With neurodegenerative diseases capturing the attention of the world as the new set of diseases and ailments that have to be collectively tackled next, it has become vital for the global and scientific discovery of a form of cure that alleviates the pain as well as reduces the fatality rates from the diseases. Not only are the patients faced with plodding cognitive and physical down slide, but most of the neuro-cognitive diseases are fatal, with patients being presented with no forms of cure or prevention. As the diseases are progressive, the provision of preventative and quality-of-life care is a medical health challenge requiring attention. This paper seeks to discuss the synthesis of novel bidentate metal chelators against Alzheimer disease. The metal ions are considered in the cause and spread of Alzheimer disease in part through their propensity to cause the harmful aggregation of proteins in the brain. First, the paper will deal with the aggregation of metal ions in the brain -with particular attention to copper and malloproteins and their propensity to cause the collective aggregation of amyloid. A discussion will thence be presented on the current understanding of collection and coordination of metal ions that is presented by the amino acids contained within these proteins together with their respective metal binding affinities. A rationally designed bidentate metal chelator will be discussed as a means of auto-completing the deleterious binding of the amino acids, with the discussion being based on the coordination mode and the resultant affinity towards the disease-causing metal ions. Overall, the paper will give a general overview of the cause of Alzheimer's, the formation of the protein plaques and metal ions causing it, as well as the design of a metal chelator coordination environment to work against the neurodegenerative disease.
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Alzheimer's disease (medically referred to by the acronym AD) is a continuously intensifying neurodegenerative disease whose prevalence within the population has continuously grown over the past century. Several attempts to unveil the causes and underlying pathogens of the disease have been carried out across a number of academic and scientific disciplines, but, even with the world wide recognition of the physical, cognitive and emotional symptoms of the disease, more needs to be researched and analyzed in regards to its etiological and pathological development (Henri, 2004). However, it has increasingly been establishment that the accumulation of amyloid- Î² (AÎ²) plaques together with the neurofibrillary tangles of the brain is the tow primary pathological causative characteristics of AD.
A primary hypothesis of the cause characteristics of AD, the amyloid cascade hypothesis, makes argument that amyloid- Î² plaques and its aggregation in the brain is the primary cause of the neurodegeneration that is observed in patients with AD. amyloid- Î² is a protein peptide with 38-43 amino acids that are sliced from the trans-membrane amyloid precursor protein (Micheau, 2005; Georgopoulos & Tennenbaum, 1997). After their generation, the AÎ²Â peptides have the capability of aggregating to form the oligomers, brain fibrils and protofibrils, effectively adopting the well-arranged and extensive Î²-sheet structure that ultimately covers the part of the affected brain tissue. Currently, the neuro-aggregation pathways and their toxicity have been researched extensively, though their involvement in the spread and increased prevalence of AD has remained elusive. These studies suggest that the presence of AÎ² monomers and fibrils are generally benign without any causative characteristics of AD, while oligomers are responsible for the general neurotoxicity and dementia characteristic in AD patients. Other studies argue that the Î²-sheet plaque in the brain is an outcome of the disease rather than its cause and development, with further experimental research being helpful in the elucidation of this aspect. However, thus far, the presence of AÎ²Â plaques in the brain has been identified as the causative agent of the disease, with the implication that curative agents developed to work against the disease have to be directed the dissolution of the plaques.
Figure 1: Postulated assembly of AÎ² (Micheau, 2005)
In this regards, metal ion chelation, dyshomeostasis and miscompartmentalization have been proposed as the primary means through which the progression of the disease can be slowed and even stopped. The responsibility of the metal ions, including their respective effects on the production of AÎ², its aggregation into plaques in the brain as well as their neurotoxicity is thus a contentious issue in the study of the spread and progression of AD. In particular, plaques created from Copper, Iron, Aluminum and Zinc have arguably been discovered to be in high concentration in brain slide samples of patients suffering from Alzheimer's, though their participation in the pathogenesis of the disease still remains unclear. It has however, been suggested that the presence of the metals in the AÎ²Â plaques causes the stabilization of the oligomers, increasing their hydrophilicity, and effectively increasing their toxicity and membrane permeability. Additionally, the presence of iron and copper bound to the AÎ²Â peptide undergoes Fenton chemical redox reaction producing reactive oxygen species- for example hydrogen peroxide- effectively causing the biological damage to body tissues that triggers neurodegeneration. Of particular interest is the fact that high concentrations of Zinc ions are discovered within the region of the brain with the highest prevalence of AD infection, the hippocampus, with the aggregation of the metal ions being directly related to the increase in the occurrence of the disease. In this regards, metal chelation studies have been carried out to reduce the level of aggregation of the metal ions in the brain, which would effectively reduce the characteristic level of symptoms witnessed amongst AD patients. A number of studies reveal that metal ion chelation practices has the clinical benefits that are sought by patients of Alzheimer's disease, with a growing number of experimental investigations showing that the chelating agents used on the metal ions have the ability of targeting multiple etiological components of the disease through prevention of the oxidation formation processes of the species.
