Therapeutic Chelating Agents Research Articles

Arsenic Induced Oxidative Neural-Damages in Rat are Mitigated by Tea-Leave Extract via MMPs and AChE Inactivation, Shown by Molecular Docking and in Vitro Studies with Pure Theaflavin and AChE.

Chronic arsenic-exposure causes neuromuscular disorders and other health anomalies. Damage to DNA and cytoskeletal/extracellular matrix is brought on by reactive-oxygen-species (ROS)-induced intrinsic antioxidant depletion (thiols/urate). Therapeutic chelating-agents have multiple side-effects. The protection of (Camellia sinensis) tea-extract and role of uric-acid (UA) or allopurinol (urate-depletor) on arsenic-toxicity were verified in rat model. Camellia sinensis (CS dry-leaves), UA or allopurinol was supplemented to arsenic-intoxicated rats for 4-weeks. Purified theaflavins and their galloyl-ester were tested in-vitro on pure AChE (acetylcholinesterase) and their PDB/PubChem 3-D structures were utilized for in-silico binding studies. The primary chemical components were evaluated from CS-extracts. Biochemical analysis, PAGE-zymogram, DNA-stability comet analysis, HE-staining was performed in arsenic-exposed rat brain tissues. Animals exposed to arsenic showed symptoms of erratic locomotion, decreased intrinsic antioxidants (catalase/SOD1/uric acid), increased AChE, and malondialdehyde. Cerebellar and cerebrum tissue damages were shown with increased levels of matrix-metalloprotease (MMP2/9) and DNA damage (comets). Allopurinol- supplemented group demonstrated somewhat similar biochemical responses. In the CS-group brain tissues especially cerebellum is considerably protected which is evident from endogenous antioxidant and DNA and cytoskeleton protection with concomitant inactivation of MMPs and AChE. Present study indicates theaflavin-digallate (TFDG) demonstrated the highest inhibition of purified AChE (IC50 = 2.19 µg/ml with the lowest binding free-energy; -369.87 kcal/mol) followed by TFMG (IC50 = 3.86 µg/ml, -347.06 kcal/mol) suggesting their possible restoring effects of cholinergic response. Favorable responses in UA-group and adverse outcome in allo-group justify the neuro-protective effects of UA as an endogenous antioxidant. Role of flavon-gallate in neuro protection mechanism may be further studied.

Convergent Synthesis of Macrocyclic and Linear Desferrioxamines

Polyhydroxamate desferrioxamines (DFO) are nontoxic siderophores endowed with high potential for development of therapeutic chelating agents. Herein, we report a modular and convergent strategy for diverse synthesis of macrocyclic and linear DFOs. The strategy employed orthogonally protected N‐hydroxy‐N‐succinylcadaverine building blocks, which allowed bidirectional extension of the DFO structure. The efficiency of the new strategy was demonstrated by the total synthesis of 44‐membered macrocyclic DFO‐T1, as well as four related DFO compounds in 11–13 linear steps and 2.1 %–10 % overall yields. Comparison of the iron binding affinity of the DFOs revealed DFO‐E as the best chelator.

DFT investigation on the selective complexation of Fe3+ and Al3+ with hydroxypyridinones used for treatment of the aluminium and iron overload diseases

The chelating agents for Al3+ and Fe3+ metal cations with therapeutic applications have been considered in the recent years. In designing of the hydroxypyridinones (HPOs) as the therapeutic chelating agents for iron and aluminium overload pathologies, quantum mechanical (QM) calculations are necessary for predicting the binding energies and thermodynamic parameters of the metal−HPO complexes. Three derivatives of the HPOs called 3-hydroxy-1,2-dimethylpyridin-4(1H)-one (DFP), 3-hydroxy-4(1H)-pyridinone (HOPO) and 5-hydroxy-2-(hydroxymethyl)pyridin-4(1H)-one (P1) were investigated for complexation with Fe3+ and Al3+ metal ions. Because of the maximum interaction between Fe3+ and HPOs, all HPOs form stable complexes with Fe3+ metal ion. Moreover, it was found that [Fe−P1]2+ is a more stable complex than [Fe−DFP]2+ and [Fe−3,4-HOPO]2+ in the gas phase and water, confirming that P1 is the strongest selective iron chelator. The more stability of [Fe−P1]2+ was attributed to an intramolecular hydrogen bond formation between the hydrogen atom of NH group and the oxygen atom of CH2OH chain. All complexes of the HPOs with Fe3+ and Al3+ were formed through the oxygen atoms of the CO and OH groups of the HPO. Natural bond orbital analysis showed that the interaction of the lone pair electrons of the oxygen atom of the chelator and antibonding orbitals of the Al3+ and Fe3+ are important in the complex formation. Topological parameters at the bond critical points confirmed the effective interaction between the Al3+ and Fe3+ metal ions and HPO as well as the nature of the metal−oxygen bonds.

