Curcumin Derivatives as Metal-Chelating Agents: Implications for Potential Therapeutic Agents for Neurological Disorders

C H A P T E R

15 Curcumin Derivatives as Metal-Chelating Agents: Implications for Potential Therapeutic Agents for Neurological Disorders Erika Ferrari Department of Chemical and Geological Sciences, University of Modena and Reggio Emilia, Modena, Italy

INTRODUCTION Neurological disorders strongly impact the modern society not only for those affected and their families but they also represent the most significant public health, social, and economic crisis of the 21st century, and their incidence is estimated to double in the next 20 years.1,2 Defeat or at least a slowdown of the progression of neurodegeneration represents a hard-to-win challenge for the public health system. Despite the different molecular basis and pathogenesis of neurodegenerative disorders (NDD), including Alzheimer’s (AD), Parkinson’s (PD), and prion protein diseases, the deposition of misfolded proteins as intra- or extracellular deposits has been recognized as a characteristic hallmark. Hyperphosphorylated tau, amyloid β (Aβ) peptide, and more recently α-synuclein (αSyn) aggregate in nonnative, organized, and highly stable cross-β sheet structures,3,4 with fibrillar appearance and high resistance to proteolytic degradation. The degree of abnormal protein deposition commonly correlates with the clinical progression and severity of the pathology.5 In addition to the accepted role of

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amyloid plaques in AD, amyloid deposition plays a key contribution in cognitive impairments associated to synucleinopathies, such as PD and related PD with dementia (hPDD) and dementia with Lewy bodies.6 Monomeric Aβ peptides normally present in the human brain have no deleterious effects on neurons. However, these have a tendency to self-assemble into neurotoxic oligomeric species responsible for the pathogenesis of AD, and cerebral amyloid angiopathy (CAA).7 To date, due to the multifactorial nature of NDD, the pathways by which misfolded aggregates are involved in neurodegeneration remain mostly unclear, and several aspects may contribute to foster their formation.8 Granted evidences pointed to increased metal concentration in brain resulting of normal aging,9
12 this phenomenon, known as metal ions dyshomeostasis, could be addressed as the pivotal factor triggering a cascade of effects responsible for the progression of neurological diseases, among which protein aggregation, redox activity, and pH compartmental change. In this landscape, the development of new chelators gifted with interesting therapeutic properties appears of utmost importance to beat the multifactorial nature of neurodegenerative diseases. Among them, curcumin, a natural antioxidant, has been investigated in depth as a potential compound for both prevention and treatment of AD,13,14 and its neuroprotective ability was demonstrated in vitro.15,16 This work aims to provide an integrated overview on recent advances in (1) the role that metals play in NDD, and how chelation may represent a successful therapeutic strategy; (2) the activity of curcumin in NDD connected to its metal chelating ability; and (3) the new scaffold modifications that may turn curcumin into stable, safe, and potent metal chelator.

ROLE OF METAL IONS IN NEUROLOGICAL DISORDERS Essential metals’ dyshomeostasis activates a sort of domino effect on several physiological factors tightly interconnected one another, as summarized in Fig. 15.1. Indeed, metal accumulation in brain triggers different kinds of metal-promoted damages related to neurodegeneration: those caused by the presence of redox-active metals, such as copper and iron, leading to reactive oxygen species (ROS) and oxidative stress responsible for severe neuronal damage, and those that involve protein modification, misfolding, and aggregation.17 These phenomena are tightly bound and dependent one to the other; actually protein aggregation and misfolding

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FIGURE 15.1

277

Summary of possible effects of metal ions in physiological environment.

have a crucial role in neuronal dysfunction, eventually leading to cell death. Several stimuli activate the apoptotic events, that is, oxidative stress, endoplasmic reticulum stress, metabolic dysfunction, DNA damage, and reduced levels of antiapoptotic genes.18
20 In particular, oxidative stress has a pivotal role in the AD and other NDD disorders’ pathophysiology; in fact, the central nervous system is particularly sensitive to oxidative damage, from which neurons and oligodendrocytes seem to be more susceptible than astrocytes and microglia. The basis for this increased sensitivity is linked to the high levels of O2 consumption (and electron leakage as a consequence), the low levels of antioxidant defenses when compared to other cells, and the abundance of lipids or fatty acids.21 In addition, ROS in association with reactive nitrogen species (RNS) on one side precede the formation of senile plaques and on the other foster their formation.22 The vicious circle, existing between ROS produced by damaged mitochondria during oxidative stress and Aβ peptides’ accumulation, accelerates AD progression.23 Many essential metal ions such as copper, iron, manganese, and zinc demonstrated metal-associated neurotoxicity, redox signaling, and protein aggregation as profusely reviewed.12,17,21,24,25 As recently reviewed by Grubman et al.,26 despite the lack of understanding regarding regulation of mitochondrial transition metal pools (Cu, Fe,