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In order to obtain a better understanding of the causative components of the diseases together with the role that metal ions play in the design and distribution of the AÎ²Â within the brain, improvements upon the current studies that have been carried out with regards to metal chelation techniques in the past have to be undertaken as a means of fashioning a potential therapeutic agent against AD (Georgopoulos & Tennenbaum, 1997). Current efforts that have previously been applied have been the use of rationale structure-based designs with the aim of developing small molecules of chelated metal ions with the capability of recognizing both the metal ions as well as those of the AÎ²Â plaque. In this light, this paper seeks the development of a new chelation therapy for the offset of the homeostatic imbalance of the metal ion polypeptides within the brains of those affected with the disease, reducing the sizes of the plaques and their toxicity levels and effectively reducing the characteristic adverse effects of the disease. The projects seeks the development of synthesis of novel bidentate metal chelators against Alzheimer disease, the project aiming at the creation of a substituted benzo Hopo via the vilsmeier type reaction, while investigating oxidation methods to synthesis the N-oxide of the corresponding 2-chloroquinoline (Micheau, 2005). The development of this bidentate metal chelatorÂ has the potential of improving on the limitations that have been previously installed by other chelating techniques, allowing for a specific metal chelation mechanism and increasing the permeability within the blood-brain barrier.
Bidentate HOPO Metal Chelator
The use of Bidentate Hydroxypyridinone chelators has been shown to effectively cause the excretion of trivalent iron from the body, leading to a decrease in the sizes of the monomers and fibrils that cause Alzheimer's disease. Amongst the developed chelators for the excretion of iron from the body, bidentate hydroxypyridinones, namely the3-hydroxy-4-(1H)-pyridinones (referred to by the common name as3,4-HOPOs), the 4-carboxy-3-hydroxy-1-methyl-2-(1H)-pyridinones (otherwise referred to by the common name of Me-3,2-HOPO) as well as TREN-1,2,3-HOPO are hydroxypyridonate derivations that have proven efficacy for the chelation of iron and other metals from the brain of an individual that has been afflicted by the formation of metal scabs.
Of particular interest in this study is the siderophore-inspired chemical generation of the multidentate hydropyridonate ligand 1,2-HOPO for use as an iron chelator against the growth and development of the Alzheimer's plaque. The 1,2 HOPO octadentate chelating ligand under development in this study consists of four 1-hydroxy-pyrind-2-one modules that are interlinked to the spermine scaffold with the use of amine linkages and is currently considered as being the most proficient experimental decoporation chemical agent for actinides. Preference for this type of HOPO in this study has been prompted by growing studies carried out by Henri (2004) and Micheau (2005) in regards to the efficiency of the ligand in the chemical decoporation of amyloids, with the efficiency in the ligand being attributed to its stability and in vivo decoporation of metal ions.
Figure 2: Structure of the 1, 2-HOPO
When ionized, the chemical compounds contained in the HOPO isomers become isoelectronic with catechol- used as the bidentate functional group of the hexabidentate enterobactin, reacting with the metal compounds of the fibrils and monomers of the plaques and reducing their size and chemical reactivity. Ionization of the monoprotoc elements that are contained within the HOPOs is achieved at physiologic ph, thereby not leading to the unnecessary endangerment of the recipient of the treatment. This additionally provides immeasurable advantage for the complexation of vivo metal elements that are contained within the plaques, in comparison with other catechol and enterobactin techniques that have been experimented in the reduction of the effects of metal-based plaques in the brain. The use of the bidentate 1, 2-HOPO metal chelators provides a more potent metal complexation at reduced metal chelator concentration thereby not increasing the chemical compound content of the body of the recipient. The 1, 2- HOPO bidentate chelator provides a complete and stable through which the chemical compounds of the plaque can be bound, producing favorable kinetic results at physiologically friendly body PH. However, the use of 1, 2-HOPO chelators has been known to provide poor gastrointestinal absorption in the body as a result of the high molecular weight of the chemicals contained within the compound in addition to their hydrophilicity. Overall, even with the high molecular weight of the compound, small levels of absorption of the compound is highly effective producing markedly high levels of metal plaque excretion.