Novel enterobactin analogues as potential therapeutic chelating agents: Synthesis, thermodynamic and antioxidant studies.

A series of novel hexadentate enterobactin analogues, which contain three catechol chelating moieties attached to different molecular scaffolds with flexible alkyl chain lengths, were prepared. The solution thermodynamic stabilities of the complexes with uranyl, ferric(III), and zinc(II) ions were then investigated. The hexadentate ligands demonstrate effective binding ability to uranyl ion, and the average uranyl affinities are two orders of magnitude higher than 2,3-dihydroxy-N1,N4-bis[(1,2-hydroxypyridinone-6-carboxamide)ethyl]terephthalamide [TMA(2Li-1,2-HOPO)2] ligand with similar denticity. The high affinity of hexadentate ligands could be due to the presence of the flexible scaffold, which favors the geometric agreement between the ligand and the uranyl coordination preference. The hexadentate ligands also exhibit higher antiradical efficiency than butylated hydroxyanisole (BHA). These results provide a basis for further studies on the potential applications of hexadentate ligands as therapeutic chelating agents.

Actinide chelation: biodistribution and in vivo complex stability of the targeted metal ions

Because of the continuing use of nuclear fuel sources and heightened threats of nuclear weapon use, the amount of produced and released radionuclides is increasing daily, as is the risk of larger human exposure to fission product actinides. A rodent model was used to follow the in vivo distribution of representative actinides, administered as free metal ions or complexed with chelating agents including diethylenetriamine pentaacetic acid (DTPA) and the hydroxypyridinonate ligands 3,4,3-LI(1,2-HOPO) and 5-LIO(Me-3,2-HOPO). Different metabolic pathways for the different metal ions were evidenced, resulting in intricate ligand- and metal-dependent decorporation mechanisms. While the three studied chelators are known for their unrivaled actinide decorporation efficiency, the corresponding metal complexes may undergo in vivo decomposition and release metal ions in various biological pools. This study sets the basis to further explore the metabolism and in vivo coordination properties of internalized actinides for the future development of viable therapeutic chelating agents.

Terephthalamide-containing ligands: fast removal of iron from transferrin

The mechanism and effectiveness of iron removal from transferrin by three series of new potential therapeutic iron sequestering agents have been analyzed with regard to the structures of the chelators. All compounds are hexadentate ligands composed of a systematically varied combination of methyl-3,2-hydroxypyridinone (Me-3,2-HOPO) and 2,3-dihydroxyterephthalamide (TAM) binding units linked to a polyamine scaffold through amide linkers; each series is based on a specific backbone: tris(2-aminoethyl)amine, spermidine, or 5-LIO(TAM), where 5-LIO is 2-(2-aminoethoxy)ethylamine. Rates of iron removal from transferrin were determined spectrophotometrically for the ten ligands, which all efficiently acquire ferric ion from diferric transferrin with a hyperbolic dependence on ligand concentration (saturation kinetics). The effect of the two iron-binding subunits Me-3,2-HOPO and TAM and of the scaffold structures on iron removal ability is discussed. At the low concentrations corresponding to therapeutic dose, TAM-containing ligands exhibit the fastest rates of iron removal, which correlates with their high affinity for ferric ion and suggests the insertion of such binding units into future therapeutic chelating agents. In addition, urea polyacrylamide gel electrophoresis was used to measure the individual microscopic rates of iron removal from the three iron-bound transferrin species (diferric transferrin, N-terminal monoferric transferrin, C-terminal monoferric transferrin) by the representative chelators 5-LIO(Me-3,2-HOPO)(2)(TAM) and 5-LIO(TAMmeg)(2)(TAM), where TAMmeg is 2,3-dihydroxy-1-(methoxyethylcarbamoyl)terephthalamide. Both ligands show preferential removal from the C-terminal site of the iron-binding protein. However, cooperative effects between the two binding sites differ with the chelator. Replacement of hydroxypyridinone moieties by terephthalamide groups renders the N-terminal site more accessible to the ligand and may represent an advantage for iron chelation therapy.