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Mn, and Zn), particularly in the brain, considerable evidence supports perturbation to these pools in several NDD. Metal dysregulation leads to impaired energy production, especially critical for the high energy demands of neurons and/or generation of ROS and activation of mitochondrial-dependent apoptosis.

Iron Iron easily redox cycles between 2 1 and 3 1 oxidation states, and if present in loosely bound form may favor the formation of ROS and RNS, so its homeostasis is tightly regulated and less than 5% of Fe is found in the so-called labile iron pool. Fe is required as cofactor of several important enzymes, and it is heterogeneously distributed in the brain; it is highly concentrated in the substantia nigra (SN), hippocampus, striatum, interpeduncular nuclei, and myelin,27 and its homeostasis is regulated by communication between the blood
brain barriers (BBB) and astrocytes. The role of iron dysregulation in neurological diseases has been pinpointed by several studies. In vivo and in vitro models of amyotrophic lateral sclerosis (ALS) highlighted the importance of many iron-containing proteins, among which iron
sulfur clusters, mitoferrin and frataxin.28,29 A key pathological hallmark of PD is the accumulation of iron in the SN,30 concomitantly with a decrease in copper content.31,32 Quite high amount of iron (1 mM) are colocalized within amyloid deposits in AD, and these are responsible first for free-radical generation and second for Fenton-like reactions. However, Fe doesn’t seem to directly promote aggregation, indeed it is found predominantly bound to ferritin with the plaques themselves, supporting the hypothesis that iron unbalance in AD is a consequence rather than one of the causes of the pathology.17,33

Copper Copper concentration in brain is quite high, and it is mainly distributed in basal ganglia, hippocampus, cerebellum, numerous synaptic membranes, cell bodies of cortical pyramidal neurons, and cerebellar granular neurons.25,34 Copper displays a pivotal role in both AD and PD pathogenesis. In AD, it promotes Aβ peptide aggregation, so doubling the sources of ROS species on the one hand due to the aggregates themselves and on the other to the redox cycling that occurs through a catalytic in-between state of Cu11/Cu21 bound by Aβ aggregates.35 The dysregulation of copper homeostasis in PD leads to downregulation of copper transporter receptor 1, reduced concentration in SN, and high levels of unbound copper in cerebrospinal fluid. In PD,

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it was observed that copper interacts with misfolded αSyn, sometimes in cooperative binding with dopamine, with an increase of oxidative stress and production of toxic oligomers.21,25,36 Contrarily, a feature of ALS is the decreased levels of copper in neurons that might account for the etiology of this ailment.37

Manganese Mn21, widespread in a plethora enzymes involved in diverse metabolic functions, can easily be oxidized to the more reactive and toxic species Mn31; anyway, neither of the two species generates free radicals via Fenton type reactions. Mn may indirectly enhance ROS generation via the Mn-catalyzed autoxidation of dopamine.38 Mn that accumulates in the mitochondria via the mitochondrial Ca21 uniporter increases the accumulation of labile Fe leading to further ROS formation and oxidative damage.24,39 Manganese upregulation leads to its accumulation in ganglia causing Mn-induced parkinsonian syndrome. In addition, MnSOD, the manganese-containing mitochondrial enzyme, was demonstrated to be upregulated in genetic PD models.40

Zinc Differently from Cu, Fe, and Mn, Zn is a redox-inactive metal ion with 21 as oxidation state; to greatest extent, it is bound to protein, and it is almost equally distributed in the cytoplasm and nucleus.41 Zn can act as enzyme cofactor, with structural function, or as a Lewis acid to promote substrates protonation, but its main role is in enzymes with Zn-dependent catalytic activity that control many cellular processes. In the brain, Zn is highly concentrated in the hippocampus and cortex.21 As for Fe, a simultaneous decrease of Zn levels in serum and plasma and an rise in SN could be associated to an increased risk for PD.32,42,43 Importantly, Zn promotes a rapid, but reversible, aggregation of Aβ that is different to the aggregation of Aβ or Aβ
Cu complexes and reduces their toxicity.44,45