Background of the study
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According to physicians, Alzheimer's disease is a neurodegenerative and clinically fatal disease that is characterized by the onset of severe memory loss and eventual loss of the cognitive abilities of the individual. While primarily being a disease that has been known to affect only the old people in the population and being the leading cause of dementia, the disease has progressively been seen to affect younger people, increasing the levels of concern and calls for public health resolutions. Today, the disease affects about 35 million people around the world, with this number being estimated to double after every two decades (Henri, 2004). There is currently no known cure or cause for the disease, with the high numbers of those affected making the finding of a cure or any rational means through which the effects of the disease can be offset an urgent medical health priority.
Pathologically, AD is highly characterized by the increased neuro-degeneration of the affected individual, with the brain of the patient being characterized by excessive intracellular proteic deposits of amyloids that are surrounded by an intracellular neurofibrillary tangle (NFT). In most cases, the presence of the plaques, proteins together with the tangles are present in the parts of the rain that are involved with memory and cognitive abilities- for example the entorhinal cortex and the hippocampus. The brain regions that have been affected by the plaques typically exhibit a decrease in the number of synapses, with the neuritis that are connected with the transfer of cognitive signals to the brain progressively becoming damaged. Neurons and other cognitive components in the brain become destroyed.
Chelation therapy is a chemical technique that refers to the use of chelating drugs for the treatment and reduction of the adverse effects of metal and metal ion poisoning. According to Mandel et al. (2004), the term "chelator" is sourced from the Greek word chele, which loosely translates to "claw". Accordingly, the chelating drugs bind themselves to the metal ions within the target regions, forming a metal drug complex which can thence be excreted out through the body as urine.
Scientifically, heavy metal toxicants bind themselves to the key parts of the body elements and enzymes, producing disturbances within the body system. Chelation therapy is thence founded on the strong attraction that exists between the chelating agents and the metal ions, with the attraction being so string that the metal chelators can compete with the body tissues carrying the toxic metal ions, reversing the attachment and thereby removing the toxicants from the body.
Metal homeostasis in the brain and their role in the occurrence of AD
The brain is a high complex organ, requiring the presence of metal ions for a number of vital roles and cellular processes. In this regards, the brain contains comparatively high concentrations of a number of transitional metals- for example Copper (Cu), Zinc (Zn) and Iron (Fe) - assisting in the neuronal activities taking places within the synapses of the brain (Micheau, 2005).
In this regards, the cells of the brain together with other tissues surrounding the brain have to develop sophisticated machinery for the adaptation and control of the homeostatic imbalances produced by the presence of the metal ions. However, the breakdown of these metal ions and the mechanisms that enforce them, together with the absorption of the metals into the body and blood stream with no known biological functionalities has the adverse effects of altering the homeostatic balance, leading to the realization of a disease state. In this regards, an understanding of the complex structural and functional exchanges that are in existence between the metal ions together with the cellular (both intracellular and extracellular) components of the CNS is essential for the design and chemical development of curative and preventative therapies against neurodegenerative diseases.
According to previous studies, the most important biometals that are involved in brain homeostatic balance are CU, Zn, and Fe, suggesting that they have two distinct functionalities in the parthenogenesis of AD:
The aggregation of the AÎ² peptide plaque
The generation of a highly-reactive oxygen species stimulated by the AÎ² peptide
Aim and Strategy
The role of the metal ions in the development and growth of the Alzheimer's disease has been incorporated into the establishment of the Amyloid cascade hypothesis arguing that "the relation between the metal ions that are contained within the polypeptide plaques of the Amyloid-Î² together with the irregular metal ion homeostatic balance in the brain of the patients has a connection to the neuropathogenic characteristics that are exhibited by persons suffering from the disease" (Henri, 2004). On the basis of this hypothesis, it then becomes possible to disrupt the metal ion interactions that are witnessed between the AÎ² polypeptide metal ions through metal chelation therapy techniques, reducing the levels of toxicity that are realized from the metal AÎ² species and creating a restoration of the homeostatic balance within the brain. In this regards, metal ion chelation is a process that seeks to restore the balance of the metal ions within the brain, through a reduction of the harmful effects of the metal ion plaques that have already been formed at the onset of the disease.
