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Review

Metal Chelation Therapy and Parkinson’s Disease: A Critical Review on the Thermodynamics of Complex Formation between Relevant Metal Ions and Promising or Established Drugs

by
Marianna Tosato
and
Valerio Di Marco
*
Analytical Chemistry Research Group, Department of Chemical Sciences, University of Padova, via Marzolo 1, 35131 Padova, Italy
*
Author to whom correspondence should be addressed.
Biomolecules 2019, 9(7), 269; https://doi.org/10.3390/biom9070269
Submission received: 21 June 2019 / Revised: 3 July 2019 / Accepted: 4 July 2019 / Published: 9 July 2019
(This article belongs to the Special Issue Advances in Parkinson's Disease Drugs)
Browse Figures
Graphical abstract
"> Figure 1
<p>Simple metal-chelating moieties (listed in alphabetical order) which are often encountered in molecules used or proposed for the metal chelation therapy in Parkinson’s disease.</p> "> Figure 1 Cont.
<p>Simple metal-chelating moieties (listed in alphabetical order) which are often encountered in molecules used or proposed for the metal chelation therapy in Parkinson’s disease.</p> ">
Review Reports Versions Notes

Abstract

:
The present review reports a list of approximately 800 compounds which have been used, tested or proposed for Parkinson’s disease (PD) therapy in the year range 2014–2019 (April): name(s), chemical structure and references are given. Among these compounds, approximately 250 have possible or established metal-chelating properties towards Cu(II), Cu(I), Fe(III), Fe(II), Mn(II), and Zn(II), which are considered to be involved in metal dyshomeostasis during PD. Speciation information regarding the complexes formed by these ions and the 250 compounds has been collected or, if not experimentally available, has been estimated from similar molecules. Stoichiometries and stability constants of the complexes have been reported; values of the cologarithm of the concentration of free metal ion at equilibrium (pM), and of the dissociation constant Kd (both computed at pH = 7.4 and at total metal and ligand concentrations of 10−6 and 10−5 mol/L, respectively), charge and stoichiometry of the most abundant metal–ligand complexes existing at physiological conditions, have been obtained. A rigorous definition of the reported amounts is given, the possible usefulness of this data is described, and the need to characterize the metal–ligand speciation of PD drugs is underlined.

Graphical Abstract">

Graphical Abstract

1. Introduction

Parkinson’s disease (PD) is a common neurodegenerative disorder (ND) [1]. It is characterized by neuronal cell loss in the substantia nigra (SN), which leads to a progressive central nervous system dysfunction. Symptoms include motor abnormalities like tremors, movement and balance issues, and non-motor problems like difficulty in swallowing and speaking, depression, cognitive impairment, and dementia. Although PD by itself is not a fatal disease, people may die from causes related to it.
Age is the most relevant risk factor: approximately 2% of people over the age of 60 years, and 3% of those at age over 80 years, suffer from PD [2]. Due to the average population aging, the occurrence of PD and of other NDs like Alzheimer’s disease and Amyotrophic Lateral Sclerosis is continuously increasing. The number of persons suffering from PD is expected to reach a value of approximately 9 million in 2030 [3] and up to more than 17 million in 2040 [4]. NDs are considered the leading source of disability around the world, and the fastest growing of these disorders is PD [5]. Although non-infectious, PD exhibits many of the characteristics of a pandemic, and it is experiencing exponential growth worldwide [4,6,7]. Together with the average population age increasing, other factors will likely contribute to increase the incidence of PD over current forecasts. In particular, reducing smoking rates in some countries may lead to a higher incidence of PD, because many studies have found that the risk of this disease is decreased among smokers by approximately 40% [8]. Also, pollutants by-produced in industrialized countries may contribute to the rising rates of PD, because specific pesticides, solvents, and heavy metals have been linked to this disease [9]. Actually, countries that underwent the most rapid industrialization have seen the greatest increase in the rates of PD [5].
PD can be due to genetic factors, and it has been found that race/ethnicity can affect the incidence of PD in the order Hispanics > non-Hispanic Whites > Asians > Blacks [10]. However, genetics appears to justify only a small amount (approximately 5–10%) of all PD cases: it is therefore possible to suggest an important role of external factors, like behavioural and environmental [2,9,11].
Existing drugs for PD provide only the relief of some symptoms, and there are no disease-modifying therapies demonstrated to slow or to stop the ongoing neurodegenerative process. In the search for such therapies, however, the primary issue lies in the multifactorial nature of PD. The main neuropathological hallmark of PD is proteopathy, as the formation and deposition of protein aggregates is generally observed in PD brains. The most typical deposits, called Lewy bodies, are due to α-synuclein (α-syn), an abundant neurological protein with yet unclear physiological functions. Other features characterizing PD brains are mitochondrial dysfunction, oxidative stress, defects in energy metabolism, aberrant axonal transport, and metal ion dyshomeostasis [12]. All the pathways operating in PD appear to be strictly inter-related, so that both the study of the molecular causes of the disease, and the search for an efficient therapy, cannot be limited to a specific pathway: a multi-targeted approach is suggested [1,12]. Much scientific effort in recent years is devoted to the comprehension of each pathological mechanism operating in PD, with the aim to understand and rationalize the biochemical processes occurring during the pathology. This review focuses on metal dyshomeostasis and on the therapy that is aimed to target this pathological process, i.e., metal chelation therapy.

2. Parkinson’s Disease and Metal Ions

Almost one hundred years ago, Lhermitte et al. [13] discovered that the brains of people who died from Parkinsonism, a form of dementia with similar symptoms as those of PD [14], contained a significantly larger amount of iron (Fe) than the corresponding brains of controls. Since that work, several studies have confirmed the abnormally high Fe content also in the brains of PD patients [15,16,17,18,19]. Conversely, other studies could not detect an overload of Fe in PD brains [20,21]. Recently, several studies have attempted to determine Fe brain levels in living patients with PD ([22,23] and references therein). Most but not all studies indicated larger Fe levels in the SN of patients with PD compared to control subjects, whereas no Fe excess was observed in many other brain parts, thus suggesting that a Fe dyshomeostasis occurs in PD brain, especially in the SN [23,24]. Bush et al. found that the reported Fe accumulation is contributed to by a disturbance in Fe export. This was explained by a significant reduction of the specific activity (but not of the levels) of ceruloplasmin in the SN of PD patients [25]. Ceruloplasmin is a multicopper ferroxidase protein facilitating cellular Fe export [26]. The same authors [27] observed a decrease in the PD SN of the soluble levels of another protein, tau, which can lower neuronal Fe levels by promoting the presentation of the amyloid protein precursor to the neuronal surface, where it favours the efflux of Fe [28]. It has also been suggested that PD-induced Fe accumulation is due to a dark pigment contained in SN, neuromelanin, that is able to bind Fe and that may act as a protection against Fe by binding and storing its excessive labile content [29].
A number of studies have also shown alterations in the copper (Cu) concentrations in the brain of post-mortem PD patients compared to non-PD controls [11,30], suggesting that metal dyshomeostasis in PD brains also regards Cu [31]. However, while Fe appeared to be systematically overloaded, Cu was significantly reduced in the degenerating regions of PD brains [30,32,33,34]. Other metal ions have been monitored in PD brains, but less definite results were reported. Conflicting data were reported for zinc (Zn) [35,36] and Genoud et al. recently evidenced no differences in Zn levels between experimental groups [30]. Parkinsonism is reported to rapidly develop in patients subjected to the exposure of high levels of manganese (Mn) [11,37], and a role in Parkinsonism onset has also been suggested for Cu [38]. However, no changes have been detected in the Mn level of post-mortem PD brains with respect to non-PD samples [30], and, as seen, even reduced levels were detected for Cu. Other elements which have been occasionally linked with PD have been aluminium (Al), arsenic (As), bismuth (Bi), cadmium (Cd), mercury (Hg), lead (Pb), thallium (Tl), and titanium (Ti) [2,11]. Bjørklund et al. [11] reviewed the works in which the exposure to metal ions was shown to correlate with the onset of PD and/or of Parkinsonism.
These results have prompted researchers to clarify the role of each metal ion in PD. In literature, the most studied metal ions have been Fe, Cu, Mn and Zn, whereas papers regarding other elements were much fewer. The huge work performed on this matter has been reviewed in detail [11,31,32,39,40,41], and it regarded the molecular mechanisms and biological aspects of these elements in the brains of controls and of PD patients.
Essential metal ions like Cu, Fe, Mn, and Zn are known to be involved in a large number of biochemical processes in the human brain [41,42], where they exert a structural (e.g., stabilizing configurations of macromolecules) or a functional role (e.g., being the active site of metalloenzymes). Both Cu and Fe can exist in vivo under two oxidation states, Cu(II) and Cu(I), Fe(III) and Fe(II), to allow biological systems activating and using O2 for energy purposes. Reactions activating O2, if not tightly regulated, can cause oxidative stress, so that healthy biological systems contain suitable antioxidants and very little exchangeable Cu and Fe ions. This metal ion fraction is also called “labile” or “free” ion [43], and it is thought to be the main contributor of metal-induced oxidative stress [24,44,45]. Metal ions in the labile pool can be loosely bound to peptides, carboxylates and phosphates as compounds with low mass, while some might exist as hydrated free ions. In healthy mammalian cells, the labile Fe concentration is less than 1 µmol/L, and less than 5% of total Fe [46]. The labile Cu and Fe fractions exert their toxicity by generating reactive oxygen species (ROS) via the Fenton and the Haber–Weiss reactions, both related to the presence of the Fe(III)/Fe(II) or of the Cu(II)/Cu(I) redox couple. The Fenton reaction for Fe is:
Fe(II) + H2O2 → Fe(III) + OH• + OH–
Fe(III) + H2O2 → Fe(II) + OOH• + H+
In PD brains, a dysregulation occurs between the production of OH• and OOH• (and of other ROS) and their removal, thus resulting in cellular damage through the oxidation of lipids, proteins, and DNA. The levels of glutathione, one of the most important antioxidants in human brain, were reported to be significantly decreased in the SN of PD patients compared with those of healthy subjects [47]. A dyshomeostasis of Fe or Cu can therefore have a significant impact on ROS regulation. Also, high labile Mn levels have been reported to increase oxidative stress [42]. Labile Zn2+ is more abundant in healthy brain cells, as it is released by neural activity at many central excitatory synapses [48], but still this metal ion was related to oxidative stress [49].
Labile metal ion pools can also undergo a pathogenic relation with α-syn. Being an unfolded protein, α-syn can easily switch in a number of conformational states in response to changes in environmental conditions [50,51]. Temperature changes, presence of pro-oxidative conditions [52,53] and of several metal ions can promote the formation of dimers and other polymeric forms of this protein [54,55]. The misfolding of α-syn is thought to be the most important factor driving the formation of Lewy bodies in PD, and, in turn, toxic forms of aggregated α-syn are released from neurons, and then spread between cells in a prion-like manner [32]. It was shown that part of RNA structure posttranscriptionally regulates α-syn production in response to cellular Fe and redox events [56,57], so that the overexpression of α-syn promotes the neuronal accumulation of Fe. Fe can promote the aggregation of this protein, and post-translational modifications of α-syn have also been found to regulate Fe transport [58]. It was found that α-syn can inhibit the lysosome-mediated degradation of ferritin (a Fe storing protein), resulting in the intracellular build-up of ferritin and consequently of Fe [59]. Also, the direct interaction between metal ions and α-syn in neurons, with the formation of metal–protein complexes, can be of primary importance to justify the protein unfolding and eventually its aggregation. Furthermore, the complexes themselves may be cytotoxic, as, e.g., it was reported to be Cu2+/α-syn [60]. The properties of the complex formation between metal ions and α-syn have been reviewed by several authors (e.g., [12,32,60,61]). As regards the binding moiety, it is known that metal ions can bind to high-affinity N-terminal (containing residues 1–60) and to lower affinity C-terminal sites of α-syn (from 96 to 140 amino acid residues). Studies have been performed to evaluate the stability of the metal–α-syn interactions: information available in the literature, given as dissociation constants (Kd, see below) of the complexes formed between metal ions and α-syn, is resumed in Table 1.
A recently discovered cell death pathway, called ferroptosis or Fe-dependent cell death, has provided further impetus to the “Fe hypothesis” of PD, Alzheimer’s disease, and Amyotrophic lateral sclerosis [39,62,63]. Fe still has an unclear role in ferroptosis, but it has been shown that Fe chelation is beneficial in preventing this cellular damage, which is also characterized by increased levels of lipid hydroperoxides and by a depletion of the important antioxidant glutathione. PD has been linked to ferroptosis because literature studies generally indicate that ferroptosis inhibitors may be effective in PD, too [39]. For example, chelation therapy can be beneficial in PD (see below), and prodrugs such as N-acetylcysteine, which enhances glutathione levels in brain, exert partial protection against PD neurodegeneration.
Many mechanisms have been considered and reviewed for the damage induced by Cu [44], Fe [49,64,65,66], Mn [67] and Zn [49] under PD conditions; in several cases, oxidative damage, metal dyshomeostasis and α-syn aggregation have been demonstrated to be strictly related to each other.
Despite the availability of many useful results, the molecular pathways describing the association between metals and PD onset are still ill defined. It remains controversial whether the dyshomeostasis of Cu, Fe, Mn, Zn, and possibly of other elements, is the primary cause or secondary consequence of PD as well as of other neurological diseases such as Alzheimer’s disease, multiple system atrophy, dementia with Lewy bodies, amyotrophic lateral sclerosis, Huntington’s disease, frontotemporal dementia, corticobasal degeneration, and progressive supranuclear palsy. The possibility that metal dyshomeostasis is just a secondary consequence of other independent molecular paths is supported by considering that the timing for PD onset is much slower (many years) than for Parkinsonism, which in turn is very rapidly induced if, e.g., Mn or other external toxins are administered to animal models. This suggests that endogenous neurotoxins, rather than exogenous ones, are responsible for the extremely slow neurodegeneration observed in PD. In their very recent review, Ndayisaba et al. tried to answer whether neurodegeneration is caused (or co-caused) by Fe dyshomeostasis, whether the latter contributes accelerating the pathological effects due to nerve cell death and to release of intracellular components, or whether neurodegeneration is simply not related to Fe accumulation [68]. The authors were not able to give a definite answer, but they observed that Fe dyshomeostasis occurs already at early PD onset, and that Fe should at least contribute to many aspects of neurodegeneration, in a way such that Fe might be proposed as a biomarker to detect for preclinical stages of NDs. Similarly, prudent conclusions have been drawn in another very recent review by Chen et al. [42], where the authors found that it was unclear whether Fe and Mn are primary or secondary causes of neurodegeneration, as they found that neurodegeneration cannot be reversed if metal overload is removed. The question about the primary or secondary role of Cu and Zn was raised by Barnham and Bush [41] in their review. They concluded that PD, Alzheimer’s disease, Huntington’s disease and amyotrophic lateral sclerosis are not caused by a simple overload of these metals, although the possibility that exposure may alter disease risk was not excluded. The authors found a number of possible molecular pathways induced by altered Cu and Zn levels in PD brains, which can at least contribute to the disease progression. The authors concluded that “the targets of metalloneurobiology are rich with pharmacological opportunities” [41].