METAL CHELATION IN NEURODEGENERATIVE DISEASES Since dysregulation of metal homeostasis contributes to neurological pathology, transition metals may represent strategical therapeutic targets in neurological disorders, providing metal delivery, sequestration,

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and related antioxidant properties of both chelator and metal complex. Bearing in mind Hard-Soft-Acid-Base classification,46,47 coordination number and geometry of the metal ion are possible to design a selective chelator able to provide a thermodynamically stable and kinetically inert metal complex. In addition to these features, a clinically useful chelator should possess low molecular weight, adequate lipophilicity to cross cellular and BBB, showing in the meantime low toxicity, and satisfy at least three of Lipinsky’s rules.48 So the requirements to fulfill are really demanding, and the efforts to develop new chelating agents are extremely challenging. If not bound to specific proteins/enzymes, copper and iron are commonly found in their oxidized state in the metal labile pool. Cu21 acts as borderline Lewis acid with high affinity for borderline/hard Lewis bases such as N and O, and complex’s geometry is typically distorted square-planar, trigonal-pyramidal, or square pyramidal.49 Zn21 is borderline and, as Cu21, prefers the interaction with N rather than O. The hard Lewis acid Fe31 is strongly bound by the hard Lewis base O, in an octahedral or distorted-octahedral geometric conformation. Like Fe31, Mn21 is hard preferring oxygen donating groups in the coordination sphere. Many classes of metal-based neuro-therapeutics have been explored, among them bis-thiosemicarbazones, pyridyl-porphyrins, hydroxamates, polydentate chelators [EDTA, diethylenetriaminepentaacetic acid (DTPA), etc.], macrocyclic polyamines (cyclam, cyclen, DOTA, NOTA), phenanthroline derivatives, and curcuminoids.17,25,26,50

CURCUMIN: A PLEIOTROPIC CHELATING AGENT, PROS AND CONS IN ITS USE Curcumin [1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadien-3,5dione], commonly classified as a natural occurring polyphenol, is the primary bioactive compound isolated from the dried rhizomes of Curcuma longa L. In the past decades, a large number of reports have been published on the beneficial effects of curcumin, and it has repeatedly been claimed that this natural active principle, which is considered safe, could be the lead compound for the development of new therapeutics.51
55 The molecular structure of curcumin (CUR) accounts for its pleiotropic set of biological properties, including antioxidant, antiinflammatory, antitumor, and neuroprotective activity. One of the most interesting features of CUR is its ability to strongly chelate metal ions through the keto
enolic (KE) moiety that undergoes keto
enol tautomerism as reported in Fig. 15.2.50 The keto
enol

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FIGURE 15.2

281

Chemical structure of curcumin and keto
enol tautomeric equilibrium.

tautomerism is strongly solvent dependent. Indeed, the keto
enol form is stabilized by six membered-ring intramolecular hydrogen bonding in low-polarity solvents, while trans or cis di-keto forms are usually stabilized by an increase in polarity and, to a smaller extent, in hydrogen-bond donating solvents.56,57 CUR in the keto
enol form is a bidentate chelator characterized by an OO donor set forming a six membered-ring when coordinated to the metal ion. Curcumin was investigated in depth for its iron(III)-chelating ability, showing interesting results if compared to other bidentate ligands such as deferiprone.58 During metal complexation in physiological conditions, CUR behaves as a weak monoprotic acid (HL), in which the keto
enol group is the only one able to dissociate with a pKa value of 8.54(3).58 The high affinity of keto
enol moiety for Fe31 shifts the equilibrium (Eq. (15.1)) toward the dissociated form (L2), lowering the pKa value of B5 units. HL $ H1 1 L2

(15.1)

However, the steric hindrance of CUR prevents the formation of 1:3 Fe31:CUR molar ratio complexes, while the 1:1 and 1:2 Fe31:CUR complexes are kinetically inert and thermodynamically stable. Unfortunately, crystallographic data of Fe
CUR complexes are not available; besides, several theoretical studies based on density functional theory (DFT) approach investigated the geometry and energy of the complex species.59,60 By recently reported trans-metalation study,61 as chelator, CUR stands out for its high selectivity for Fe31 and Cu21 rather than Zn21 and Mn21, suggesting that its metal-chelating ability in vivo could be exploited only for the first two species. Only few studies are reported on the concomitant role of iron and CUR in protein aggregation; recently an in vivo study on Swiss albino male mice model highlighted the ability of Fe
CUR to reduce the accumulation of Aβ 25
35, a peptide involved in AD.62 So, a sensible hypothesis could be that in