Currently, several metal ion chelators have been proposed as solutions to the homeostatic imbalances within the brain. Some of these chelators include the EDTA, the clioquinol (CQ), and the 8-hydroxyquinoline (PBT2) derivative.
Figure 3: Chemical structures of EDTA, clioquinol and cyclen (Bohn, 2002)
Studies conducted from the use of the chelators on patients suffering from AD showed that CQ and PBT2 chelators improved the cognitive abilities of the patients during phase of the clinical trials, though long terms use of the CQ chelator produced unfavorable side-effects (Georgopoulos & Tennenbaum, 1997). However, even with the unfavorable side effects, the metal chelation techniques have showed that metal ion imbalance within the brain can be homeostatically offset through aggregation and reduction of their toxicity. This suggests that with continued advancement in the study of metal chelation techniques, the pursuit of a favorable cure for AD can be sought and brought to those who require.
In order to obtain a better understanding of the causative components of the diseases together with the role that metal ions play in the design and distribution of the AÎ²Â within the brain, improvements upon the current studies that have been carried out with regards to metal chelation techniques in the past have to be undertaken as a means of fashioning a potential therapeutic agent against AD. Current efforts that have previously been applied have been the use of rationale structure-based designs with the aim of developing small molecules of chelated metal ions with the capability of recognizing both the metal ions as well as those of the AÎ²Â plaque. In this light, this paper seeks the development of a new chelation therapy for the offset of the homeostatic imbalance of the metal ion polypeptides within the brains of those affected with the disease, reducing the sizes of the plaques and their toxicity levels and effectively reducing the characteristic adverse effects of the disease. The projects seeks the development of synthesis of novel bidentate metal chelators against Alzheimer disease, the project's aim being the creation of a substituted benzo Hopo via the vilsmeier type reaction, while investigating oxidation methods to synthesis the N-oxide of the corresponding 2-chloroquinoline. The development of this bidentate metal chelatorÂ has the potential of improving on the limitations that have been previously installed by other chelating techniques, allowing for a specific metal chelation mechanism and increasing the permeability within the blood-brain barrier.
Relevance of the study
The onset and progressive adverse characteristics of Alzheimer's disease has, in the current century, rapidly become a worsening public health problem. With the present absence of effective medical health treatment plans for the disease, it has become imperative for medical health practitioners and academic individuals to come up with new pharmacological therapies for the treatment of the disease, even if these treatments work towards reducing the levels of the adverse characteristics that are exhibited by those affected. Presently, the treatment for the disease includes the alleviation of the characteristics through the use of acetylcholinesterase inhibitors, working towards increasing the levels of acetylcholine within the brain and thereby improving the cognitive abilities of the individuals (Micheau, 2005; Georgopoulos & Tennenbaum, 1997). Scientific reports from studies previously carried out on the disease provide substantiation that the parthenogenesis of the dreaded AD can be connected to presence and coagulate development of the neocortical amyloid-Î² deposited within the brain. The deposition of the polypeptides and increase in metal ion presence within the surrounding plaque can be mediated through the use of modern abnormal metal ion chelation practices, together with metal-based oxidative stress. In this regards, considerations have to be placed in the development of chemical agents that target the abnormal metal ion accumulation in the brain of those who are affected together with the adverse effects that this accumulation has, as well as the prevention and possible reversal of the formation of the AÎ²Â plaques.
Metal ions associated with the formation and development of AÎ²Â plaques within the brain have been suggested as being the primary causative agents of AD neuropathogenesis. However, the molecular participation of the components together with role of the metal ions in the development of the disease has yet to be elucidated. In order to understand the role of the metal ions surrounding the AÎ²Â in the development of the disease and eventually to be able to diagnose, treat and possibly prevent the occurrence of disease, small molecules with bi-functional capabilities- they can be able to under metal chelation exercises as well as positively interact with the AÎ²Â compound to reduce the toxicity within the brain- have to be designed and developed as chemical agents and/or possible therapeutic agents against the characteristic adverse effects of the disease, with the design being done on the basis of the two rational structure design strategies.