3. Metal Chelation Therapy in Parkinson’s Disease

Metal chelation therapy (MCT) was proposed more than 50 years ago for the therapy of pathologies produced in the body by an overload of a metal. Metal chelation therapy involves the use of a chelating agent (CA), i.e., a molecule which forms stable coordination complexes with the target metal ion. Once administered to the patient, the CA acts as a scavenger removing the metal from its stores and favouring its decorporation from the body [69]. An efficient CA should be orally active and have a low cost, and both the ligand and the complexes formed in vivo should possess suitable hydrophilicity/hydrophobicity, and no redox activity [70]. In particular, the CA affinity towards the overloaded metal ion should be as high as possible. Last but not least, CAs and their metal complexes should display no toxicity and no or negligible side effects, but these properties are still only partially verified for established CAs. For example, the common Fe and Al chelator Desferrioxamine (also known as Desferal, DFO or Deferoxamine) is reported to cause a number of severe side effects [71], among which heart diseases [72] and retinopathy [73] appear to be the most important ones. Adverse effects were also reported for the other two established Fe chelators, Deferiprone and Deferasirox. According to Fisher et al. [74], side effects increased in patients treated with Deferiprone compared with Desferrioxamine. Kontoghiorghes et al. [71,75] reported a number of fatal renal, liver, and bone marrow failures due to Deferasirox. Another common CA used for Cu overload, D-Penicillamine, causes neuropsychiatric or hepatic complications in up to one-third of patients [76]. Toxic effects have also been observed with other CAs (2,3-dimercaptopropanol, meso-2,3-dimercaptosuccinic acid, 2,3-dimercaptopropane-1-sulfonic acid, EDTA calcium or sodium salts) used in the therapy for the overload of As, Au, Hg, Pb [77].
Despite these toxicity reports, the occurrence of a metal ion dyshomeostasis in PD has suggested to also employ MCT for the therapy of this disease and of other NDs such as corticobasal degeneration, the Westfal variant of Huntington’s disease, Alzheimer’s disease, Friedreich’s ataxia, pantothenate kinase-associated neurodegeneration, and other neuropathologies associated with brain metal overload [12,24,78,79]. In these cases, MCT was also referred to as “metal targeting”, “metal attenuating” or “metal protein attenuating” [41,80,81], in order to underline the differences occurring when MCT is employed in NDs instead of in metal overloads. Poujois et al. [82] have further improved this chelation strategy, and they called it “conservative chelation”. For the design of metal-based therapeutic strategies in NDs, the complete removal of metals from affected tissues is not the desired mechanism of action of these drugs. The terms “targeting”, “attenuating” and “conservative” evidence that the CA should remove only labile essential metal ions, which are considered to be not functionally required. Essential metal ions are aimed to be removed from the biological targets where they might be harmful, in particular, to avoid the α-syn complex formation and ROS-generating redox reactions, but they should also be allowed acting their normal physiological functions, as for example in metallo-enzymes, thus preventing severe side effects. Another important feature of a conservative CA is that the labile metal pool should be redeployed to cell acceptors or transport proteins (e.g., transferrin for Fe) [82]. This mode of action is expected to correct aberrant metal distribution, minimising systemic loss of chelated metal, thus avoiding the CA to cause metal-deficiency anemia and interfere with metal-dependent mechanisms essential for normal physiological functions. Conservative chelation, instead of a more aggressive metal removal, appeas to be particularly suitable in PD if Fe is the target, as patients suffering from this ND are mainly elderly people who are often on the border or already with Fe deficiency. Nevertheless, the unspecific removal of any essential trace metals may lead to harmful adverse effects to people of all ages, and metal deficiency can be regarding not only targeted but also untargeted metal ions. Excessive removal of Cu and Zn has been often reported for β-thalassemic patients undergoing MCT with Fe-chelators such as Deferiprone, and especially Desferrioxamine and Deferasirox [83,84]. Cu and Zn anemia, in turn, can lead to delay in growth and development, immunodeficiency, and abnormal hematopoiesis [84]. Metal redistribution, rather than metal removal, is therefore the goal in PD [24,85]. To allow a conservative chelation, a CA to be employed in PD should form moderate but not too strong complexes with the target metal ion. As an additional property, the drug should be able to pass the blood–brain barrier [78]. The ability of a CA to pass this barrier can be improved by the prochelator strategy, which for PD and also for other pathologies has been extensively reviewed by Oliveri and Vecchio [86].
In PD, MCT was proposed to target dysregulated essential metal ions [85], mainly the labile pool of Fe and Cu [24,78] but also of Zn [81] and, more rarely, of Mn [40], rather than for the decorporation of total toxic ions such as Al, Hg, Pb, etc. MCT has been tested in a number of translational studies on cell lines or on animal PD models, where Parkinsonism was induced by the administration of OHDA (6-hydroxydopamine) or MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). The Fe chelator Desferrioxamine was reported to reduce iron-induced oxidative stress in SK-N-SH cell line and dopaminergic cells aggregation [87], and its intranasal administration significantly improved PD symptoms in MPTP-treated mice [88]. The other Fe chelator Deferiprone, differently than Desferrioxamine, is orally active and is better able to cross the blood–brain barrier [89]. Deferiprone demonstrated to be efficacious in MPTP and OHDA-induced animal models of PD [90]. Other CAs tested in cell lines or in animal models for the PD therapy have been Clioquinol [91], VK-28 [92,93], M30 [94], PBT2 [95], Q1, Q4 [96] and several other compounds, as reviewed recently by Singh et al. [89].
The first clinical evidence about the efficacy of a conservative Fe chelation regimen for human PD was given by Devos et al. [90], who orally administered Deferiprone to PD patients for 12 months. The Fe deposits in the SN were significantly reduced, and the Unified Parkinson’s Disease Rating Scale motor indicators of disease progression were significantly improved. However, when the treatment was suspended, Fe started to accumulate again, suggesting a reversal to the pathological state. Deferiprone, differently than other well-known Fe chelators such as Desferrioxamine and Desferal, has the important feature to rescue transfusional hemosiderosis in the hearts of β-thalassemia patients without inducing significant anemia, largely attributable to the redeployment of captured Fe to extracellular iron-free transferrin and subsequent distribution [97], thus allowing this CA to be employed for a conservative chelation strategy. Devos et al. [90] reported that none of the Deferiprone-treated PD patients developed new neurological signs, and no level changes (of Fe and of other transition metals) were detected in brain parts not involved in PD. The conservative chelation strategy used by the authors prevented side effects typically due to Fe-deficiency anemia in the brain such as the restless legs syndrome [98]. Other Fe chelators forming stronger complexes with the targeted metal ion could have caused such unwanted side effects as they would likely also remove the non-labile part of Fe or of other metal ions [90]. The authors concluded that Deferiprone can represent a paradigm for conservative Fe chelation. The encouraging results obtained for this CA prompted the development of other clinical trials with Deferiprone. A search in https://clinicaltrials.gov indicated four ongoing or finished tests of this molecule for the treatment of PD, as also recently reported by Nuñez and Chana-Cuevas [79].
To the best of our knowledge, no other CA is still being subjected to clinical trials. However, other than Deferiprone, there is a number of molecules which have been or are being considered good therapeutic candidates for PD therapy [24,79,85,89]. Nowadays, due to the multi-faced nature of PD, the proposed strategy for MCT requires the use of multifunctional molecules able not only to bind metal ions thus controlling metal dyshomeostasis, but also to counterbalance other toxic pathways in PD. Multifunctional molecules for PD have recently been reviewed by Savelieff et al. [12].
All previously cited reviews list the names and sometimes the chemical structures of CAs used as or tested for PD therapy. However, these reviews do not report which complexes can form between relevant metal ions and CAs (metal–ligand stoichiometries) and how stable they are (metal–ligand stability constants), i.e., they lack speciation information. Some lists of metal–ligand stoichiometries and of stability constants (given as logβ, see below) for promising PD drugs have been reported, for example by Gumienna-Kontecka et al. [24], Kasprzak et al. [99], and Prachayasittikul et al. [100]. The Gumienna-Kontecka logβ list was however limited to very few compounds and to the complexes formed with Fe(III), the Kasprzak and Prachayasittikul lists report only the complex formation of flavonoids and 8-hydroxyquinolines, respectively. Many of the reported lists also lack the ligand acidity constants, which (see below) are necessary to achieve a complete speciation picture.
The knowledge of metal–ligand speciation can allow modeling the CA activity in vitro or in vivo, i.e., to perform calculations (e.g., [101]) describing the distribution of the metal ion of interest at any conditions. Some examples of information which can be gathered from speciation calculations in the frame of MCT will be briefly given below. We think, and it has been stated (see, e.g., [101,102]), that knowledge about metal–ligand speciation should be easily available to researchers interested in the study of pathologies involving metal ions, such as PD. As regards CAs, the aforementioned knowledge should at first regard all essential metal ions (in all their possible oxidation states) undergoing dyshomeostasis in PD. The relevant ions are therefore Cu(II), Cu(I), Fe(III), Fe(II), Mn(II), and Zn(II) (Mn(III) should also be considered in principle, however we decided to exclude it because its content in the body is generally considered to be minimal [103]).
It is also necessary to note that there are several other established or promising PD drugs, not specifically designed for MCT, which can also act as CAs. A typical example is L-Dopa (levodopa), the gold standard in the therapy against PD: its pharmacological activity is aimed to increase the dopamine deficit in vivo, but it can also form stable complexes with several metal ions including the PD relevant ones [104]. These compounds are by themselves multifunctional drugs, and their potential influence on the pathological mechanisms involving metal ions cannot be neglected. In the present review, all drugs displaying metal chelation properties, not only those specifically designed for MCT, will be considered.
A bibliographic search has been performed with the aim to collect all promising and established drugs for the PD therapy. Keywords and boolean logics employed for this bibliographic search are given in the Supplementary Materials. Several reviews appeared in 2014 or later, reporting lists of anti-PD compounds [1,12,105,106,107,108,109,110]. These reviews list mainly molecules in use, or which underwent in vivo, or clinical phase tests against PD; here, we also decided to consider compounds which have just been tested in vitro, or even only proposed, e.g., after an in silico approach, because it is likely that some of these will undergo further tests in the following years. Clearly, if a compound was proposed and/or tested in vitro several years ago, and after not more considered as anti-PD drug, likely it was not suitable for this aim and has been abandoned. Due to the latter consideration, and given the availability of the above listed reviews, we decided to limit our bibliographic search to papers published starting from 2014.
For each compound, name(s), chemical structure and the reference(s) were collected. The whole list of these substances is reported in Table S1 of the Supplementary Materials. This table lists approximately 800 compounds and, to the best of our knowledge, it is the most complete table available to date which reports established or potential anti-PD drugs. Table S1 also contains the compounds listed in all above mentioned reviews of PD drugs [1,12,24,79,85,89,104,105,106,107,108,109,110]. Table S1 does not report natural extracts, e.g., drugs obtained from plants or animals, unless the active components have been identified. This therapeutic approach is extensively considered in the literature: for a recent review see, e.g., [111].
Table 2 represents a subset of Table S1 and it lists all compounds (nearly 250) displaying metal-chelating properties which have been used, tested or only proposed for the therapy against PD.
It is rather easy to predict whether a given compound can form stable complexes with metal ions, and thus whether it in principle can affect metal homeostasis in the brain: the presence of at least two functional groups with metal-binding ability is suggested, and the formed chelation ring should have five or six members. Truly, monodentate ligands and those forming chelating rings of a different size to 5 or 6 can also coordinate metal ions, but the resulting complexes are generally too weak to allow these ligands to affect metal speciation in vivo. Coordinating functional groups can be negatively charged (or partially charged) oxygens such as carboxylates, phenolates, N-oxides, as well as nitrogen and sulphur atoms with non-delocalized lone pairs such as amines and thio-derivatives. For example, l-Dopa (chemical structure drawn in Table S1) has two possible binding sites, one given by the two phenolic oxygens (catechol-like), and the other by the amino-acidic tail (glycine-like). Both binding sites, upon chelation, form a five membered ring with the metal ion. Some simple metal-chelating moieties often contained in CAs are depicted in Figure 1
The formation of stable metal–ligand complexes is more difficult to predict for peptides, because their metal chelation ability is strongly influenced by their spatial configuration. Also, it is not possible to assess the metal–ligand speciation of molecules bearing many chelating functional groups. Molecules of this kind, cited in Table S1, were not reported in Table 2. For the relevant metal ions (Cu(II), Cu(I), Fe(III), Fe(II), Mn(II), and Zn(II)) and for the compounds listed in Table 2, the metal–ligand speciation will be given.