A new bis(3-hydroxy-4-pyridinone)-IDA derivative as a potential therapeutic chelating agent. Synthesis, metal-complexation and biological assays

A new bis(3-hydroxy-4-pyridinone) derivative of iminodiacetic acid, imino-bis(acetyl(1-(3'-aminopropyl)-3-hydroxy-2-methyl-4-pyridinone)), IDAPr(3,4-HP)(2), has been prepared and studied in its interaction with a set of hard metal ions. This tetradentate ligand presents a much higher chelating efficiency for trivalent hard metal ions (Fe, Ga, Al) than the monodentate derivative Deferriprone, namely at the diluted conditions prevailing in physiological conditions and at low clinical doses. A similar behaviour was also observed for the complexation with Zn(II) but at a significantly lower extent. This compound presents a moderate hydrophilic character at physiological pH (logD=-1.72). In vivo assays showed much more rapid clearance of (67)Ga from most tissues of metal-loaded mice than the drug Deferriprone and the radioactivity excretion occurs mostly through the kidneys. Therefore, results from in vitro and in vivo studies indicated good perspectives for this compound to be a potential decorporating agent for hard metal ions in overload situations without depletion of essential metal ions such as zinc.

Histological and Histochemical Alterations in the Kidney Induced by Lead

Although lead intoxication is one of the most common forms of metal intoxication, the histochemical alterations in the renal tissues due to chronic lead exposure is limited and has not yet been well identified. A total of 60 male Wistar albino rats (Rattus norvegicus) were exposed to lead acetate trihydrate (0.0, 0.25, 0.5, 1.0 and 2% for 1 to 12 months) in drinking water to investigate the histological and histochemical alterations in the renal tissues due to lead. Chronic exposure to subtoxic doses of lead produced distinct progressive tubular, glomerular and interstitial damages. Tubular changes occurred earlier than glomerular and interstitial ones, and included anisokaryosis, nuclear pyknosis, karyomeglay, development of intranuclear and cytoplasmic inclusions together with tubular dilation, necrosis, vacuolization, tubular hyperplasia and solid tubular adenoma. The glomerular alterations were mainly mesangial hypercellularity, segmental proliferation, focal and segmental glomeruloscleriosis, glomerural hyalinization and glomerular tuft alterations. The findings indicate that lead produces significant histological and histochemical changes in the kidney that lead to severe complications.

Design of therapeutic chelating agents.

The successful design of orally active non-toxic selective metal chelators is a much sought-after goal. In order to identify an ideal chelator for clinical use, a range of specifications must be considered, such as metal selectivity and affinity, kinetic stability of the complex, bioavailability and toxicity. In this overview the comparative properties of ligands capable of endowing complexes with such properties will be discussed.

Computer-Modelling of Metal Speciation in Human Blood Serum

This paper briefly describes two computer programs, BEST and ECCLES, both available on disc, that can generate distribution diagrams for various metal-complexes in human blood plasma. Two heavy metals, lead and mercury, are used as examples. The species distribution vs pH diagrams are based on formation constants obtained from our own potentiometric study of the mercury-glutathione system. The efficacy of a chelating agent for mobilizing a metal ion from the liable metal-protein complex portion of blood, PMI index, is discussed as well. The paper points out that computer modelling of metal speciation in human blood plasma has led to the design of important new therapeutic chelating agents.

