Using Ruthenium In 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 have lead to the replication of cancerous cells, these defective genes passed down by daughter cell .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. 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. a) 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].

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

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 current active anticancer compounds contain ruthenium ions in the last two decades that show promising results 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 yielding mild side effects and of as 2006 phase II trials are currently in progress[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 interaction between ligand and protein interaction of the drug group to develop more specific targeting ruthenium complexes .One example of a new fields of interest in ruthenium drugs is using known attributes of NAMI-A to compare new ligand structures such as the RAPTA complex (see fig.3)to investigate toxicity and effectiveness of the compound on carcinoma, work 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 hydroxytamoxifen-Ru(see fig 4) , though the 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 that have the potential be used to enhance other methods of targeted therapeutic treatment [8] and Ruthenium-Based Protein Kinase Inhibitors a strategy were synthesized ruthenium compounds mimic inhibitors as a delivery method with strong binding affinity. A ruthenium Pim-1mimic has been synthesized and has shown the 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 a Selective estrogen receptor modulators

Ruthenium anticancer drugs as stated previously are chemotherapeutic agents used in cancer treatment. Another more accurate term for the 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 targeted drug doesn't 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 less side effects than other metal complexed compounds. Ruthenium drugs are grouped as "classical" or "non classical". This paper will focus on the classical classes of drugs that have been well researched [8]. Examples of non classical drugs were previously mentioned i.e. RAPTA and SERMS.

The classification of ruthenium based drugs is classified by the complexes that are formed by ligands 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.5) 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].

Figure 5: Examples of polypyridyl-Ru complexes [8]

the development and use of polyaminocarboxylate (pac) ligands coordinated to ruthenium ions (see fig.6) as they exhibit strong binding with metal centers and have similar carboxylate and amino binding entities found in biological systems[8][11]

Figure .6; Examples of Ru-pac complexes [8]

The classes of classical ruthenium drug that have been developed are based primarily on the ligand structures that are coordinated to ruthenium ions. These structures

Mechanism of action in regards to disease condition ,drug category

QSar

[1] Baylin SB, Herman JG, Graff JR, Vertino PM, Issa JP (1998). "Alterations in DNA methylation: a fundamental aspect of neoplasia". Adv. Cancer Res. 72: 141-96. doi:10.1016/S0065-230X(08)60702-2. PMID 9338076

[2] Knudson AG (1971). "Mutation and cancer: statistical study of retinoblastoma". Proc Natl Acad of Sci 68 (4): 820-3. doi:10.1073/pnas.68.4.820. PMID 

[3] Ruthenium Complexes as Anticancer Agents

Irena Kostova*

[4] Non Platinum Metal Complexes as Anti-cancer Drugs

Ingo Ott and Ronald Gust

Institute of Pharmacy, Freie Universit_t Berlin, Berlin, Germany

[5]The Discovery and Development of CisplatinRebecca A. Alderden , Matthew D. Hall and Trevor W. Hambley Centre for Heavy Metals Research, School of Chemistry, The University of Sydney, 2006 NSW, AustraliaJ. Chem. Educ., 2006, 83 (5), p 72DOI: 10.1021/ed083p728Publication Date (Web): May 1, 2006

[6] B. E. Cavit, K. R. Grundy and W. R. Roper (1972). "Ru(CO)2(PPh3)3 and Os(CO)2(PPh3)3. An ethylene complex of ruthenium and a dioxygen complex of osmium". Journal of the Chemical Society, Chemical Communications (2): 60-61. doi:10.1039/C3972000060b.

[7] M. J. Clarke,Met. Ions Biol. Syst. 1980, 11, 231-283.

[8]Classical and Non-Classical Ruthenium-Based Anticancer Drugs: Towards

Targeted Chemotherapy

Wee Han Ang[a] and Paul J. Dyson*[a] Eur. J. Inorg. Chem. 2006, 4003-4018

[9] C. G. Hartinger, S. Zorbas -Seifried, M. A. Jakupec, B.

Kynast, et al., J. Inorg. Biochem. 2006, 100, 891-904.

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[12] A. Bergamo, C. Scolaro, G. Sava, P. J. Dyson, unpublished results.

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[15] R. M. Schultz, In Advances in Targeted Cancer Therapy (Eds.:

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