4. The Measurement of the Stability of Metal–Ligand Complexes

While no ambiguities exist for reporting the stoichiometries of the complexes, it is worth describing all possible amounts used in literature to measure the stability of metal–ligand complexes: cumulative stability constants, stepwise stability constants, conditional stability constants, cologarithm of the concentration of free metal ion at equilibrium (pM), association constants, and dissociation constants.
Cumulative (or overall) stability constants are generally indicated with the Greek letter β. Each complex forming in solution is characterized by a β value. If M is the metal ion, H the proton, and L the ligand, and MmHhLl is the complex formed, β is defined as:
β = [ M m H h L l ] [ M ] m [ H ] h [ L ] l
where square brackets denote concentrations at equilibrium. The use of concentration amounts instead of activities (i.e., concentrations multiplied by activity coefficients) is generally allowed by maintaining a constant ionic strength during the experimental measurements. The (at least formal) presence of activities in equation (2) justifies why β values are commonly indicated without a measuring unit. Cumulative constants are usually given as logarithm (logβ), and their knowledge is required for performing metal–ligand speciation calculations. Their experimental determination is however complicated as many experimental details have to be considered in order to obtain accurate results [312,313]. In addition, β values do not allow to state the effective complex stability, which is also affected by the acid—base properties of metal ion and ligand, by the total metal (cM) and ligand (cL) concentrations, and by the pH. In other words, logβ values by themselves are not informative and cannot be used to compare the stability of complexes formed by different metal ions and ligands.
Stepwise stability constants are generally indicated with the letter K and they are written as logK. Stepwise constants are more commonly employed if the complexes existing in solution contain one metal ion and one or more ligands (MLl, with l ≥ 1). For example, for the complex MLl, K can be defined as:
K = [ M L l ] [ M L l − 1 ] [ L ]
Stepwise constants are related with cumulative ones, so that the former can be computed from the latter and vice versa— e.g., for the complexes ML and ML2, logβML = logKML and logβML2 = logKML + logKML2, respectively.
Conditional (or effective) stability constants may be cumulative or stepwise and are indicated with the apostrophe (β ‘ or K ‘). For example, the conditional cumulative constant of the complex ML2 is defined as:
β ′ = [ M L 2 ] ∑ [ M ′ ] ( ∑ [ L ′ ] ) 2
where Σ[M′] and Σ[L′] represent the sum of the concentrations of uncomplexed metal ion and uncomplexed ligand at equilibrium, i.e., [M] + [M(OH)] + [M(OH)2] + … and [L] + [HL] + [H2L] + …, respectively. As Σ[M′] and Σ[L′] depend on pH, also logβ′ and logK′ values depend on pH. These constants represent the effective stability of the given complexes in the presence of acid—base equilibria, so that they can be used to compare the stability of complexes formed by different metal ions and ligands. However, the comparison is possible only if the complexes have the same stoichiometries.
The other three amounts used to measure metal–ligand affinities, i.e., pM, association constants, and dissociation constants, differ from logβ, logK, and from their conditional values, because only one number is given to characterize a solution containing the given metal and ligand. This is particularly useful when many complexes are formed and, in overall, one value resumes their strength.
pM represents the cologarithm of the concentration of free metal ion at equilibrium (pM = –log[M]), and it can be calculated if log β or logK values are known. The larger is pM, i.e., the lower is [M], the stronger are the complexes; pM can be used to compare the relative strength of the complexes, irrespective of their number and their stoichiometry. As pM depends on pH and also on cM and cL, calculation must be performed under the same conditions: usually the pM value for MCT relevant conditions is computed at pH = 7.4, cM = 10−6 mol/L and cL = 10−5 mol/L [24,70,314]. The only (but important) disadvantage of pM is that it can be computed if logβ or logK values are known, i.e., the experimental procedure required to gain a pM value remains complicated.
Association constants, indicated as Ka, are defined like β or K if only one complex ML forms in solution and no acid–base equilibria coexist:
K a = [ M L ] [ M ] [ L ]
If M and/or L undergo acid–base equilibria, Ka for the complex ML is defined like K′ or β′. When more complexes of general stoichiometry MmHhLl coexist in solution, more K′ or β′ are needed, whereas still only one Ka suffices and is defined as:
K a = ∑ [ M m H h L l ] ∑ [ M ′ ] ∑ [ L ′ ]
where Σ[MmHhLl] represents the sum of the concentrations of all complexes existing in solution. As Ka values are not thermodynamically defined, i.e., concentration values are employed instead of activities, they bear a measuring unit, which according to equation (6) is L/mol (or, more commonly, a multiple).
The dissociation constant, indicated as Kd, is the inverse of Ka (measuring unit of Kd: mol/L or a multiple). For example, if complexes of general stoichiometry MmHhLl coexist in solution, Kd can be defined as:
K d = ∑ [ M ′ ] ∑ [ L ′ ] ∑ [ M m H h L l ]
Kiss et al. [102] reported a similar definition of Kd, where [M] was used instead of Σ[M’]. However, as the proton content is experimentally not controlled when Kd values are measured, not only for the ligand but also for the metal ion, we think that Equation (7) allows a more rigorous calculation of Kd values. Literature appears to have preference for measuring and reporting Kd more than Ka [313,315]. This is probably due to the chemical usefulness and significance of Kd, as it represents the concentration of free metal ion at which the concentrations of free ligand and of the complexes are equivalent [313]. In the following, Kd values will be considered instead of Ka ones.
Values of Kd can be determined with a much simpler experimental design than that used to obtain logβ, logK and pM [313,315]. This is a crucial advantage when complicated ligands are studied, such as proteins, for which the determination of logβ or logK is practically impossible. Still, Kd can be computed from Equation (7) if logβ or logK values are available, so that the concentrations of all species existing in solution can be calculated. Therefore, Kd represents a simple tool and practically the only way to compare metal–ligand and metal–protein complex stabilities each other.
The main disadvantage of Kd is that it depends not only on pH, cM and cL, but also on the copresence of other ligands or other metal ions [316], as these affect Σ[M′] and Σ[L′] in Equation (7) (the same applies for Ka in equation 6, too). This explains at least in part why reported Kd values are scarcely reproducible (see Table 1) and depend on the experimental conditions [12]. Equations to correct Kd values, by taking into account the effect of a competing ligand (e.g., the buffer) and of the different pH, have been proposed [316]. Standardized conditions to measure the Kd of metal–protein complexes are also being proposed [317,318,319], and this should lead to more reproducible results, thus eventually allowing a more reliable comparison among Kd numbers.

5. The Metal–Ligand Speciation of Anti-Parkinson Drugs

Table S2 (Supplementary Materials) reports the metal–ligand speciation available in the literature for the ligands listed in Table 2 (rows) and the relevant metal ions, i.e., Cu(II), Cu(I), Fe(III), Fe(II), Mn(II), and Zn(II) (columns). If not differently specified in the notes of Table S2, speciation information (stoichiometries of the complexes, and stability constants given as logβ) has been obtained from the IUPAC stability constant database [320].
The ionic product of water, the stability constants of the metal ion hydrolysis products, and the acidity constants of each ligand, have to be considered to complete the speciation picture and allow speciation calculations. The ionic product of water and the stability constants for hydrolysis products of the considered metal ions are resumed in Table S3 in the Supplementary Materials (it is worth noting that these values are only sometimes reported in papers dealing with metal speciation). The acidity constants of the ligands listed in Table 2 have also been taken from the IUPAC stability constant database [320] or from the papers reported in the notes, and they are given as logβ values in Table S2 (column marked ‘H+’).
For some metal–ligand complexes, and for many ligand acidity constants, more than one speciation set has been reported in literature, and/or different logβ values were proposed. For example, 27 different speciation models have been obtained for the Cu(II)/L-Dopa complexes [320] In Table S2 only one speciation set has been reported, obtained at ionic strength and temperature as close as possible to 0.1 mol/L and 25 °C, respectively. This ionic strength represents a reasonable physiological environment; as regards temperature, 37 °C would better resemble physiological conditions, but speciation data at this temperature are few. For comparison purposes, we preferentially reported data at the most studied temperature of 25 °C. Notes were added in Table S2 if the studied temperature and ionic strength were different than 25 °C and 0.1 mol/L, respectively.
For many other ligands listed in Table 2, no metal speciation set, and sometimes also no acidity constants, were available. This can be ascribed to several reasons, which for some CAs include their very recent development or proposal. For example, 3-(7-Amino-5-(cyclohexylamino)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-2-yl)-2-cyanoacrylamide, Aromadendrin, Astilbin, and many other CAs listed in Table 2 have been proposed for MCT in PD only approximately (or less than) one year ago. Possibly, the absence of equilibrium constants can also be justified by the above-mentioned experimental difficulties associated to accurate speciation measurements, which for complicated and often poorly water-soluble molecules may become formidable. Nevertheless, it is possible to tentatively predict the metal speciation of such ligands, by individuating the chelating moiety which is responsible for the complex formation (see also Figure 1), and by considering a simpler ligand having a known metal speciation and bearing the same moiety: ligands having the same chelating functional groups are expected to have a similar metal speciation. For example, complicated molecules bearing a 1,2-diaminoethane chelating group have been considered to have the same metal speciation as 1,2-diaminoethane itself. This predicted speciation should be employed with caution, because inductive and steric effects (and especially resonance ones, if existing) of the remaining part of the molecule might significantly modify the speciation picture. However, these estimations should represent the most reliable values available, until dedicated experimental measurements will be performed. Whenever this kind of assignation has been done, the reported metal-speciation has been marked as “tentative” in the notes of Table S2. A speciation prediction has also been attempted for molecules bearing two or a maximum of three chelating moieties, by considering their speciation to be similar to that of a simpler ligand bearing the moiety forming the most stable complexes. In these cases, however, the inaccuracy of the predicted speciation might be relatively large.
Table 3 reports selected speciation information regarding Cu(II) which has been computed from the data of Tables S2 and S3. Only the ligands for which a Cu(II) speciation was available or has been tentatively estimated were reported in Table 3. Calculations have been performed by the software PITMAT (see [70] and references therein). The first reported value is that of pM (pCu(II) = –log[Cu(II)], which has been computed at pH = 7.4, at cM = 10−6 mol/L and at cL = 10−5 mol/L, as recommended in MCT modeling [70,314]. Besides pM, Kd also was computed according to Equation (7). To the best of our knowledge, no reference pH, cM and cL values have been hitherto adopted for the calculation of Kd. We propose here that this calculation should be performed at the same conditions as for pM: pH = 7.4, cM = 10−6 mol/L, and cL = 10−5 mol/L. The last column of Table 3 reports the most abundant metal complex existing for each ligand at these same physiologically relevant conditions; if available, the charge of this complex is reported as well. Table 4, Table 5, Table 6, Table 7, Table 8 report the same information computed for Cu(I) (Table 4), Fe(III) (Table 5), Fe(II) (Table 6), Mn(II) (Table 7), and Zn(II) (Table 8).

6. Possible Usages of Speciation Data for Metal Chelation Therapy against Parkinson’s Disease

Speciation calculations allow to predict which metal and ligand species exist in solution at a given pH and metal and ligand total concentrations. A speciation model can therefore be obtained: this was done for the calculations performed in Table 3, Table 4, Table 5, Table 6, Table 7 and Table 8, where only some information has been given.
As anticipated, values of pM and Kd are useful to compare the relative strength of the complexes formed by different ligands with the same metal ion, or, conversely, by different metal ions with the same ligand. For example, the complexes formed by Fe(III) with 3-hydroxy-4(1H)-pyridinone (Deferiprone) have larger pM and lower Kd values than those formed with Luteolin, thus Fe(III)-Deferiprone complexes are stronger than Fe(III)-Luteolin ones. The values of pFe(III) for Deferiprone (19.3) or for Desferrioxamine (26.8) are often considered as milestones when new CAs are proposed for the chelation therapy of Fe overload [314]: new compounds are considered to be effective enough if their pFe(III) is larger than that of Deferiprone or of Desferrioxamine.
More importantly, Kd values can be compared with those reported in Table 1, allowing the assessment of whether a given ligand is able to remove a metal ion from α-syn: removal can occur if the Kd value is lower than that of α-syn. This approach has been proposed for MCT in Alzheimer’s disease, where Kd values of the CA + metal ion complexes were recommended to be 10–100 times lower than Kd values of the amyloid β protein + metal ion ones [316]. If the same approach is adopted for PD, it can be, e.g., deduced that Desferrioxamine (Kd = 1.81 × 10−7) is able to remove Fe(III) from α-syn (Kd = 10−4), and L-Dopa (Kd = 7.95 × 10−6) is able to remove Cu(II) from α-syn (Kd = 102). Many other ligands, including L-Dopa (Kd = 2.96 × 104), cannot remove Fe(III) from α-syn. However, it is necessary to underline that the Kd values reported in Table 1 are not completely reliable (the same also applies for Kd values of amyloid β protein + metal ion [12]), for the reasons stated above, so this approach does not (still) allow drawing definite conclusions about the removal of the relevant metal ion from proteins. On the other hand, the control of metal ion dyshomeostasis in PD requires that the CAs do not form too strong metal complexes to avoid metal anemia and allow metal redeployment to other compartments, according to the conservative chelation strategy. Too high or too low Kd values are thus not suitable. Unfortunately, the limiting Kd values which an ideal CA should possess to be employed for the PD therapy are not known.
The information regarding the most abundant complex existing at physiological conditions can be useful for two reasons. The identity of the existing complexes (and in particular of the most abundant one) and their charge are crucial in determining their redistribution once the target metal ion has been complexed by the CA. For example, a charged complex is expected to be hydrophilic, thus being unable to pass cellular barriers and preferring to be solubilised in aqueous solutions (e.g., in the blood), whereas neutral species should behave in an opposite way. The structure of the complexes, which might be deduced from the stoichiometry, also has a main role in determining their properties and toxicity [321].
As regards Fe and Cu, it is necessary to consider that they can undergo redox reactions even when complexed by a ligand. These reactions might be as harmful as or even more dangerous than those caused by the target metal ion at pathological in vivo conditions. The redox-induced toxicity of Fe and Cu complexes formed by several ligands is well known, so it has been used to develop new anti-cancer drugs [322], but it appears to have been generally overlooked when MCT is employed for PD. The redox activity of Fe and Cu complexes depends on the relative stability of the complexes formed by the ions at the two oxidation states. As regards Fe, if a ligand L forms the complexes FeIIIL and FeIIL with Fe(III) and Fe(II), respectively, a redox half-reaction can occur:
FeIIIL + e− = FeIIL
By means of simple substitutions in the Nernst equation of Fe(III)/Fe(II), the standard reduction potential of (8) can be computed:
E F e I I I L / F e I I L 0 = E 0 F e I I I / F e I I + R T F ln β F e I I L β F e I I I L
where E0Fe(III)/Fe(II) is the standard reduction potential for free Fe (0.771 V), and βFeIIIL and βFeIIL are the cumulative stability constants of FeIIIL and FeIIL, respectively. Values of E0 of any Fe or Cu complexes can be derived in a similar way if metal–ligand speciation at both oxidation states is known. Alternatively, electrochemical values can experimentally be obtained from voltammetric measurements (see, e.g., [323]). The standard reduction potentials of Fe complexes might have an important role in determining whether they can undergo harmful redox cycling in vivo, as extensively descrived by Merkofer et al. [324] and recently reviewed by Koppenol and Hider [325]: in general, it appears that negative E0 values can guarantee the absence of such toxic phenomena. However, further work is necessary to evaluate limiting Fe and Cu E0 values under which no redox damage occurs in PD brains.
Other possible information which can be gathered from speciation calculations, even if focused on the bloodstream, has recently been reviewed by Kiss et al. [326,327].

7. Concluding Remarks

The development of drugs able to target several pathological pathways appears to be the best approach for PD therapy and of other important NDs such as Alzheimer’s disease and Amyotrophic Lateral Sclerosis. Compounds which form complexes with the PD relevant metal ions, i.e., Cu(II), Cu(I), Fe(III), Fe(II), Mn(II) and Zn(II), are aimed to target metal dyshomeostasis. For these CAs and for these metal ions, the knowledge of metal–ligand speciation is of primary importance to predict the efficacy of the CA, its ability to remove dysregulated metal ions from toxic storages such as the α-syn complex and redeploy metal ions to safe stores (conservative chelation), the possible toxic effects induced by the metal complexes formed in PD brain, and in general to be able to model the distribution of the metal–ligand species in vivo. Still much work has to be performed to define the upper and the lower limiting metal Kd values required by a CA to disrupt the α-syn complex without causing excessive metal removal, as well as the suitable standard reduction potentials required by the complexes to avoid harmful redox cycling in the brain. Also, available speciation information is in part lacking, especially as regards Cu(I), for which very few stability constants values have been hitherto determined (possible strategies for effective studies of Cu(I) speciations have been proposed [328]), but also for other metal ions and for several complicated or recently proposed CAs. If a complete metal–ligand speciation study (aimed to determine stability constants) cannot be performed, a Kd value should at least be determined. This amount represents a key number which can be used to compare simple metal–ligand complexes, for which the full speciation picture is available, with complicated ones like those involving α-syn, for which this information cannot be obtained. However, standardized experimental procedures are recommended to allow Kd values to be more rigorously and reliably compared with each other.