The Design of Therapeutic Chelating Agents

Abstract The factors involved in the design of therapeutic chelating agents are outlined on the basis of the theoretical analyses of ligand design and experimental data obtained in animal studies. The starting point in such design must always be those factors which assure that a sufficiently high stability constant be achieved, and here the analyses presented by Martell and his co-workers furnish a general approach. If the removal of intracellular metal deposits is to be achieved, additional factors need to be considered to incorporate variables which govern the interaction of the chelating agent with the membrane systems of those organs within which the toxic metal is concentrated. For these, the QSAR (quantitative structure activity relationship) procedure of Hansch furnishes a useful guide. This allows the development of direct structure-efficacy correlations (DSEC) involving molecular parameters in addition to those which are directly involved in the determination of the stability constant. In several...

New Developments in Therapeutic Chelating Agents as Antidotes for Metal Poisoning

An examination of the studies on therapeutic chelating agents that have been carried out during the last decade reveals that extensive efforts have been made to develop compounds superior to those previously available for the treatment of acute and chronic intoxication by many metals. These metals include primarily iron, plutonium, cadmium, lead, and arsenic, but also many other elements for which acute and chronic intoxication is less common. These studies have revealed the importance of several additional factors of importance in the design of such compounds and have led to many new compounds of considerable clinical promise. An additional development has been the introduction of previously developed chelating agents for use with certain metals on a broader scale.

The search for chelate antagonists for chronic cadmium intoxication

Cadmium is unique among the metals because of its combination of toxicity in low dosages, long biological half-life (of about 30 years in humans), its low rate of excretion from the body and the fact that it is stored predominantly in the soft tissues (liver and kidney). There has been an increase in exposure to cadmium because its presence in fertilizers and sewage sludge and also its increased industrial use in Cd-Ni batteries. Although there are a number of reports on occupational and environmental exposures to cadmium compounds, treatment of cadmium poisoning has been difficult because there is neither a safe practical means of evaluating bioavailable body burden nor is there a recommended therapeutic chelating agent for chronic cadmium intoxication. In this review, the various factors affecting the chelation of cadmium such as its binding to intracellular metallothionein, the structural requirements of compounds for effective removal of cadmium, the excretion pattern of cadmium after its mobilization from intracellular stores and the recent developments in the design and synthesis of new compounds for cadmium chelation are discussed. The importance of protecting sensitive organs such as kidney and brain during cadmium chelation is addressed. The progress made during the last decade on the synthesis of new compounds, especially derivatives of dithiocarbamates, is remarkable. Some of these compounds provide promise for development of a useful and safe therapeutic chelating agent which can be used for the assessment of cadmium body burden and for preventive removal of cadmium as well as for use in overt cadmium poisoning in humans.

The effect of kinetic factors on the thermodynamic evaluations of therapeutic chelating agents

The effect of certain kinetic factors on thermodynamic evaluations of several therapeutic chelating agents is examined. This allows the in vivo behavior of these drugs to be understood in more detail. The main kinetic factors examined are: (a) the pharmacokinetics of the chelating agents in vivo; (b) the kinetics by which the toxic metal ions are distributed between the serum and other organs; and (c) the rates of the reactions between the therapeutic chelating agent and the complexes formed by the toxic metal ion with serum constituents. A new parameter is proposed for predicting the efficacy of metal binding in plasma. This takes into account changes in the chelating agent concentration with time. Predictions of the relative efficacy of the therapeutic agents based solely on thermodynamic calculations are shown to provide a useful differential indicator for spontaneous detoxification processes, whereas kinetic factors become more important in delayed treatments or when the chelating agents exhibit similar thermodynamic behavior.

An alternative model for the selection of therapeutic chelating agents

An alternative model is presented for the selection of therapeutic chelating agents to enhance the mobilization and excretion of a toxic metal. The model is based on the in vivo patterns of absorption, distribution, reaction and excretion of the chelating agent, a typical toxic metal ion and complexes of the two. The model emphasizes the kinetic aspects of the processes involved and indicates how other processes may be incorporated such as redox reactions involving the chelating agent or metal. The identification of rate determining steps and methods for their manipulation are assumed to be of importance. The application of this model to specific metals is outlined.

