Iron Complexes in Cancer Treatment
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The use of metal complexes such as iron to fight cancerous compounds and cells is predicated on the regulation and reactivity of metals with organic complexes. Transition metals such as iron play critical roles in the normal functioning of organisms, from electron transfers to catalysis to structural roles and are associated with active sites of proteins and enzymes. Compared to various other transition metals, iron has been shown to exhibit lower levels of toxicity, higher selectivity, and a broader spectrum of activity.
The advantages of metallodrugs in cancer treatment is their ability to coordinate ligands in three dimensional configuration and allowing the functional groups to be manipulated to binding molecular targets. These metal-based complexes offer an environment to build upon that can accommodate distinct molecular structures and geometries because of the partially filled d-orbitals. The oxidation state of metals also play an influential role in the formation of coordination compounds and the undergoing of ligand exchange reactions that offers opportunities for metals to coordinate to biological molecules.
Recent Research Development
editMajor areas pursued by researchers so far cover the following categories of iron complexes: photocytotoxic complexes, multinuclear iron complexes, ferrocenyl complexes and salen complexes.
Photocytotoxic and redox reactive iron complexes have shown effect on the destruction of cancer cells by producing radicals of oxygen species or ROS (reactive oxygen species) that target cancer cells[1]. This action requires the synergy of light, oxygen and photosensitizing drug where the ionising radiation of light puts enough energy to break up molecules and produce free radicals. Further studies in this classification of iron complexes are highly anticipated because the activation of drugs is easily controlled using specific wavelengths of light thus reducing damage done to normal cells.
Multinuclear iron complexes are organometallic compounds containing more than one metallic nucleus in a complex, “each capable of covalently binding with DNA”[2], where such binding leads to cross-linkage that results in the obstruction of DNA replication and ultimately leads to cell death. Z. Dvorak et al.[3] found an increase in anticancer activity in polymeric iron (III) complexes. However, there is a lot yet to be studied as the action of these multinuclear complexes vary drastically with the incorporation of different specific metal ions; This is because metal ions have their unique geometry and its interaction with biomolecules.
Ferrocenyl Derivatives incorporate ferrocene moieties that are inherently stable in aqueous environments[4] making it a popular area of investigation. Fiorina et al. reported that these complexes have anticancer effect on lymphocytic leukemia cells[5] and de Oliverira et al. revealed a decrease in concentration of cancer cells through apoptosis by 2-ferrocenyl-1,1-diphenylbut-1-ene[6]. More importantly certain ferrorcenyl compounds showed no effect on non-cancerous cells, implying its potential in being an effective and safe anticancer agent.
Salen, a category of chelating ligand widely used for homogenous catalysis, has been utilised to create diverse ligand systems that showed signs of anticancer properties. Moreover, certain complexes, such as ones with bis-imidazolium complexes were documented to have increased the water solubility of iron complexes[7]. The solubility is due to the hydrogen bonding interactions in the enol-imine and keto-enamine of the o-hydroxy Schiff base. This is an important aspect in the distribution of therapeutically active drugs in biological systems and hence is a potential field of development. Additionally, Salen ligands provide high stereospecificity, determining the orientation of coordination planes of the complex ion that interacts with DNA, making some of these chiral Salen complexes possess higher reactivity and efficiency than cisplatin.
Mechanism
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Iron complexes have shown a broad spectrum of anticancer activities. Due to their selectivity and low toxicity, some of these complexes are suggested to be able to overcome inherited or acquired resistance by cancer cells. Several iron complexes have been demonstrated to overcome cancer cell resistance and considerable selectivity against cancer cells[8].
Similar to Cisplatin, a rutin iron complex has been reported to act as a DNA cleaver via an intercalative mode of interaction. While rutin alone was found to cause DNA degradation through torsional stress, the rutin-iron complex does not. This is due to a better stabilization of the double helix via pi-pi* and electrostatic interactions[9].
Bis-imidazolium salts, on the other hand, have been implicated to produce asymmetric catalysis and in catalyzing the hydrolytic cleavage of DNA and RNA. Moreover, recent studies have demonstrated that this same compound may induce apoptosis via the mitochondrial pathway[7].
Additionally, iron-based coordination polymer particles have also become a source of interest because of their plasticity and their ability to encapsulate organic anticancer drugs. The structure of this nanocarrier allows targeted, pH activated delivery[10].
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References
edit- ^ Sarkar, T.; Banerjee, S.; Hussain, A. RSC Adv. 2015, 5, 29276.
- ^ W. A.; Baig, U.; Shreaz, S.; Shiekh, R. A.; Iqbal, P. F.; Jameel, E.; Ahmad, A.; Mohd-Setapar, S. H.; Mushtaque, M.; Ting Hun, L. New J. Chem. 2016, 40, 1063–1090.
- ^ Dvořák, Z.; Štarha, P.; Šindelář, Z.; Trávníček, Z. Toxicol. Vitr. 2012, 26 (3), 480–484.
- ^ Metzler-Nolte, N.; Salmain, M. Ferrocenes Ligands, Mater. Biomol. 2008, No. 0, 499–639.
- ^ Fiorina, V. J.; Dubois, R. J.; Brynes, S. Ferrocenyl Polyamines as Agents for the Chemoimmunotherapy of Cancer. J. Med. Chem. 1978, 21 (24), 393–395.
- ^ De Oliveira, A. C.; Da Silva, E. G.; Rocha, D. D.; Hillard, E. A.; Pigeon, P.; Jaouen, G.; Rodrigues, F. A. R.; De Abreu, F. C.; Da Rocha Ferreira, F.; Goulart, M. O. F.; Costa-Lotufo, L. V. ChemMedChem2014, 9 (11), 2580–2586.
- ^ a b Elshaarawy, R. F. M.; Janiak, C. Tetrahedron 2014, 70 (43), 8023–8032.
- ^ Wani, W. A.; Baig, U.; Shreaz, S.; Shiekh, R. A.; Iqbal, P. F.; Jameel, E.; Ahmad, A.; Mohd-Setapar, S. H.; Mushtaque, M.; Ting Hun, L. Recent Advances in Iron Complexes as Potential Anticancer Agents. New J. Chem. 2016, 40, 1063–1090.
- ^ Selvaraj, S.; Krishnaswamy, S.; Devashya, V.; Sethuraman, S.; Krishnan, U. M. Synthesis, Characterization and DNA Binding Properties of Rutin–iron Complex. RSC Adv. 2012, 2 (7), 2797.
- ^ Xu, S.; Liu, J.; Li, D.; Wang, L.; Guo, J.; Wang, C.; Chen, C. Fe-Salphen Complexes from Intracellular pH-Triggered Degradation ofFe3O4@Salphen-InIII CPPs for Selectively Killing Cancer Cells. Biomaterials 2014, 35 (5), 1676–1685.