Supplementary Materials

The following are available online at https://www.mdpi.com/2218-273X/9/7/269/s1. Keywords and boolean logics used to perform the bibliographic search of this review. Table S1: Compounds used, tested or proposed for the therapy against Parkinson’s disease, as obtained from a Literature survey in the year range 2014–2019 (April). Table S2: Acid—base and metal chelation properties of the compounds listed in Table 2. Table S3: Ionic product of water and stability constants for hydrolysis products of Cu(II), Cu(I), Fe(III), Fe(II), Mn(II), and Zn(II).

Funding

This research received no external funding.

Conflicts of Interest

The authors declare no conflict of interest.

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Biomolecules 09 00269 g001a 550Biomolecules 09 00269 g001b 550
Figure 1. Simple metal-chelating moieties (listed in alphabetical order) which are often encountered in molecules used or proposed for the metal chelation therapy in Parkinson’s disease.
Figure 1. Simple metal-chelating moieties (listed in alphabetical order) which are often encountered in molecules used or proposed for the metal chelation therapy in Parkinson’s disease.
Biomolecules 09 00269 g001aBiomolecules 09 00269 g001b
Table
Table 1. Dissociation constants (Kd) obtained at physiological pH for the complexes formed between metal ions and α-synuclein (values computed for the highest affinity binding site), and references (reviews).
Table 1. Dissociation constants (Kd) obtained at physiological pH for the complexes formed between metal ions and α-synuclein (values computed for the highest affinity binding site), and references (reviews).
Metal IonKd (nmol/L)References
Cu(II)102[12,61]
Cu(I)104–103[61]
Fe(III)10−4[12,60]
Fe(II)106–5 × 104[12,60]
Mn(II)106[60]
Zn(II)>106[61]
Table
Table 2. Compounds displaying metal-chelation properties which have been used, tested or proposed for the therapy against PD, as obtained from a literature survey in the year range 2014–2019 (April). Substances are listed in the first column according to their alphabetical order. Only the latest and/or the most important references (e.g., reviews) are given in the last column. This Table is a subset of Table S1, which also includes non-chelating compounds and compounds with non-predictable metal–ligand speciation. The chemical structure of each substance is reported in Table S1.
Table 2. Compounds displaying metal-chelation properties which have been used, tested or proposed for the therapy against PD, as obtained from a literature survey in the year range 2014–2019 (April). Substances are listed in the first column according to their alphabetical order. Only the latest and/or the most important references (e.g., reviews) are given in the last column. This Table is a subset of Table S1, which also includes non-chelating compounds and compounds with non-predictable metal–ligand speciation. The chemical structure of each substance is reported in Table S1.
Compound Name(s)References
7DH[112]
7MH[112]
8A[89]
8B[89]
8C[89]
8E[89]
8F[89]
N-Acetylcysteine[113,114]
ACPT-I[115]
ADX88178[116]
Alaternin[117]
Alvespimycin[118]
AM-251[119,120]
Ambroxol[121,122]
3-(7-Amino-5-(cyclohexyl-amino)
-[1,2,4]triazolo[1,5-a]
[1,3,5]triazin-2-yl)-2
-cyanoacrylamide		[123]
Aminothiazoles derivatives as SUMOylation activators[124]
AMN082[115]
Amodiaquine[125,126]
Antagonist of the A(2A) adenosine receptor-derivative 49[127]
Apigenin[128,129,130,131]
Apomorphine[132,133]
l-Arginine[134]
Aromadendrin[128]
Ascorbic acid[135,136]
ASI-1[12]
ASI-5[12]
Astilbin[137]
Azilsartan[138]
Baicalein[139,140,141]
Benserazide[142,143]
7H-Benzo, perimidin-7-one derivatives (R6 = OH)[144]
4H-1-Benzopyran-4-one[145]
8-Benzyl-tetrahydropyrazino, purinedione derivatives (derivative n.57)[146]
Bikaverin[147]
(−)-N6-(2-(4-(Biphenyl-4-yl)
piperazin-1-yl)-ethyl)-N6-
propyl-4,5,6,7-tetrahydro-
benzo, thiazole-2,6-diamine derivatives		[148]
2.2’-Bipyridyl (2,2’-bipyridine)[112]
4-((5-Bromo-3-chloro-2-
hydroxybenzyl) amino)-2-
hydroxybenzoic acid (LX007, ZL006)		[149,150]
C-3 (α carboxyfullerene)[151]
Caffeic acid amide analogues[152,153,154,155]
Carbazole-derived compounds[156]
Carbidopa[135,157]
Carnosic acid[154,158]
Catechin[24,128]
Ceftriaxone[12,159,160,161]
Celastrol[162,163]
CEP-1347[164,165]
Chebulagic acid[166]
Chlorogenic acid[167]
3′-O-(3-Chloropivaloyl)
quercetin		[168]
Chlorpromazine[108]
Chrysin[128,169,170]
Clioquinol[89,91,171,172]
Clioquinol-selegiline hybrid[79]
Clovamide analogues
(R1 and R2 = OH,
and/or R3 and R4 = OH)		[173]
“Compound 1”[174]
“Compound (−)-8a”[175]
“Compound 8”[176]
“Compound 21”, derivative of 3-methyl-1-(2,4,6-trihydroxy
phenyl) butan-1-one		[177]
“Compound (−)-21a”
, derivative of N-6-(2-(4-(1H-indol-5-yl)
piperazin-1-yl)ethyl)-N-6-
propyl-4,5,6,7-tetrahydro-
benzo[d]thiazole-2,6-diamine		[178]
Creatine[179,180]
Cudraflavone B[181]
Curcumin[89,117,182,183,184]
Cyanidin[185,186]
D-512[187]
D-607 (bipyridyl-D2R/D3R agonist hybrid)[12,188,189]
DA-2 (8D)[12,89]
DA-3[12]
DA-4[12]
Dabigatran etexilate[190]
Dabrafenib[191]
(S)-3,4-DCPG[115]
Deferasirox[24]
Deferricoprogen[192]
Delphinidin[160,185,193,194]
Demethoxycurcumin[195]
Dendropanax morbifera active compound[196]
Desferrioxamine (Desferoxamine, Desferal, DFO)[112]
(S)-N-(3-(3,6-Dibromo-9H
-carbazol-9-yl)-2-fluoropropyl)-6-methoxypyridin-2-amine		[197]
4,5-O-Dicaffeoyl-1-O-(malic acid methyl ester)-quinic acid derivatives (R1, R2, R3, R4, or R5 = caffeoyl)[198]
Dihydromyricetin[199]
5-(3,4-Dihydroxybenzylidene) -2,2-dimethyl-1,3-dioxane-4,6-dione[200]
7,8-Dihydroxycoumarin derivative DHC12[79]
3′,4′-Dihydroxyflavone[201]
7,8-Dihydroxyflavone[202,203]
5,7-Dihydroxy-4′-methoxy
flavone		[204]
(E)-3,4-Dihydroxystyryl aralkyl sulfones[205]
(E)-3,4-Dihydroxystyryl aralkyl sulfoxides[205]
5,3’-Dihydroxy-3,7,4’
-trimethoxyflavone		[206]
2-[[(1,1-Dimethylethyl) oxidoimino]-methyl]-3,5,6-
trimethylpyrazine		[207]
DKP[85]
L-DOPA (levodopa, CVT-301)[132,135,208]
DOPA-derived peptido-mimetics (deprotected)[209]
DOPA-derived peptido-mimetics (protected)[209]
L-DOPA deuterated (D3-L-DOPA)[210]
Doxycycline[211,212]
Droxidopa[110]
Echinacoside[213]
Ellagic acid[214]
Entacapone (Comtan, ASI-6)[12,215,216]
Enzastaurin[164]
Epicatechin[128,160,193,194]
Epigallocatechin-3-gallate[117,217,218]
Etidronate (HEDPA)[219]
Exifone[12]
F13714[220]
F15599[220,221]
Farrerol[222]
Fisetin (3,3′,4′,7-Tetrahydroxy
flavone)		[223,224,225]
Fraxetin[117]
Galangin[226]
Gallic acid and derivatives[214,227,228]
Gallocatechin[128]
Garcinol[229]
Genistein[117,128,230,231]
Glutamine[232]
Glutathione derivatives[63]
Glutathione
-hydroxyquinoline compound		[233]
Glutathione-l-DOPA compound[234]
Gly-N-C-DOPA[209]
GSK2795039[108]
Guanabenz[235]
Hesperidin[128,236]
Hinokitiol[237]
8-HQ-MC-5 (VK-28)[12,24,89,92,93]
4-Hydroxyisophthalic acid[238]
1-Hydroxy-2-pyridinone derivatives[89,239]
3-Hydroxy-4(1H)-pyridinone (Deferiprone)[112,239,240]
8-Hydroxyquinoline[241]
8-Hydroxyquinoline-2-
carboxaldehyde isonicotinoyl hydrazone		[242]
Hydroxyquinoline-propargyl hybrid (HLA 20)[12,79,89]
Hydroxytyrosol butyrate[243]
Hyperoside[117]
IC87201[150]
Icariin[244]
Icariside II[245]
l-(7-imino-3-propyl-2,3-
dihydrothiazolo [4,5-d]pyrimidin-6(7H)-yl)urea		[246]
Imipramine[247]
Isobavachalcone[248]
Isochlorogenic acid[167]
Isoquercetin (Isoquercitrin)[249]
Kaempferol[128,160,193,194]
Kaempferol, 3-O-a-l arabinofuranoside-7-O-a-l-rhamnopyranoside[214]
KR33493[250]
Kukoamine[251]
Lestaurtinib[164]
Lipoic acid[252,253,254]
Luteolin[128]
LY354740[115]
M10[24]
M30 (VAR10303)[112,255]
M99[24]
Macranthoin G[256]
Magnesium lithospermate B[257]
α-Mangostin[258]
γ-Mangostin[259]
MAOI-1[12]
MAOI-2[12]
MAOI-4[12]
MAOI-8[12]
Meclofenamic acid[260]
Metformin (Met)[261,262]
Methoxy-6-acetyl-7-
methylijuglone		[117]
N’-(4-Methylbenzylidene)-5-phenylisoxazole-3-carbohydrazide[263]
Mildronate[264]
Minocycline[12,160,265]
Mitomycin C[266]
MitoQ[108]
Morin (3,5,7,29,49-pentahydroxy
flavone)		[160,193,194,267]
[18F]MPPF[107]
MSX-3[268]
Myricetin[128,269,270]
Myricitrin[271]
Naringenin[128,272]
Naringin[117,273,274]
Nicotinamide adenine dinucleotide phosphate (NADPH)[275,276]
Nicotinamide mononucleotide[277]
Nitecapone[278]
Nordihydroguaiaretic[160,193,194]
Oleuropein[279]
Opicapone[278]
P7C3[280,281]
PBF-509[282]
PBT2[89,283]
PBT434[284]
Petunidin[185]
Phenothiazine 2Bc (n = 0 and n = 1)[285]
Phenylhydroxamates[286]
Piceatannol[160,193,194]
Pinostrobin[287]
Piperazine-8-OH-quinolone hybrid[79]
Preladenant[282,288]
Promethazine[289]
Protocatechuic acid[170]
Protosappanin A[290]
Punicalangin[270,291]
Pyrazolobenzothiazine-based carbothioamides[292]
Pyridoxal isonicotinoyl hydrazone (PIH) and related compounds[24,89]
Pyrimidinone 8[293]
Q1[89]
Q4[89]
Quercetin[117,294,295]
Quinolines Derivatives as SUMOylation activators[124]
Radotinib[296]
Riboflavin[297,298]
Rifampicin (ASI-3)[12,160]
Rimonabant[119,120,282]
Rosmarinic acid[154,299]
Rotigotine[105,133,278,300]
Rutin[128,249]
Salicylate, sodium salt[301]
Salvianolic Acid B[117]
SCH-58261[105,302]
SCH412348[105]
Silibinin (silybin) A, B[89]
Silydianin[24]
ST1535[282]
ST4206[282]
Staurosporine[164]
Stemazole[303]
Sulfuretin[304]
Tannic acid[160,193,194]
Tanshinol[117]
Taurine[305]
Taxifolin[128]
Tectorigenin[306]
Tetracycline [307]
Tolcapone (ASI-7)[12,105]
Tozadenant[282,302]
Transilitin[270]
O-Trensox[24]
2′,3′,4′-Trihydroxyflavone[270]
2,3,3-Trisphosphonate[219]
V81444[282]
VAS3947[108]
VAS2870[108]
Verbascoside[160,193,194]
WIN 55,212-2[119,120]
WR-1065[308]
Zonisamide[309,310,311]
Table
Table 3. pCu(II) and Kd values, and the most abundant Cu(II) complex, obtained at physiologically relevant conditions: pH = 7.4, cCu = 10–6 mol/L, and cL = 10–5 mol/L. Computations have been performed from data of Tables S2 and S3 (Supplementary Materials). Refer to Table S2 to identify ligands for which only tentative speciations were proposed, and ligands whose complexes have unknown charges.
Table 3. pCu(II) and Kd values, and the most abundant Cu(II) complex, obtained at physiologically relevant conditions: pH = 7.4, cCu = 10–6 mol/L, and cL = 10–5 mol/L. Computations have been performed from data of Tables S2 and S3 (Supplementary Materials). Refer to Table S2 to identify ligands for which only tentative speciations were proposed, and ligands whose complexes have unknown charges.
Compound Name(s)pCu(II)Kd (nmol/L)Most Abundant Complex
7DH
7MH		14.25.91 × 10−5CuL2
8A
8B
8C		14.25.91 × 10−5CuL2
8E
8F 		10.62.35 × 10−1CuL2
N-Acetyl cysteine6.23.82 × 104CuL
ACPT-I7.35.93 × 102CuL
ADX881787.45.15 × 102CuL
Alaternin16.53.39 × 10−7CuL2
Alvespimycin10.35.35 × 10−1CuL22+
AM-2516.31.47 × 104CuL
Ambroxol9.27.26CuL+
3-(7-Amino-5-(cyclohexylamino)-[1,2,4]triazolo[1,5-a][1,3,5]
triazin-2-yl)-2-cyanoacrylamide		9.17.58CuL2
Aminothiazoles derivatives as SUMOylation activators9.71.86CuL2
AMN08210.35.35 × 10−1CuL22+
Amodiaquine6.11.90 × 107CuHL
Antagonist of the A(2A) adenosine receptor-derivative 496.49.65 × 103CuL
Apigenin6.82.39 × 103CuH2L+
Apomorphine7.45.06 × 102CuL
l-Arginine7.19.57 × 102CuL2+
Aromadendrin11.18.29 × 10−2CuL
Ascorbic acid6.12.43 × 105Cu2H–2L2
ASI-17.91.21 × 102CuL2
ASI-56.12.23 × 106CuL
Astilbin7.45.06 × 102CuL
Azilsartan6.14.53 × 105CuL
Baicalein9.35.41CuL22−
Benserazide9.35.30CuL2
7H-benzo[e] perimidin-7-one derivatives141.05 × 10−4CuL2
8-Benzyl-tetrahydropyrazino[2,1-f]purinedione (derivative n. 57)6.13.36 × 106CuL
Bikaverin141.05 × 10−4CuL2
(−)-N6-(2-(4-(Biphenyl-4-yl)piperazin-1-yl)-ethyl)-N6-propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine derivatives10.35.35 × 10−1CuL22+
2,2′-bipyridyl10.62.35 × 10−1CuL22+
4-((5-bromo-3-chloro-2-hydroxybenzyl) amino)-2-hydroxybenzoic acid (LX007, ZL006)6.26.51 × 104CuL
C-3 (α-carboxyfullerene)6.91.96 × 103CuL
Caffeic acid amide analogues7.36.02 × 102CuH−1L
Carbazole-derived compounds10.35.35 × 10−1CuL22+
Carbidopa15.18.11 × 10−6CuH−2L
Carnosic acid7.45.06 × 102CuL
Catechin7.91.50 × 102CuH2L
Ceftriaxone6.14.04 × 106CuL