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presence of iron, CUR prevents ROS formation by trapping the labile redox-active iron pool in a stable and protected form, as observed in many animal studies.26 With respect to iron, copper has a stronger protein aggregating capacity known to account for AD and PD pathology. Molecular dynamics studies of Aβ aggregation63 pinpointed how conformational behavior of Aβ-42 is affected by high concentration of Cu21, leading to a decrease of the C-terminus β-sheet structures, supposed to be relevant for the formation of toxic oligomers. In relation to the effect of CUR on Cu(II)-induced cortical neuronal damage, Huang et al. demonstrated that CUR has a potential dosedependent activity in AD: at low dosage, CUR is safe and able to reverse neuronal impairment by ROS scavenging; however, if the dosage is increased, it might have a prooxidant activity triggering neuronal damage.64 Recently Abbaoui et al. investigated the neurotoxic effect of copper on dopaminergic neurons and the negative outcomes on locomotor performance, typical of PD. They reported that these deleterious effects were completely reversed by CUR that may qualify as a therapeutic agent against Cu neurotoxicity in general and DAergic system dysfunction in particular.65,66 To wrap up, in the presence of copper, CUR is able to inhibit aggregation, on the one side directly interacting with Aβ and on the other by chelating Cu21 and consequently removing the source of ROS/NRS species.63,67,68

NEW CURCUMIN-DERIVED CHELATORS Despite curcumin possesses pleiotropic activities of considerable benefit in neurological disorders12,69
72 and many clinical trials were carried out and some are still recruiting,73 its use in clinical applications remains limited by low bioavailability, instability, and poor water solubility, as recently pinpointed by Nelson et al.74 These drawbacks triggered different strategies to solve the problem; these may imply the development of new drug delivery systems, vehicles, and formulations75 or the design of synthetic analogs with improved properties.76 The last option lays on a structure-activity relationship (SAR) knowledge of curcumin, a unique molecule due to its chemical structure that gathers many possible biological targets able to trigger several effects, as recently highlighted by Hatamipour et al.77 As depicted in Fig. 15.3, curcumin assembles many functional groups with different potential reactivity, but in order to simplify and focus on a rational design of new derivatives, two principal structural moieties of CUR can be addressed to provide a successful functionalization: the β-keto
enol group and the aromatic rings.

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FIGURE 15.3 Functional groups and moieties of curcumin responsible for pharmacological activity, chemical interaction, and metabolism.

Sometimes, apparently minor modifications, such as those of meta and para substituents on the aromatic rings, result in major consequences for biological properties. For instance, if OH and OCH3 groups of curcumin are exchanged with H, all antiinflammatory and anticancer activities are lost.78,79 The functionalization of the aromatic rings gave birth to the first generation of curcumin analogs that can be distinguished according to the level of structural modification in two families: (1) change in the meta/para aromatic substituents only and (2) alteration of aromatic rings and their substituents. These compounds maintain the β-keto
enolic moiety that accounts for high reactivity, being a weak acid (pKa 5 8.5), Michael acceptor, and metal chelator, but potentially responsible for molecule degradation. Since tautomeric equilibrium is supposed to play a key role in curcumin instability, the replacement of the 1,3-dicarbonilic portion with isosteres is a promising strategy. Shifting the tautomeric equilibrium toward the di-keto form by the insertion of a bulky substituent in α position between the two carbonyl groups may enhance stability, and if the substituent is featured with an additional ligating site, on the overall, this may improve the chelating ability and metal-complex stability, preserving the β-keto
enol structure and reactivity.80 Finally, the removal of keto
enol moiety in favor of another functional group, typically a cyclic structure, allows to stiffen curcumin backbone and favors π conjugation, features that might improve both stability and interaction with Aβ aggregates In the past decades, huge synthetic efforts allowed to gain several derivatives, which biological properties were investigated in depth. A summary of the most promising analogs classified as “aromatic rings” and “β-keto
enol” modifications, together with their metalchelating ability and applications in neurological disorders, is reported hereafter.