Structureactivity relationship with therapeutic chelating agents

Although the vast majority of therapeutic chelating agents are water soluble rather than lipid soluble (e.g. EDTA, D-penicillamine, DTPA, desferrioxamine and unithiol, among others,) recent studies [1, 2] have shown that lipid soluble chelating agents and those that give soluble metal chelates, may be the only effective means of mobilizing intracellular deposits of certain metals. This has been shown most strikingly in the case of cadmium present in the kidney (as metallothionein). Such deposits can be mobilized by both BAL and sodium diethyldithiocarbamate. Because it is possible to synthesize derivatives of sodium diethyldithiocarbamate with varying lipophilicity, we have undertaken to prepare some of these compounds and examine their behavior as antidotes for acute cadmium intoxication. The animal experiments have been carried out using procedure of Gale et al. [2, 3], while syntheses have been done using published procedures [4]. The dithiocarbamates prepared and examined are shown in Table I, together with information on their efficacy as antidotes. The behavior of these compounds as antidotes can be correlated using the pi substituent constants of Hansch, as tabulated by Chu [5]. For each compound the relative hydrophobic nature can be estimated as the sum of the pi substituent constants of R 1 and R 2. These sums are shon in the last column of Table I. Figure 1 below shows the survival ratio variation with Σπ. One of the adverse effects of such dithiocarbamates is their ability to transport cadmium to the brain, an effect which is also related to the lipophilicity of the chelating agent. If the Net Efficacy of the chelating agent is defined as ▪ t001 Antidotal Behavior of Dithiocarbamates ( −S 2CNR 1R 2) Compd. R 1 R 2 Relative Survival Ratio a Relative Brain Cd b Σπ A C 2H 5 C 2H 5 1.00 1.00 2.04 B CH 3 CH 3 1.00 0.88 1.12 C C 2H 4OH C 2H 4OH 0.88 0.30 −1.54 D CH 3 CH 2COO − 0.63 0.14 −4.16 E CH 3 C 2H 4OH 1.00 0.00 −0.21 F CH 2COO − 0.38 0.02 −5.44 a Relative Survival Ratio = Survival Rate/Survival Rate for A. b Relative Brain Cd = Brain Cd/Brain Cd for A. ▪ then such a net efficacy (with n = 2), as plotted in Fig. 2, can be seen to reach a maximum in the region Σπ≈0. It is possible that such correlations will prove useful in the development of optimal chelating agents for the removal of intracellularly deposited metal ions.

Cyclic nucleotides and the nervous system

A therapeutic chelating agent may be defined as a chelating agent which i$ given orally, i.v. or i.m. with the goal of corn plexinp it with a toxic metal ion and facilitating its excretion, generally in the urine and more rarely in the feces’ 2.‘u. The administration to the patient immcdialely faces us with one of the main charac&srics desirable in such compounds: a very IOU inherent level OC toxicity of both the corn-- pound itself ctnd its metal complexes. II also forces us

Mechanism of binding of iron to potential therapeutic chelating agents

AbstractTo aid in designing new therapeutic iron chelating agents, the mechanism of iron binding to prototypic heterocyclic carboxaldehyde thiosemicarbazones has been studied. Based on molecular orbital and spectroscopic studies, iron (II) is found to bind in a covalent manner, while iron(III) seems to interact ionically. However, with both iron(II) and iron(III), chelate formation is dependent on charge interaction between the metal and the coordinating atoms of the ligand.

HSAB theory and acute metal ion toxicity and detoxification processes

The theory of hard and soft acids and bases (HSAB theory) can be used to correlate information on metal ion toxicity and the relative effectiveness of therapeutic chelating agents with parameters used to characterize “hardness” and “softness”. HSAB considerations appear to govern at least some of the non-specific aspects of metal ion toxicity. They are also useful in explaining some of the known patterns of metal ion detoxification and how situations arise where the rate behavior, rather than equilibrium factors, may be of importance in determining the success of a given chelating agent in enhancing the excretion of a given toxic metal. In many instances an effective evaluation of the applicability of HSAB theory to such systems is prevented by the limited availability of the necessary biological data. The correlations found can be used to estimate the toxicity of chemical species for which HSAB parameters but not toxicity data are available, as well as to preselect the most promising chelating agents for therapeutic testing.