Celastrol 6.55.27 × 103CuL
Chebulagic acid6.31.51 × 104CuHL
Chlorogenic acid8.35.04 × 101CuL−
3′-O-(3-chloropivaloyl) quercetin11.18.29 × 10−2CuL
Chlorpromazine6.31.47 × 104CuL2+
Chrysin10.62.97 × 10−1CuHL+
Clioquinol14.25.91 × 10−5CuL2
Clovamide analogues (R1 and R2 = OH, and/or R3 and R4 = OH)7.45.06 × 102CuL
“Compound 1”10.35.35 × 10−1CuL22+
“Compound 8”6.14.37 × 105CuL2
“Compound 21”, derivative of
3-methyl-1-(2,4,6-trihydroxyphenyl) butan-1-one		7.35.93 × 102CuL+
“Compound (−)-21a”, derivative of N-6-(2-(4-(1H-indol-5-yl)
piperazin-1-yl)ethyl)-N-6-propyl-4,5,6,7-tetrahydrobenzo[d]
thiazole-2,6-diamine		10.35.35 × 10−1CuL23+
Creatine6.82.26 × 103CuH−1L
Cudraflavone B11.18.29 × 10−2CuL
Curcumin7.91.21 × 102CuL2
Cyanidin7.45.06 × 102CuL
D51210.35.35 × 10−1CuL22+
D607 (bipyridyl-D2R/D3R agonist hybrid)10.62.35 × 10−1CuL2
DA-2 (8D)14.25.91 × 10−5CuL2
DA-310.35.35 × 10−1CuL2
DA-410.35.35 × 10−1CuL2
Dabigatran etexilate10.35.35 × 10−1CuL2
Dabrafenib6.13.36 × 106CuL
(S)-3-4-DCPG6.14.54 × 105CuL
Deferricoprogen12.63.17 × 10−3CuHL
Delphinidin9.35.30CuL2
Demethoxycurcumin7.91.21 × 102CuL2
Dendropanax morbifera active compound7.45.06 × 102CuL
Desferrioxamine (Deferoxamine, Desferal, DFO)11.44.98 × 10−2CuH2L+
(S)-N-(3-(3-6-dibromo-9H-carbazol-9-yl)-2-fluoropropyl)-6-
methoxypyridin-2-amine		6.31.47 × 104CuL
4, 5-O-Dicaffeoyl-1-O-(malic acid methyl ester)-quinic acid
(R1, R2, R3, R4, or R5 = caffeoyl)		7.45.06 × 102CuL
Dihydromyricetin9.35.30CuL2
5-(3,4-Dihydroxybenzylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione7.45.06 × 102CuL
7,8-Dihydroxycoumarin derivative DHC127.45.06 × 102CuL
3′,4′-Dihydroxyflavone7.45.06 × 102CuL
7,8-Dihydroxyflavone7.45.06 × 102CuL
5,7-Dihydroxy-4′-methoxyflavone6.64.58 × 103CuL
(E)-3, 4-Dihydroxystyryl aralkyl sulfones7.45.06 × 102CuL
(E)-3, 4-Dihydroxystyryl aralkyl sulfoxides7.45.06 × 102CuL
5,3′-Dihydroxy-3,7,4′-trimethoxyflavone6.64.58 × 103CuL
2-[[(1,1-Dimethylethyl) oxidoimino]-methyl]-3,5,6-trimethylpyrazine9.62.98CuL
DKP8.18.43 × 101CuL
l-DOPA (levodopa, CVT-301)15.27.95 × 10−6CuH−2L3−
DOPA-derived peptido-mimetics (deprotected)15.27.95 × 10−6CuH−2L2
DOPA-derived peptido-mimetics (protected)7.45.06 × 102CuL
l-DOPA deuterated15.27.95 × 10−6CuH−2L3−
Doxycycline8.91.28 × 101CuL
Droxidopa15.27.95 × 10−6CuH−2L3−
Echinacoside7.45.06 × 102CuL
Ellagic acid7.45.06 × 102CuL
Entacapone (comtan, ASI-6)10.18.00 × 10−1CuL22−
Enzastaurin10.35.35 × 10−1CuL2
Epigallocatechin-3-gallate6.11.33 × 105CuH2L2
Etidronate (HEDPA)91.11 × 101CuL2−
Exifone6.31.51 × 104CuHL
F13714,
F15599		9.71.86CuL2
Farrerol11.18.29 × 10−2CuL
Fisetin (3,3′,4′,7-tetra-hydroxy-flavone)7.45.06 × 102CuL
Fraxetin7.45.06 × 102CuL
Galangin9.18.20CuL
Gallic acid derivatives6.31.51 × 104CuHL−
Gallocatechin9.35.30CuL2
Garcinol7.45.06 × 102CuL
Genistein11.18.29 × 10−2CuL
Glutamine7.35.38 × 102CuL+
Glutathione derivatives6.27.23 × 104CuL−
Glutathione-hydroxy-quinoline compound9.45.00CuH−1L+
Glutathione-l-DOPA compound13.53.98 × 10−4CuH−1L
Gly-N-C-DOPA15.27.95 × 10−6CuH−2L3−
GSK2795039121.02 × 10−2CuL2
Guanabenz10.35.35 × 10−1CuL2
Hesperidin11.18.29 × 10−2CuL
Hinokitiol7.36.69 × 102CuL+
8-HQ-MC-5 (VK-28)14.25.91 × 10−5CuL2
4-Hydroxyisophthalic acid6.32.06 × 104CuL
1-Hydroxy-2-pyridinone derivatives8.44.26 × 101CuL2
3-Hydroxy-4(1H)pyridinone (Deferiprone)10.26.60 × 10−1CuL2
3-Hydroxy-4(1H)pyridinone derivatives (R = H)10.26.60 × 10−1CuL2
8-Hydroxyquinoline14.25.91 × 10−5CuL2
8-Hydroxyquinoline-2-carboxaldehyde isonicotinoyl hydrazone14.25.91 × 10−5CuL2
Hydroxy-quinoline-propargyl hybrids (HLA20)14.25.91 × 10−5CuL2
Hydroxytyrosol butyrate7.45.06 × 102CuL
Hyperoside9.18.20CuL
IC872016.11.90 × 107CuHL
Icariin6.64.58 × 103CuL
Icariside II6.64.58 × 103CuL
l-(7-Imino-3-propyl-2,3-dihydrothiazolo[4,5-d]pyrimidin
-6(7H)-yl)urea		6.14.37 × 105CuL2
Imipramine6.31.47 × 104CuL2+
Isobavachalcone6.28.13 × 104CuL+
Isochlorogenic acid8.35.04 × 101CuL−
Isoquercetin (isoquercitrin)9.18.20CuL
Kaempferol9.18.20CuL
KR334937.35.93 × 102CuL
Kukoamine7.45.06 × 102CuL
Lestaurtinib10.35.35 × 10−1CuL2
Lipoic acid6.14.41 × 105CuL+
Luteolin7.45.06 × 102CuL
M10
M30 (VAR10303)
M99		14.25.91 × 10−5CuL2
Macranthoin G7.45.06 × 102CuL
Magnesium lithospermate B7.45.06 × 102CuL
α-mangostin7.45.06 × 102CuL
γ-Mangostin7.45.06 × 102CuL
MAOI-19.35.30CuL2
MAOI-210.35.35 × 10−1CuL2
MAOI-46.31.47 × 104CuL
MAOI-86.11.90 × 107CuHL
Metformin (met)6.31.61 × 104CuL+
Methoxy-6-acetyl-7-methylijuglone141.05 × 10−4CuL2
N′-(4-methylbenzylidene)-5-phenylisoxazole-3-carbohydrazide6.31.38 × 104CuL
Minocycline11.62.83 × 10−2CuL
Mitomycin C7.19.14 × 102CuL
Morin6.12.27 × 1015CuH3L
[18F]MPPF10.35.35 × 10−1CuL2
MSX-36.12.01 × 106CuL
Myricetin
Myricitrin		9.18.20CuL
Naringin6.91.58 × 103CuHL
Naringenin6.91.58 × 103CuHL
Nicotinamide adenine dinucleotide phosphate (NADPH)6.48.91 × 103CuL
Nicotinamide mononucleotide6.12.01 × 106CuL
Nitecapone10.18.00 × 10−1CuL22−
Nordihydroguaiaretic acid7.45.06 × 102CuL
Oleuropein7.45.06 × 102CuL
Opicapone10.18.00 × 10−1CuL2
P7C3 7.83.76 × 102Cu2H−2L2+
PBT212.44.04 × 10−3CuL+
PBT434 11.27.21 × 10−2CuL+
Petunidin7.45.06 × 102CuL
Phenothiazine 2Bc (n=0)10.35.35 × 10−1CuL22+
Phenothiazine 2Bc (n=1)6.31.47 × 104CuL2+
Phenylhydroxamates71.46 × 103CuL
Piceatannol7.45.06 × 102CuL
Pinostrobin (5-hydroxy-7-methoxy-flavone)6.64.58 × 103CuL+
Piperazine-8-OH-quinolone hybrid14.25.91 × 10−5CuL2
Preladenant10.35.35 × 10−1CuL2
Promethazine8.27.99 × 101CuL2+
Protocatechuic acid8.18.13 × 101CuL−
Protosappanin A7.45.06 × 102CuL
Punicalangin8.26.89 × 101CuL
Pyrazolobenzothiazine-based carbothioamides6.14.66 × 105CuL
Pyrimidinone 810.35.35 × 10−1CuL2
Q1
Q4		14.25.91 × 10−5CuL2
Quercetin9.18.20CuL3−
Quinoline derivatives SUMOylation activators 7.27.26 × 102CuL2+
Radotinib10.62.35 × 10−1CuL2
Riboflavin6.11.65 × 105CuHL3+
Rifampicin (ASI-3)6.56.97 × 103CuL
Rimonabant8.18.43 × 101CuL
Rosmarinic acid7.45.06 × 102CuL
Rotigotine6.11.45 × 108CuL2
Rutin9.18.20CuL
Salicylate, sodium salt6.32.06 × 104CuL
Salvianolic acid B7.45.06 × 102CuL
SCH58261
SCH412348		9.17.58CuL2
ST1535
ST4206		9.17.58CuL2
Staurosporine10.35.35 × 10−1CuL2
Stemazole6.14.66 × 105CuL
Sulfuretin7.45.06 × 102CuL
Tannic acid 6.11.84 × 105CuL
Tanshinol7.45.06 × 102CuL
Taurine6.11.23 × 107CuL+
Taxifolin10.44.55 × 10−1CuL2−
Tectorigenin11.18.29 × 10−2CuL
Tetracycline6.41.08 × 104CuL
Tolcapone (ASI-7)10.18.00 × 10−1CuL2
Transilitin7.45.06 × 102CuL
o-Trensox22.91.51 × 10−13CuL4−
2′, 3′, 4′-Trihydroxyflavone9.35.30CuL22−
2,3,3-Trisphosphonate149.98 × 10−5CuL2
V814449.71.86CuL2
VAS3947
VAS2870		6.14.37 × 105CuL2
Verbascoside7.36.02 × 102CuH−1L
WIN 55, 212-210.35.35 × 10−1CuL22+
WR-10656.63.67 × 103CuL2+
Zonisamide7.44.62 × 102CuL
Table
Table 4. pCu(I) and Kd values, and the most abundant Cu(I) complex, obtained at physiologically relevant conditions: pH = 7.4, cCu = 10−6 mol/L, and cL = 10−5 mol/L. See caption of Table 3 for other notes.
Table 4. pCu(I) and Kd values, and the most abundant Cu(I) complex, obtained at physiologically relevant conditions: pH = 7.4, cCu = 10−6 mol/L, and cL = 10−5 mol/L. See caption of Table 3 for other notes.
Compound Name(s)pCu(I)Kd (nmol/L)Most Abundant Complex
7DH
7MH		6.38.38 × 103CuL2
8A
8B
8C		6.38.38 × 103CuL2
8E
8F 		6.21.87 × 104CuL
ACPT-I62.54 × 108CuL2
ADX881787.71.77 × 102CuL
Alvespimycin67.98 × 107CuL2+
3-(7-Amino-5-(cyclohexylamino)-[1,2,4]triazolo[1,5-a]
[1,3,5]triazin-2-yl)-2-cyanoacrylamide		67.98 × 107CuL2
Aminothiazoles derivatives as SUMOylation activators62.66 × 106CuL2
AMN08267.98 × 107CuL2
Antagonist of the A(2A) adenosine receptor (derivative 49)63.06 × 107CuL2
8-Benzyl-tetrahydropyrazino[2,1-f]purinedione (derivative 57)7.62.17 × 102CuL
(−)-N6-(2-(4-(Biphenyl-4-yl)piperazin-1-yl)-ethyl)-N6-propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine derivatives67.98 × 107CuL2+
2,2′-bipyridyl6.21.87 × 104CuL+
Carbazole-derived compounds67.98 × 107CuL2+
Ceftriaxone62.54 × 108CuL2
Clioquinol7.25.79 × 102CuL2−
“Compound 1”67.98 × 107CuL2+
“Compound 8”7.62.17 × 102CuL
“Compound 21”, derivative of 3-methyl-1-(2,4,6-trihydroxy
phenyl) butan-1-one		62.54 × 108CuL2−
“Compound (−)-21a”, derivative of N-6-(2-(4-(1H-indol-5-yl)
piperazin-1-yl)ethyl)-N-6-propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine		67.98 × 107CuL2+
Creatine62.54 × 108CuL2−
D51267.98 × 107CuL2+
D607(bipyridyl-D2R/D3R agonist hybrid)6.21.87 × 104CuL
DA-2 (8D)6.38.38 × 103CuL2
DA-367.98 × 107CuL2
DA-467.98 × 107CuL2
Dabigatran etexilate67.98 × 107CuL2
Dabrafenib7.71.77 × 102CuL
2-[[(1,1-Dimethylethyl) oxidoimino]-methyl]-3,5,6-trimethylpyrazine6.91.07 × 103CuH2L2
DKP7.43.64 × 102CuL
Doxycycline9.21.26 × 101Cu2L
Enzastaurin67.98 × 107CuL2
F13714
F15599		67.83 × 105Cu2L
Glutathione-hydroxy-quinoline compound6.38.38 × 103CuL2−
Glutathione derivatives15.26.21 × 10−6CuHL−
Guanabenz67.98 × 107CuL2
8-HQ-MC-5 (VK-28)6.38.38 × 103CuL2
8-hydroxyquinoline6.38.38 × 103CuL2−
8-hydroxyquinoline-2-carboxaldehyde isonicotinoyl hydrazone6.38.38 × 103CuL2
Hydroxy-quinoline-propargyl hybrids (HLA20)6.38.38 × 103CuL2
l-(7-Imino-3-propyl-2,3-dihydrothiazolo [4,5-d]
pyrimidin-6(7H)-yl)urea		7.62.17 × 102CuL
KR3349362.54 × 108CuL2
Lestaurtinib67.98 × 107CuL2
M10
M30 (VAR10303)
M99		6.38.38 × 103CuL2
MAOI-267.98 × 107CuL2
[18F]MPPF67.98 × 107CuL2
PBF-50967.98 × 107CuL2
PBT26.38.38 × 103CuL2
Phenothiazine 2Bc (n=0)67.98 × 107CuL2+
Piperazine-8-OH-quinolone hybrid6.38.38 × 103CuL2
Preladenant67.98 × 107CuL2
Promethazine67.98 × 107CuL2+
Pyrimidinone 867.98 × 107CuL2
Q1
Q4		6.38.38 × 103CuL2
Radotinib6.21.87 × 104CuL
Rifampicin (ASI-3)9.21.26 × 101Cu2L
Rimonabant7.43.64 × 102CuL
Rotigotine7.71.77 × 102CuL
SCH58261
SCH412348		67.98 × 107CuL2
ST1535 ST420667.98 × 107CuL2
Staurosporine67.98 × 107CuL2
V8144462.66 × 106CuL2
VAS3947
VAS2870		7.62.17 × 102CuL
WIN 55, 212-267.98 × 107CuL2+
WR-10657.62.17 × 102CuL
Table
Table 5. pFe(III) and Kd values, and the most abundant Fe(III) complex, obtained at physiologically relevant conditions: pH = 7.4, cFe = 10–6 mol/L, and cL = 10–5 mol/L. See caption of Table 3 for other notes.
Table 5. pFe(III) and Kd values, and the most abundant Fe(III) complex, obtained at physiologically relevant conditions: pH = 7.4, cFe = 10–6 mol/L, and cL = 10–5 mol/L. See caption of Table 3 for other notes.
Compound Name(s)pFe(III)Kd (nmol/L)Most Abundant Complex
7DH
7MH		20.62.15 × 10−1FeL3
8A
8B
8C		20.62.15 × 10−1FeL3
8E
8F 		21.53.01 × 10−2FeH–2L2
N-Acetyl cysteine16.14.59 × 109FeL2−
ACPT-I16.19.59 × 107FeL2
Ambroxol16.31.70 × 104FeL2+
Apigenin16.17.55 × 108FeL2+
Apomorphine16.31.35 × 104FeL2
l-Arginine16.11.18 × 1012FeL3+
Aromadendrin16.17.55 × 108FeL
Ascorbic acid16.14.99 × 1017FeL2+
ASI-116.82.28 × 103FeL
ASI-5181.06 × 102FeL
Astilbin16.31.35 × 104FeL2
Baicalein16.17.55 × 108FeL2+
4H-1-benzopyran-4-one18.18.14 × 101FeL2
2,2′-bipyridyl21.53.01 × 10−2FeH−2L2+
4-((5-bromo-3-chloro-2-hydroxybenzyl) amino)-2-hydroxybenzoic acid (LX007, ZL006)16.14.46 × 107FeL2
C-3 (α carboxyfullerene)16.12.54 × 1010FeL2
Caffeic acid amide analogues16.31.35 × 104FeL2
Carbidopa16.22.96 × 104FeL
Carnosic acid16.31.35 × 104FeL2
Catechin16.14.49 × 1017FeHL
Ceftriaxone16.19.59 × 107FeL2
Celastrol 19.26.33FeL2
Chebulagic acid16.17.45 × 105FeHL
Chlorogenic acid16.11.07 × 107FeL
3′-O-(3-Chloropivaloyl) quercetin16.17.55 × 108FeL
Chrysin16.17.55 × 108FeL+
Clioquinol20.62.15 × 10−1FeL3
Clioquinol-selegiline hybrid22.91.07 × 10−3FeL2
Clovamide analogues (R1 and R2 = OH, and/or R3 and R4 = OH) 16.31.35 × 104FeL2
“Compound (−)-8a”16.31.35 × 104FeL2
“Compound 21”, derivative of 3-methyl-1-(2,4,6-trihydroxyphenyl) butan-1-one16.19.59 × 107FeL2+
Creatine16.19.59 × 107FeL2+
Cudraflavone B16.17.55 × 108FeL
Curcumin16.64.09 × 103FeL
Cyanidin16.31.35 × 104FeL2
D607 (bipyridyl-D2R/D3R agonist hybrid)21.53.01 × 10−2FeH−2L2
DA-2 (8D)20.62.15 × 10−1FeL3
DA-317.25.61 × 102FeL2
DA-417.25.61 × 102FeL2
Deferasirox23.53.22 × 10−4FeL23−
Delphinidin16.31.35 × 104FeL2
Demethoxycurcumin16.82.28 × 103FeL
Dendropanax morbifera active compound16.31.35 × 104FeL2
Desferrioxamine (Deferoxamine, Desferal, DFO)26.81.81 × 10−7FeHL+