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Aromatic Ring Modifications The synthetic curcuminoids with aromatic modifications were first synthesized by Pabon in 1964, with a synthetic pathway that to date was renamed “Pabon reaction.”81 Some of these compounds, such as diacetylcurcumin (DAC), bis-dehydroxy curcumin (bDHC), and bisdemethoxy curcumin (bDMC) (Fig. 15.4), demonstrated comparable activities with respect to curcumin, but with an improved stability in physiological media. The compounds behave as good iron-chelating agents58 and copper (II) chelators50,82 and demonstrated high affinity to Aβ1240 amyloid synthetic fibrils.83
85 Beside therapeutic applications, the metalchelating ability of curcuminoids can be exploited for diagnostic purposes, in particular for the development of radiotracers for early diagnosis of AD. Curcumin was employed as OO bidentate ligand in some complexes with a technetium-99m tricarbonyl core, providing a class of radiotracers gifted with high affinity for Aβ
amyloid plaques ex vivo on a section of brain tissue of a neuropathologically diagnosed AD patient.86 Besides technetium-99m, another interesting radiometal is gallium-68 that exhibits advantageous features being a generator produced positron emitter radionuclide with physical and chemical characteristics suitable for positron emission tomography diagnostic nuclear medicine and directly labeling of biomolecules (89% β 1 , maximum energy 5 1.92 MeV; T1/2 5 67.7 minutes). Curcumin derivatives demonstrated high affinity for natGa31 with the formation of 1:2 metalto-ligand complex,87 metal complexation slows down the degradation of curcuminoids in vitro at least in the first 2 hours,88 and all the O

OH

R2

R2 R1

R1

R1 = OCH3; R2 = OH

CURCUMIN

R1 = H; R2 = OH

bDMC

R1 = OCH3; R2 = H

bDHC

R1 = OCH3; R2 = OAc

DAC

FIGURE 15.4 Chemical structure of curcuminoids: DAC, bDHC, bDMC. DAC, Diacetylcurcumin; bDHC, bis-dehydroxy curcumin; bDMC, bis-demethoxy curcumin.

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complexes showed high and comparable stability to transchelation and transmetalation when challenged with DTPA, Fe31, Cu21, and Zn21 solution.83 Similarly to thioflavin, due to their unique structural features including a flexible backbone and hydrophobic nature, curcuminoid 68 Ga complexes might insert among the β-strand and form hydrogen bonds with the several available H donor and acceptor atoms. The affinity of 68Ga(CUR)21, 68Ga(DAC)21, and 68Ga(bDHC)21 was moderate for synthetic Aβ fibrils in vitro83 and high for Aβ plaques ex vivo on brain tissue of Tg2576 mice.84 On the other hand, amyloid plaques could not be visualized on brain sections of Tg2576 mice after injection, probably due to the low stability of the complexes in vivo and of a hampered passage through the BBB. In order to improve water solubility and kinetic stability, many glycosyl curcuminoids were synthesized and investigated, particularly in relation to chelating ability. The addition of glucose moieties on phenolic groups doesn’t affect Fe31 chelation by the keto
enol donating group, with a reactivity almost equivalent to the lead curcumin.87
89 Glycosyl curcuminoids form 1:1 and 1:2 metal-to-ligand complex species with Fe31 and Cu21. The coordination mode for Fe31 can be investigated in solution by 1H and 13C nuclear magnetic resonance (NMR), using Ga31 as NMR probe for Fe31. Typically for curcuminoids, addition of Ga31 to a solution of the free ligand at acidic pH immediately originates a metal-complex species, in slow chemical exchange with respect to NMR time scale (Fig. 15.5). The spectral pattern of the metal complex resembles that of the free ligand but it is strongly downfield shifted. Protons on the double bond of the aliphatic chain are the most affected by the presence of the metal ion, as clearly reported by Ferrari et al.90 The complex species are stable over a wide pH range, maintaining Fe31 in a soluble form and preventing iron-induced toxicity. In addition, the ligands demonstrated to possess a poor affinity for the potentially competitive biological metal ion Ca21.88 In addition to glycosyl-curcuminoids, with the aim to improve water solubility and bioavailability, curcumin was covalently functionalized on phenolic groups with a low molecular weight polyethylene glycol (PEG) (Fig. 15.6A). This compound self-organizes into nanoparticles in water and forms stable dispersions. In addition, it efficiently interacts with metal ions, such as Cu21, Al31, and Hg21, suggesting it as a potential candidate for metal chelation. A successful therapeutic strategy to defeat complex ailments such as NDD, such as AD, could be the use of hybrid drugs able to affect multiple targets simultaneously. In this landscape, Elmegeed et al.91 synthesized hybrid drugs through the combination of the steroid moiety with curcumin molecule (Fig. 15.6B). This family of compounds possesses

