[11].The drug class has had promising results in the treatment of breast and colon cancer cells. The drugs have been found to interact selectively with guanine bases forming monofunctional adducts creating cross chaining that destabilizes protein structure. This binding to a base shows promise for target specific gene sequences on DNA chains [16].The aspects of these organometallic ruthenium complexes have been used in the development of the RAPTA class of anticancer drugs.

Figure 9: Examples of some (η6-arene) ruthenium complexes [8].

The class dimethyl sulfoxide-Ru complexes are a class that has been heavily researched in order to improve there level cytotoxicity over the past few decades. Compounds such as and trans-Ru (DMSO)4Cl2 were found to have a degree of low cytotoxicity . Derivatives of Dimethyl Sulfoxide-Ru compounds were made to counter the poor results of this class though yielded results with little improvement. Despite the problems in creating working anticancer agents, the synthesis of trans-Na[RuCl4(dmso)L] was studied which led to development of the complex trans-Na[RuCl4(dmso)(Him)] known as NAMI [20],that showed promising anticancer activity with lessened degree of toxicity than other metal complexes. It was found that QSAR of NAMI trans isomer had a stronger bonding identity than the cis isomer. The one problem with NAMI was it was difficult to synthesis and not very stable. To counter this the next stage in development of dimethyl sulfoxide-Ru complexes was synthesized ,.(H2im)trans-[RuCl4(dmso)(Him)] or NAMI-A yield a stable reproducible product that exhibited similar properties to NAMI but with a much higher degree of cytotoxicity with similar low level toxicity[16][21]

The classes of drugs such as NAMI type drugs are of great interest today as they have proven clinically effective as anticancer drugs in phase I and II trials. The mechanisms to this day still require research though several observations have been made to how the compound interacts within a system. One report suggests that NAMI-A exhibits strong covalent binding to serum proteins signifying the possibility of selective targets in a cancer cell by exploiting receptor-mediated delivery by transferrin [19][24]. It has been observed that NAMI-A can control anti-invasive and anti-angiogenic effects on cancer cells and a tumors blood vessels by inhibiting matrix metalloproteinases [16]and the drugs scavenging properties of nitric oxide [22].evidence also suggest that the anticancer activity NAMI-A is highly dependant on ph under physiological conditions.

Figure 10 : Two type of NAMI compounds and KP1019[8]

Another phase I and II clinically successful compound is KP1019. KP1019 Indazolium trans-[tetrachloridobis(1H-indazole)ruthenate(III)] is a compound derived from the NAMI model with changes made to the N-ligand structures. KP1019 is a compound that has anionic properties that has shown successful antitumor activity a variety of cancer types that NAMI had no effect. The research of the QSAR of KP1019 shows covalent binding occurs by the exchange of four chloride ligands of the drug with hydroxide ions or aqua molecules of the target genes found on proteins such as albium and transferrin [16].These bound proteins then transport the compound into the cell and induces apoptosis or inhibition via oxidative stress and DNA damage. Evidence of the mechanism of how KP1019 was carried out by binding the compound to cytochrome that yielded results that cell apoptosis was due to change in protein conformation that modified the proteins tertiary structure[23].

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