4,5-O-Dicaffeoyl-1-O-(malic acid methyl ester)-quinic acid derivatives (R1, R2, R3, R4, or R5 = caffeoyl)16.31.35 × 104FeL2
Dihydromyricetin16.31.35 × 104FeL2
5-(3,4-dihydroxybenzylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione16.31.35 × 104FeL2−
7,8-dihydroxycoumarin derivative DHC1216.31.35 × 104FeL2
3′,4′-dihydroxyflavone16.31.35 × 104FeL2−
7,8-dihydroxyflavone16.31.35 × 104FeL2−
5,7-dihydroxy-4′-methoxyflavone18.18.14 × 101FeL2
(E)-3,4-dihydroxystyryl aralkyl sulfones16.31.35 × 104FeL2−
(E)-3,4-dihydroxystyryl aralkyl sulfoxides16.31.35 × 104FeL2−
5,3′-dihydroxy-3,7,4′-trimethoxyflavone18.18.14 × 101FeL2
2-[[(1,1-Dimethylethyl) oxidoimino]-methyl]-3,5,6-trimethylpyrazine16.11.86 × 1010FeL
DKP16.17.43 × 1021FeL2
l-DOPA (levodopa, CVT-301)16.22.96 × 104FeL
DOPA-derived peptido-mimetics (deprotected)16.22.96 × 104FeL
DOPA-derived peptido-mimetics (protected)16.31.35 × 104FeL2
l-dopa deuterated16.22.96 × 104FeL
Doxycycline18.17.22 × 101FeL2
Droxidopa16.22.96 × 104FeL
Echinacoside16.31.35 × 104FeL2
Ellagic acid16.31.35 × 104FeL2
Entacapone (comtan, ASI-6)19.33.99FeL33−
Epicatechin16.31.35 × 104FeL2
Epigallocatechin-3-gallate16.17.45 × 105FeHL
Etidronate (HEDPA)23.53.22 × 10−4FeH−1L
Exifone16.17.45 × 105FeHL
Farrerol16.17.55 × 108FeL
Fiset (3,3′,4′,7-tetra-hydroxy-flavone)16.31.35 × 104FeL2
Fraxetin16.31.35 × 104FeL2−
Galangin27.09.36 × 10−8FeH−1L
Gallic acid derivatives16.17.45 × 105FeHL
Garcinol16.31.35 × 104FeL2
Genistein16.17.55 × 108FeL
Glutathione-hydroxy-quinoline compound181.04 × 102FeH−2L+
Glutathione-l-DOPA compound16.31.35 × 104FeL2
Gly-N-C-DOPA16.22.96 × 104FeL
Hesperidin 16.17.55 × 108FeL
Hinokitiol16.14.30 × 108FeL2+
8-HQ-MC-5 (VK-28)20.62.15 × 10−1FeL3
4-Hydroxyisophthalic acid16.11.64 × 106FeL3
1-Hydroxy-2-pyridinone derivatives17.71.50 × 102FeL3
3-Hydroxy-4(1H)pyridinone (Deferiprone)19.33.92FeL3
3-Hydroxy-4(1H)pyridinone derivatives (R = H)19.33.92FeL3
8-Hydroxyquinoline20.62.15 × 10−1FeL3
8-Hydroxyquinoline-2-carboxaldehyde isonicotinoyl hydrazone20.62.15 × 10−1FeL3
Hydroxy-quinoline-propargyl hybrids (HLA20)20.62.15 × 10−1FeL3
Hydroxytyrosol butyrate16.31.35 × 104FeL2−
Hyperoside27.09.36 × 10−8FeH−1L
Icariin18.18.14 × 101FeL2
Icariside II18.18.14 × 101FeL2
Isobavachalcone16.13.23 × 108FeL2+
Isochlorogenic acid16.11.07 × 107FeL
Isoquercetin (isoquercitrin)27.09.36 × 10−8FeH−1L
Kaempferol27.09.36 × 10−8FeH−1L
Kaempferol, 3-O-a-L arabino-furanoside-7-O-a-L-
rhamno-pyranoside		18.18.14 × 101FeL2
KR3349316.31.06 × 104FeL2
Kukoamine16.31.35 × 104FeL2
Luteolin16.31.35 × 104FeL2
M10
M30 (VAR10303)
M99		20.62.15 × 10−1FeL3
Macranthoin G16.31.35 × 104FeL2
Magnesium lithospermate B16.31.35 × 104FeL2
α-mangostin16.31.35 × 104FeL2
γ-mangostin16.31.35 × 104FeL2
Metformin (Met)16.11.36 × 109FeL2+
MitoQ16.15.72 × 1010FeL2
Morin18.18.14 × 101FeL2
Myricetin
Myricitrin		27.09.36 × 10−8FeH−1L
Naringenin16.17.55 × 108FeL
Naringin16.17.55 × 108FeL
Nicotinamide adenine dinucleotide phosphate (NADPH)16.16.01 × 1010FeL2
Nitecapone 16.82.04 × 103FeL2−
Nordihydroguaiaretic acid16.31.35 × 104FeL2
Oleuropein16.31.35 × 104FeL2−
Opicapone16.82.04 × 103FeL2
PBT220.62.15 × 10−1FeL3
PBT43416.13.22 × 109FeL2+
Petunidin16.31.35 × 104FeL2
Phenylhydroxamates16.19.46 × 104FeL2
Piceatannol16.31.35 × 104FeL2
Pinostrobin (5-hydroxy-7-methoxy-flavone)18.18.14 × 101FeL2
Piperazine-8-OH-quinolone hybrid20.62.15 × 10−1FeL3
Protocatechuic acid22.26.16 × 10−3FeL23−
Protosappanin A16.31.35 × 104FeL2
Punicalangin16.11.14 × 1012FeL
Pyridoxal isonicotinoyl hydrazone (PIH)22.91.07 × 10−3FeL2
Pyridoxal isonicotinoyl hydrazone derivatives:
PCIH
PCTH
H2NPH
H2PPH		22.91.07 × 10−3FeL2
Q1
Q4		20.62.15 × 10−1FeL3
Quercetin 27.09.36 × 10−8FeH–1L3−
Quinoline derivatives as SUMOylation activators16.11.14 × 1016FeL2+
Radotinib21.53.01 × 10−2FeH−2L2
Rimonabant16.17.43 × 1021FeL2
Rosmarinic acid16.31.35 × 104FeL2
Rutin27.09.36 × 10−8FeH−1L
Salicylate, sodium salt16.11.64 × 106FeL33−
Salvianolic acid B16.31.35 × 104FeL2
Silibinin (silybin) A, B16.11.99 × 1019FeH3L3+
Silydianin16.11.99 × 1019FeH3L3+
Sulfuretin16.31.35 × 104FeL2
Tanshinol16.31.35 × 104FeL2
Tannic acid16.16.05 × 1049Fe4L
Taxifolin16.17.55 × 108FeL
Tectorigenin16.17.55 × 108FeL
Tetracycline16.18.35 × 1010FeL22−
Tolcapone (ASI-7)16.82.04 × 103FeL2−
Transilitin16.31.35 × 104FeL2
o-Trensox29.53.36 × 10−10FeL3−
2,3,3-Trisphosphonate181.06 × 102FeL
Verbascoside16.31.35 × 104FeL2
Zonisamide16.11.86 × 1011FeL2
Table
Table 6. pFe(II) and Kd values, and the most abundant Fe(II) complex, obtained at physiologically relevant conditions: pH = 7.4, cFe = 10−6 mol/L, and cL = 10−5 mol/L. See caption of Table 3 for other notes.
Table 6. pFe(II) and Kd values, and the most abundant Fe(II) complex, obtained at physiologically relevant conditions: pH = 7.4, cFe = 10−6 mol/L, and cL = 10−5 mol/L. See caption of Table 3 for other notes.
Compound Name(s)pFe(II)Kd (nmol/L)Most Abundant Complex
7DH
7MH		6.91.35 × 103FeL
8A
8B
8C		6.91.35 × 103FeL
8E
8F		6.14.62 × 104FeL2
ACPT-I61.20 × 107FeL
Alvespimycin62.07 × 107FeL2+
Aminothiazoles derivatives as SUMOylation activators62.77 × 106FeL
AMN08262.07 × 107FeL2+
Apomorphine61.53 × 107FeHL
l-Arginine63.30 × 107FeL2+
Ascorbic acid61.89 × 109FeL+
ASI-161.78 × 105FeL+
ASI-510.71.95 × 10−1FeL
Astilbin61.53 × 107FeHL
Azilsartan62.53 × 1015FeL2
Baicalein9.91.09FeL22−
Benserazide9.91.09FeL2
(−)-N6-(2-(4-(Biphenyl-4-yl)piperazin-1-yl)-ethyl)-N6-propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine derivatives62.07 × 107FeL2+
2,2′-Bipyridyl6.14.62 × 104FeL22+
4-((5-bromo-3-chloro-2-hydroxybenzyl) amino)-2-hydroxybenzoic acid (LX007, ZL006)63.13 × 108FeL
C-3 (α carboxyfullerene)66.90 × 106FeL
Caffeic acid amide analogues6.72.02 × 103FeH−1L
Carbazole-derived compounds62.07 × 107FeL2+
Carbidopa6.31.07 × 104FeL
Carnosic acid61.53 × 107FeHL
Catechin61.53 × 107FeHL
Ceftriaxone61.20 × 107FeL
Celastrol61.53 × 107FeHL
CEP-134761.53 × 107FeHL
Chebulagic acid65.66 × 105FeL
Chlorogenic acid62.93 × 106FeHL
Clioquinol7.91.01 × 102FeL2
Clioquinol-selegiline hybrid7.16.37 × 102FeH2L2
Clovamide analogues (R1 and R2 = OH, and/or R3 and R4 = OH)61.53 × 107FeHL
“Compound 1”62.07 × 107FeL2+
“Compound (−)-8a”61.53 × 107FeHL
“Compound 21”, derivative of 3-methyl-1-(2,4,6-trihydroxyphenyl) butan-1-one61.20 × 107FeL+
“Compound (−)-21a”, derivative of N-6-(2-(4-(1H-indol-5-yl)
piperazin-1-yl)ethyl)-N-6-propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine		62.07 × 107FeL2+
Creatine61.20 × 107FeL+
Curcumin64.16 × 109FeH2L+
Cyanidin61.53 × 107FeHL
D51262.07 × 107FeL2+
D607 (bipyridyl-D2R/D3R agonist hybrid)6.14.63 × 104FeL2
DA-2 (8D)6.91.35 × 103FeL
DA-362.07 × 107FeL
DA-462.07 × 107FeL
Dabigatran etexilate62.07 × 107FeL
Delphinidin9.91.09FeL2
Demethoxycurcumin61.78 × 105FeL
Dendropanax morbifera61.53 × 107FeHL
Desferrioxamine (Deferoxamine, Desferal, DFO)6.22.24 × 104FeH2L+
4,5-O-Dicaffeoyl-1-O-(malic acid methyl ester)-quinic acid derivatives (R1, R2, R3, R4, or R5 = caffeoyl)61.53 × 107FeHL
Dihydromyricetin9.91.09FeL2
5-(3,4-Dihydroxybenzylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione61.53 × 107FeHL+
7, 8-Dihydroxycoumarin derivative DHC1261.53 × 107FeHL
3′,4′-Dihydroxyflavone14.81.58 × 10−5FeL+
7,8-Dihydroxyflavone61.53 × 107FeHL+
(E)-3,4-Dihydroxystyryl aralkyl sulfones61.53 × 107FeHL+
(E)-3,4-Dihydroxystyryl aralkyl sulfoxides61.53 × 107FeHL+
2-[[(1,1-Dimethylethyl) oxidoimino]-methyl]-3,5,6-trimethylpyrazine8.25.40 × 101FeL2
DKP64.33 × 105FeL
l-DOPA (levodopa, CVT-301)6.31.07 × 104FeL−
DOPA-derived peptido-mimetics (deprotected)10.52.82 × 10−1FeHL
DOPA-derived peptido-mimetics (protected)61.53 × 107FeHL
l-DOPA deuterated6.31.07 × 104FeL−
Doxycycline64.07 × 108FeL
Droxidopa6.31.07 × 104FeL−
Echinacoside61.53 × 107FeHL
Ellagic acid61.53 × 107FeHL
Entacapone (comtan, ASI-6)12.71.65 × 10−3FeL22−
Enzastaurin62.07 × 107FeL
Epicatechin61.53 × 107FeHL
Etidronate (HEDPA)9.91.14FeL2−
F13714
F15599		62.77 × 106FeL
FIsetin (3,3′,4′,7-tetra-hydroxy-flavone)61.53 × 107FeHL
Fraxetin61.53 × 107FeHL+
Gallocatechin9.91.09FeL2
Garcinol61.53 × 107FeHL
Glutamine67.54 × 105FeL+
Glutathione-hydroxy-quinoline compound6.91.35 × 103FeL+
Glutathione-l-DOPA compound61.53 × 107FeHL
Gly-N-C-DOPA6.31.07 × 104FeL−
Guanabenz62.07 × 107FeL
8-HQ-MC-5 (VK28)6.91.35 × 103FeL
4-Hydroxyisophthalic acid63.13 × 108FeL
8-hydroxyquinoline6.91.35 × 103FeL+
8-hydroxyquinoline-2-carboxaldehyde isonicotinoyl hydrazone6.91.35 × 103FeL
Hydroxy-quinoline-propargyl hybrids (HLA20) 6.91.35 × 103FeL
Hydroxytyrosol butyrate61.53 × 107FeHL+
Isochlorogenic acid62.93 × 106FeHL
KR3349361.20 × 107FeL
Kukoamine61.53 × 107FeHL
Lestaurtinib62.07 × 107FeL
M10
M30 (VAR10303)
M99		6.91.35 × 103FeL
Macranthoin G61.53 × 107FeHL
Magnesium lithospermate B61.53 × 107FeHL
α-mangostin61.53 × 107FeHL
γ-mangostin61.53 × 107FeHL
MAOI-19.91.09FeL2
MAOI-262.07 × 107FeL
Meclofenamic acid62.53 × 1015FeL2
Mildronate62.53 × 1015FeL2
Mitomycin C66.57 × 107FeL
[18F]MPPF62.07 × 107FeL
Nitecapone12.71.65 × 10−3FeL22−
Nordihydroguaiaretic acid61.53 × 107FeHL
Oleuropein61.53 × 107FeHL+
Opicapone12.71.65 × 10−3FeL2
PBF-50962.07 × 107FeL
PBT26.91.35 × 103FeL
PBT4346.21.80 × 104FeL+
Petunidin61.53 × 107FeHL
Phenothiazine 2Bc (n=0)62.07 × 107FeL2+
Phenylhydroxamates65.96 × 107FeL2
Piceatannol61.53 × 107FeHL
Piperazine-8-OH-quinolone hybrid6.91.35 × 103FeL
Preladenant62.07 × 107FeL
Promethazine62.07 × 107FeL2+
Protosappanin A61.53 × 107FeHL
Pyridoxal isonicotinoyl hydrazone (PIH)7.16.37 × 102FeH2L2
Pyridoxal isonicotinoyl hydrazone derivatives:
PCIH
PCTH
H2NPH
H2PPH		7.16.37 × 102FeH2L22+
Pyrimidinone 862.07 × 107FeL
Q1
Q4		6.91.35 × 103FeL
Radotinib6.14.62 × 104FeL2
Riboflavin61.22 × 105FeL2+
Rifampicin (ASI-3)64.07 × 108FeL
Rimonabant64.85 × 1011FeL
Rosmarinic acid61.53 × 107FeLH
Salicylate, sodium salt63.13 × 108FeL
Salvianolic acid B61.53 × 107FeHL
SCH58261SCH41234862.07 × 107FeL
ST1535
ST4206		62.07 × 107FeL
Staurosporine62.07 × 107FeL
Sulfuretin61.53 × 107FeHL
Tanshinol61.53 × 107FeHL
Tetracycline62.73 × 106FeL
Tolcapone (ASI-7)12.71.65 × 10−3FeL22−
Transilitin61.53 × 107FeHL
2′,3′,4′-trihydroxyflavone9.91.09FeL22−
2,3,3-trisphosphonate10.71.95 × 10−1FeL
V8144462.77 × 106FeL
Verbascoside62.02 × 106FeL
WIN 55, 212-262.07 × 107FeL2+
Table
Table 7. pMn(II) and Kd values, and the most abundant Mn(II) complex, obtained at physiologically relevant conditions: pH = 7.4, cMn = 10−6 mol/L, and cL = 10−5 mol/L. See caption of Table 3 for other notes.
Table 7. pMn(II) and Kd values, and the most abundant Mn(II) complex, obtained at physiologically relevant conditions: pH = 7.4, cMn = 10−6 mol/L, and cL = 10−5 mol/L. See caption of Table 3 for other notes.
Compound Name(s)pMn(II)Kd (nmol/L)Most Abundant Complex
7DH
7MH		6.72.35 × 103MnL+
8A
8B
8C		6.72.35 × 103MnL
8E
8F		62.40 × 106MnL
N-Acetyl cysteine68.97 × 105MnHL+
ACPT-I62.25 × 108MnL
Alvespimycin67.61 × 108MnL2+
Ambroxol6.72.47 × 103MnL+
3-(7-amino-5-(cyclohexylamino)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-2-yl)-2-cyanoacrylamide67.61 × 108MnL
Aminothiazoles derivatives as SUMOylation activators67.64 × 107MnL
AMN08267.61 × 108MnL2+
Apomorphine67.16 × 108MnL
l-Arginine61.45 × 108MnL2+
ASI-163.44 × 106MnL+
ASI-567.81 × 106MnL
Astilbin67.16 × 108MnL
Azilsartan63.71 × 109MnL
Baicalein62.62 × 107MnL
Benserazide62.62 × 107MnL
(−)-N6-(2-(4-(Biphenyl-4-yl)piperazin-1-yl)-ethyl)-N6-propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine derivatives67.61 × 108MnL2+
2,2′-bipyridyl62.40 × 106MnL2+
4-((5-bromo-3-chloro-2-hydroxybenzyl) amino)-2-hydroxybenzoic acid (LX007, ZL006)68.72 × 108MnL
C-3 (α carboxyfullerene)65.06 × 106MnL
Caffeic acid amide analogues66.62 × 107MnH−1L
Carbazole-derived compounds67.61 × 108MnL2+
Carbidopa7.62.33 × 102MnHL
Carnosic acid67.16 × 108MnL
Catechin 67.16 × 108MnL
Ceftriaxone62.25 × 108MnL
Celastrol67.16 × 108MnL
CEP134763.71 × 109MnL
Chebulagic acid62.62 × 107MnL
Chlorogenic acid63.91 × 107MnL−
Clioquinol6.72.35 × 103MnL+
Clovamide analogues (R1 and R2 = OH, and/or R3 and R4 = OH)67.16 × 108MnL
“Compound 1”67.61 × 108MnL++
“Compound (−)-8a”67.16 × 108MnL
“Compound 21”, derivative of 3-methyl-1-(2,4,6-trihydroxyphenyl) butan-1-one62.25 × 108MnL+
“Compound (−)-21a”, derivative of N-6-(2-(4-(1H
-indol-5-yl)piperazin-1-yl)ethyl)-N-6-propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine		67.61 × 108MnL++
Creatine62.25 × 108MnL+
Curcumin63.44 × 106MnL
Cyanidin67.16 × 108MnL
D51267.61 × 108MnL2+
D607 (bipyridyl-D2R/D3R agonist hybrid)62.40 × 106MnL
DA-2 (8D)6.72.35 × 103MnL
DA-367.61 × 108MnL
DA-467.61 × 108MnL
Dabigatran etexilate67.61 × 108MnL
(S)-3,4-DCPG65.91 × 106MnL
Delphinidin62.62 × 107MnL
Demethoxycurcumin63.44 × 106MnL
Dendropanax morbifera active compound67.16 × 108MnL
4,5-O-Dicaffeoyl-1-O-(malic acid methyl ester)-quinic acid derivatives (R1, R2, R3, R4, or R5 = caffeoyl)67.16 × 108MnL
Dihydromyricetin62.62 × 107MnL
5-(3,4-Dihydroxybenzylidene) -2,2-dimethyl-1,3-dioxane-4,6-dione67.16 × 108MnL
7,8-Dihydroxycoumarin derivative DHC1267.16 × 108MnL
3′,4′-Dihydroxyflavone67.16 × 108MnL
7,8-dihydroxyflavone67.16 × 108MnL
(E)-3,4-Dihydroxystyryl aralkyl sulfones67.16 × 108MnL
(E)-3,4-Dihydroxystyryl aralkyl sulfoxides67.16 × 108MnL
2-[[(1,1-Dimethylethyl) oxidoimino]-methyl]-3,5,6-trimethylpyrazine62.58 × 106MnL
DKP61.00 × 106MnHL
l-DOPA (levodopa, CVT-301)7.62.26 × 102MnHL
DOPA-derived peptido-mimetics (deprotected)7.62.33 × 102MnHL
DOPA-derived peptido-mimetics (protected)67.16 × 108MnL
l-dopa deuterated7.62.26 × 102MnHL
Droxidopa7.62.33 × 102MnHL
Echinacoside67.16 × 108MnL
Ellagic acid67.16 × 108MnL
Entacapone (comtan, ASI-6)66.74 × 105MnL
Enzastaurin67.61 × 108MnL
Epicatechin67.16 × 108MnL
Etidronate (HEDPA)61.03 × 106MnL2−
F13714
F15599		67.64 × 107MnL
Fisetin (3,3′,4′,7-tetra-hydroxy-flavone)67.16 × 108MnL
Fraxetin67.16 × 108MnL
Gallocatechin62.62 × 107MnL
Garcinol67.16 × 108MnL
Glutamine62.30 × 107MnL+
Glutathione derivatives64.07 × 105MnL−
Glutathione-hydroxy-quinoline compound6.72.35 × 103MnL+
Glutathione-l-DOPA compound67.16 × 108MnL
Gly-N-C-DOPA7.62.33 × 102MnHL
Guanabenz67.61 × 108MnL
Hinokitiol6.12.99 × 104MnL+
8-HQ-MC-5 (VK-28)6.72.35 × 103MnL
4-Hydroxyisophthalic acid68.72 × 108MnL
8-hydroxyquinoline6.72.35 × 103MnL+
8-Hydroxyquinoline-2-carboxaldehyde isonicotinoyl hydrazone6.72.35 × 103MnL
Hydroxy-quinoline-propargyl hybrids (HLA20)6.72.35 × 103MnL
Hydroxytyrosol butyrate67.16 × 108MnL
Isobavachalcone6.21.55 × 104MnL+
Isochlorogenic acid63.91 × 107MnL−
KR3349362.25 × 108MnL
Kukoamine67.16 × 108MnL
Lestaurtinib67.61 × 108MnL
Lipoic acid69.53 × 106MnL+
Luteolin67.16 × 108MnL
M10
M30 (VAR10303)
M99		6.72.35 × 103MnL
Macranthoin G67.16 × 108MnL
Magnesium lithospermate B67.16 × 108MnL
α-mangostin67.16 × 108MnL
γ-mangostin67.16 × 108MnL
MAOI-162.62 × 107MnL
MAOI-267.61 × 108MnL
Meclofenamic acid63.71 × 109MnL
Mildronate63.71 × 109MnL
Mitomycin C67.46 × 107MnL
MitoQ61.29 × 105MnL
[18F]MPPF 67.61 × 108MnL
Nicotinamide adenine dinucleotide phosphate (NADPH)62.01 × 107MnL
Nicotinamide mononucleotide66.59 × 106MnL
Nitecapone 66.74 × 105MnL
Nordihydroguaiaretic acid67.16 × 108MnL
Oleuropein67.16 × 108MnL
Opicapone66.74 × 105MnL
PBF-50962.41 × 109MnL
PBT265.22 × 105MnL+
Petunidin67.16 × 108MnL
Phenothiazine 2Bc (n=0)67.61 × 108MnL2+
Phenylhydroxamates65.81 × 106MnL
Piceatannol67.16 × 108MnL
Piperazine-8-OH-quinolone hybrid6.72.35 × 103MnL
Preladenant67.61 × 108MnL
Promethazine67.61 × 108MnL2+
Protocatechuic acid63.66 × 108MnL−
Protosappanin A67.16 × 108MnL
Pyrimidinone 867.61 × 108MnL
Q1
Q4		6.72.35 × 103MnL
Radotinib62.40 × 106MnL
Riboflavin65.75 × 105MnHL3+
Rifampicin (ASI-3)61.03 × 106MnL
Rimonabant61.00 × 106MnHL
Rosmarinic acid67.16 × 108MnL
Salicylate, sodium salt68.72 × 108MnL
Salvianolic acid B67.16 × 108MnL
SCH58261
SCH412348		67.61 × 108MnL
ST1535
ST4206		67.61 × 108MnL
Staurosporine67.61 × 108MnL
Sulfuretin67.16 × 108MnL
Tanshinol67.16 × 108MnL
Taurine66.39 × 1011MnL2
Tetracycline62.14 × 107MnL
Tolcapone (ASI-7)66.74 × 105MnL
Transilitin67.16 × 108MnL
2′,3′,4′-Trihydroxyflavone62.62 × 107MnL
V8144467.64 × 107MnL
Verbascoside66.62 × 107MnH−1L
WIN 55,212-267.61 × 108MnL2+
Table
Table 8. pZn(II) and Kd values, and the most abundant Zn(II) complex, obtained at physiologically relevant conditions: pH = 7.4, cZn = 10−6 mol/L, and cL = 10−5 mol/L. See caption of Table 3 for other notes.
Table 8. pZn(II) and Kd values, and the most abundant Zn(II) complex, obtained at physiologically relevant conditions: pH = 7.4, cZn = 10−6 mol/L, and cL = 10−5 mol/L. See caption of Table 3 for other notes.
Compound Name(s)pZn(II)Kd (nmol/L)Most Abundant Complex
7DH
7MH		7.53.16 × 102ZnL
8A
8B
8C		7.53.16 × 102ZnL
8E
8F		6.46.31 × 103ZnL
N-acetyl cystein61.66 × 106ZnL
ACPT-I61.46 × 107ZnL
Alaternin6.81.83 × 103ZnL
Alvespimycin67.85 × 105ZnL2+
AM-25161.95 × 106ZnHL
Ambroxol7.71.90 × 102ZnL2
3-(7-amino-5-(cyclohexylamino)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-2-yl)-2-cyanoacrylamide67.85 × 105ZnL
Aminothiazoles derivatives as SUMOylation activators62.28 × 105ZnL
AMN08267.85 × 105ZnL2+
Antagonist of the A(2A) adenosine receptor - derivative 4961.95 × 106ZnHL
Apigenin61.23 × 1029ZnH3L
Apomorphine67.76 × 106ZnL
l-Arginine64.14 × 106ZnL2+
Ascorbic acid6.14.67 × 104ZnL+
ASI-165.76 × 105ZnL+
ASI-569.06 × 106ZnL
Astilbin67.76 × 106ZnL
Azilsartan65.22 × 105ZnL
Baicalein62.71 × 105ZnL
Benserazide62.71 × 105ZnL
7H-Benzo[e] perimidin-7-one derivatives (R6 = OH)6.14.82 × 104ZnL2
4H-1-benzopyran-4-one63.56 × 1020ZnH3L
8-Benzyl-tetrahydropyrazino[2,1-f]purinedione (derivative n. 57)69.67 × 1011ZnL
Bikaverin6.31.07 × 104ZnH−2L2−
(−)-N6-(2-(4-(Biphenyl-4-yl)piperazin-1-yl)-ethyl)-N6-propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine derivatives67.85 × 105ZnL2+
2,2′-bipyridyl6.46.31 × 103ZnL2+
4-((5-Bromo-3-chloro-2-hydroxybenzyl) amino)-2-hydroxybenzoic acid (LX007, ZL006)68.04 × 108ZnH−1L
C-3 (α carboxyfullerene)62.08 × 106ZnL
Caffeic acid amide analogues69.29 × 105ZnH−1L
Carbazole-derived compounds67.85 × 105ZnL2+
Carbidopa62.96 × 106ZnHL
Carnosic acid67.76 × 106ZnL
Cathechin67.76 × 106ZnL
Ceftriaxone6.13.68 × 104ZnL
Celastrol67.76 × 106ZnL
Chebulagic acid61.81 × 1013Zn2L
Chlorogenic acid66.86 × 105ZnL−
3′-O-(3-Chloropivaloyl) quercetin65.69 × 1016ZnH3L
Chlorpromazine61.95 × 106ZnHL3+
Chrysin65.69 × 1016ZnH3L
Clioquinol7.53.16 × 102ZnL+
Clovamide analogues (R1 and R2 = OH, and/or R3 and R4 = OH)67.76 × 106ZnL
“Compound 1”67.85 × 105ZnL2+
“Compound (−)-8a”67.76 × 106ZnL
“Compound 8”6.46.47 × 103ZnH−1L
“Compound 21”, derivative of 3-methyl-1-(2,4,6-trihydroxyphenyl) butan-1-one61.54 × 106ZnL+
“Compound (−)-21a”, derivative of N-6-(2-(4-(1H
-indol-5-yl)piperazin-1-yl)ethyl)-N-6-propyl-4,5,6,7-tetrahydrobenzo
[d]thiazole-2,6-diamine		67.85 × 105ZnL2+
Creatine61.54 × 106ZnL+
Cudraflavone B65.69 × 1016ZnH3L
Curcumin65.76 × 105ZnL
Cyanidin67.76 × 106ZnL
D51267.85 × 105ZnL2+
D607 (bipyridyl-D2R/D3R agonist hybrid)6.46.31 × 103ZnL
DA-2 (8D)7.52.80 × 102ZnL
DA-367.85 × 105ZnL
DA-467.85 × 105ZnL
Dabigatran etexilate67.85 × 105ZnL
Dabrafenib68.23 × 107ZnL
(S)-3,4-DCPG66.84 × 106ZnL
Deferricoprogen8.34.35 × 101ZnHL
Delphinidin62.71 × 105ZnL
Demethoxycurcumin65.76 × 105ZnL
Dendropanax morbifera active compound67.76 × 106ZnL
Desferrioxamine (Deferoxamine, Desferal, DFO)7.43.97 × 102ZnH2L+
(S)-N-(3-(3,6-Dibromo-9H-carbazol-9-yl)-2-fluoropropyl)
-6-methoxypyridin-2-amine		61.95 × 106ZnHL
4,5-O-Dicaffeoyl-1-O-(malic acid methyl ester)-quinic acid derivatives (R1, R2, R3, R4, or R5 = caffeoyl)67.76 × 106ZnL
Dihydromyricetin62.71 × 105ZnL
5-(3,4-Dihydroxybenzylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione67.76 × 106ZnL
7,8-Dihydroxycoumarin derivative DHC1267.76 × 106ZnL
3′,4′-Dihydroxyflavone67.76 × 106ZnL
7,8-Dihydroxyflavone67.76 × 106ZnL
(E)-3,4-Dihydroxystyryl aralkyl sulfones67.76 × 106ZnL
(E)-3,4-Dihydroxystyryl aralkyl sulfoxides67.76 × 106ZnL
2-[[(1,1-Dimethylethyl) oxidoimino]-methyl]-3,5,6-trimethylpyrazine62.20 × 106ZnL
DKP61.52 × 106ZnL
l-DOPA (levodopa, CVT-301)62.96 × 106ZnHL
DOPA-derived peptido-mimetics (deprotected)62.96 × 106ZnHL
DOPA-derived peptido-mimetics (protected)67.76 × 106ZnL
l-dopa deuterated62.96 × 106ZnHL
Doxycycline6.13.88 × 104ZnL
Droxidopa10.91.18 × 10−1ZnHL
Echinacoside67.76 × 106ZnL
Ellagic acid67.76 × 106ZnL
Entacapone (comtan, ASI-6)6.22.62 × 104ZnL
Enzastaurin67.85 × 105ZnL
Epicatechin67.76 × 106ZnL
Epigallocatechin-3-gallate61.81 × 1013Zn2L
Etidronate (HEDPA)7.44.32 × 102ZnL2−
Exifone61.81 × 1013Zn2L
F13714,
F15599		62.28 × 105ZnL
Fisetin (3,3′,4′,7-tetra-hydroxy-flavone)67.76 × 106ZnL
Fraxetin67.76 × 106ZnL
Gallic acid derivatives61.81 × 1013Zn2L
Gallocatechin62.71 × 105ZnL
Garcinol67.76 × 106ZnL
Glutamine68.61 × 105ZnL+
Glutathione derivatives14.81.20 × 10−5ZnH−2L22−
Glutathione-hydroxy-quinoline compound7.81.37 × 102ZnH−1L+
Glutathione-l-DOPA compound6.31.20 × 104ZnH−1L
Gly-N-C-DOPA62.96 × 106ZnHL
GSK27950399.71.64ZnL2
Guanabenz67.85 × 105ZnL
Hinokitiol6.22.06 × 104ZnL+
8-HQ-MC-5 (VK-28)7.53.16 × 102ZnL
4-Hydroxyisophthalic acid69.02 × 107ZnL
1-Hydroxy-2-pyridinone derivatives6.31.01 × 104ZnL
3-Hydroxy-4(1H)pyridinone (Deferiprone)6.21.45 × 104ZnL+
3-Hydroxy-4(1H)pyridinone derivatives (R = H)6.21.45 × 104ZnL
8-hydroxyquinoline-2-carboxaldehyde isonicotinoyl hydrazone7.53.16 × 102ZnL
Hydroxy-quinoline-propargyl hybrids (HLA20)7.53.16 × 102ZnL
Hydroxytyrosol butyrate67.76 × 106ZnL
l-(7-Imino-3-propyl-2,3-dihydrothiazolo [4,5-d]
pyrimidin-6(7H)-yl)urea		6.55.10 × 103ZnH−1L
Imipramine61.95 × 106ZnHL3+
Isobavachalcone62.12 × 105ZnL+
Isochlorogenic acid66.86 × 105ZnL−
Isoquercetin (isoquercitrin)63.94 × 1024ZnH4L
Kaempferol 63.94 × 1024ZnH4L+
Kaempferol, 3-O-a-L arabino-furanoside-7-O-a-
L-rhamno-pyranoside		63.56 × 1020ZnH3L
KR3349361.54 × 106ZnL
Kukoamine67.76 × 106ZnL
Lestaurtinib67.85 × 105ZnL
Lipoic acid63.84 × 106ZnL+
LY35474061.46 × 107ZnL
M10
M30 (VAR10303)
M99		7.53.16 × 102ZnL
Macranthoin G67.76 × 106ZnL
Magnesium lithospermate B67.76 × 106ZnL
α-mangostin67.76 × 106ZnL
γ- mangostin67.76 × 106ZnL
MAOI-162.71 × 105ZnL
MAOI-267.85 × 105ZnL
MAOI-465.88 × 105ZnHL
Metformin (Met)61.87 × 106ZnL+
Methoxy-6-acetyl-7-methylijuglone 6.14.82 × 104ZnL2
N′-(4-methylbenzylidene)-5-phenylisoxazole-3-carbohydrazide61.76 × 106ZnL
Minocycline6.47.52 × 103ZnHL
Mitomycin C63.49 × 106ZnL
MitoQ7.18.74 × 102ZnL
Morin65.69 × 1016ZnH3L
[18F]MPPF67.85 × 105ZnL
MSX-368.19 × 106ZnL
Nicotinamide adenine dinucleotide phosphate (NADPH)6.13.72 × 104ZnL
Nicotinamide mononucleotide68.19 × 106ZnL
Nitecapone 6.22.62 × 104ZnL
Nordihydroguaiaretic acid67.76 × 106ZnL
Oleuropein67.76 × 106ZnL
Opicapone6.22.62 × 104ZnL
P7C361.96 × 107ZnL2+
PBF-50967.85 × 105ZnL
PBT27.53.16 × 102ZnL
PBT4347.91.19 × 102ZnL2
Petunidin67.76 × 106ZnL
Phenothiazine 2Bc (n=0)67.85 × 105ZnL2+
Phenothiazine 2Bc (n=1)61.95 × 106ZnHL3+
Phenylhydroxamates62.07 × 105ZnL
Piceatannol67.76 × 106ZnL
Piperazine-8-OH-quinolone hybrid7.53.16 × 102ZnL
Preladenant67.85 × 105ZnL
Promethazine67.85 × 105ZnL2+
Protocatechuic acid61.25 × 107ZnL−
Protosappanin A67.76 × 106ZnL
Pyrazolobenzothiazine-based carbothioamides64.73 × 107ZnL
Pyrimidinone 867.85 × 105ZnL
Q1
Q4		7.53.16 × 102ZnL
Quercetin63.94 × 1024ZnH4L+
Quinoline derivatives as SUMOylation activators63.94 × 106ZnL2+
Radotinib6.46.31 × 103ZnL
Riboflavin62.16 × 105ZnHL3+
Rifampicin (ASI-3)6.17.04 × 104ZnL
Rimonabant61.52 × 106ZnL
Rosmarinic acid67.76 × 106ZnL
Rutin63.94 × 1024ZnH4L+
Salicylate, sodium salt69.02 × 107ZnL
Salvianolic acid B67.76 × 106ZnL
SCH58261
SCH412348		67.85 × 105ZnL
ST1535 ST420667.85 × 105ZnL
Staurosporine67.85 × 105ZnL
Stemazole64.73 × 107ZnL
Sulfuretin67.76 × 106ZnL
Tannic acid61.22 × 105ZnL
Tanshinol67.76 × 106ZnL
Taurine61.26 × 1012ZnL2
Tetracycline67.01 × 106ZnL
Tolcapone (ASI-7)6.22.62 × 104ZnL
Tozadenant8.71.62 × 101ZnL2
Transilitin6.18.21 × 104ZnL
o-Trensox21.71.95 × 10−12ZnL4−
2′, 3′, 4′-Trihydroxyflavone62.71 × 105ZnL
2,3,3-Trisphosphonate12.17.93 × 10−3ZnL
V8144462.28 × 105ZnL
VAS3947
VAS2870		6.55.10 × 103ZnH−1L
Verbascoside69.29 × 105ZnH−1L
WIN 55,212-267.85 × 105ZnL2+
WR-106561.95 × 106ZnHL3+
Zonisamide88.81 × 101ZnL

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MDPI and ACS Style

Tosato, M.; Di Marco, V. Metal Chelation Therapy and Parkinson’s Disease: A Critical Review on the Thermodynamics of Complex Formation between Relevant Metal Ions and Promising or Established Drugs. Biomolecules 2019, 9, 269. https://doi.org/10.3390/biom9070269

AMA Style

Tosato M, Di Marco V. Metal Chelation Therapy and Parkinson’s Disease: A Critical Review on the Thermodynamics of Complex Formation between Relevant Metal Ions and Promising or Established Drugs. Biomolecules. 2019; 9(7):269. https://doi.org/10.3390/biom9070269

Chicago/Turabian Style

Tosato, Marianna, and Valerio Di Marco. 2019. "Metal Chelation Therapy and Parkinson’s Disease: A Critical Review on the Thermodynamics of Complex Formation between Relevant Metal Ions and Promising or Established Drugs" Biomolecules 9, no. 7: 269. https://doi.org/10.3390/biom9070269

APA Style

Tosato, M., & Di Marco, V. (2019). Metal Chelation Therapy and Parkinson’s Disease: A Critical Review on the Thermodynamics of Complex Formation between Relevant Metal Ions and Promising or Established Drugs. Biomolecules, 9(7), 269. https://doi.org/10.3390/biom9070269

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