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HO OCH3

OCH3 O

OH

O

O

HO

H-3 HO

O

H-3

OH OH

H-4

O

OH

H-4

1:1 metal-to-ligand complex

1:2 metal-to-ligand complex

Free ligand

FIGURE 15.5 1H NMR titration of glucosyl-curcumin with Ga31 in CD3OD-d4, from bottom to top the free ligand, 1:2 metal-to-ligand complex and 1:1 metal-to-ligand complex. NMR, Nuclear magnetic resonance.

anti-AD properties by enhancing Ach synthesis, GSH level, paraoxonase level, and BCL2 lymphoma level in vitro, and by decreasing AchE brain activity, 8-OHG, Caspase-3, and P53 brain level in vivo.91 Being the steroid moieties quite distant from the chelating site, probably this

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R1 = OCH3

FIGURE 15.6 Hybrid curcuminoids obtained through functionalization of phenolic groups with a PEG moiety (A) and a steroid moiety (B).

FIGURE 15.7

Chemical structure of lipid PEG-curcumin derivative, taken from

Ref. [91].

compound can act as metal sequestering agent in vivo for copper, iron, and to minor extent zinc. The removal of one insaturation and the addition of a lipid PEG group to curcumin were proposed and investigated to formulate multifunctional nanosized liposomes able to target amyloid deposits in AD brains (Fig. 15.7). Liposomes showed high affinity for the amyloid deposits, on postmortem brains samples of AD patients, and slowed down Aβ1
42 peptide aggregation.92 This derivative is still able to bind metal ions through the β-keto
enol group, although the lipid-PEG moiety may hamper complex formation by steric hindrance. Recently, the chelating ability of the β-keto
enol moiety of curcumin was exploited to obtain fluorinated boron complexes for two-photon microscopy, an important technique for investigating Aβ species, able to provide insight into the dynamics of individual plaque expansion and disruption of the microenvironment.93,94 One of these boron complexes (CRANAD-28) demonstrated not only to label Aβ plaques and CAAs in 9-month old amyloid precursor protein (APP)/PS1 mice but also to attenuate Aβ crosslinking in brain. These outcomes account for its

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potential use as theranostic agent, combining therapeutical properties in a diagnostic tool.95 Zhang et al. investigated CRANAD-like structures able to reduce fibrillary aggregation, in particular, they designed and synthesized the analog CRANAD-17, in which a curcumin scaffold was used as an anchoring moiety to usher the designed compound to the vicinity of H13 and H14 of Aβ, and imidazole rings were incorporated to compete with H13/H14 within Aβ for copper binding. This compound was on purpose monodentate in order to bind copper but only minimally disrupt brain metal homeostasis/balance.96

β-Keto
Enol Modifications β-keto
enol modifications were mainly investigated to switch the tautomeric equilibrium toward the diketo form, in order to improve stability. Many research efforts allowed gaining a huge amount of curcumin analogs in which the β-keto
enol moiety was modified by inserting an alkylic/arylic group in α position to the two carbonyl groups, or exchanging the β-keto
enol with another functional group. Most of these modifications, as reported in Fig. 15.8, allowed metal chelation providing mono-, bi-, or tridentate ligands. Several computational studies were devoted to the disentanglement of curcumin/curcuminoids interactions with Aβ fibrillar aggregates.97
100 The derivatives were investigated both in diketo (DK)

FIGURE 15.8 General chemical structures of β-keto
enol modified curcumin ligands and denticity.

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and KE forms; the simulations resulted essentially the same, suggesting that switching the keto
enol equilibrium may not significantly affect affinity for Aβ fibrillar aggregates, while a most important role is played by the aromatic substituents and by the nature of the substituent on the β-keto
enol moiety. Indeed, curcumin shows a significant tendency to destabilize the protofibril by binding to the top site. While the effect of distortion of the peripheral chain by curcumin may inhibit the process of elongation of the fibril along the principal axes and/or catalyze the disruption of the β secondary structure. This perturbation is particularly strong at the peptide C-terminals, where M35 lies and can exert an indirect detrimental effect on the conformation/dynamics of this zone responsible for the hierarchical assembly of amyloid fibrils.100,101 Unfortunately, to date, the mechanisms of fibril destabilization upon ligand interaction with curcuminoids in the presence of metal ions (Fe31, Cu21, Mn21, and Zn21) remain still obscure, and there are no published computational studies on this topic in literature. On the other hand, quite a lot of experimental studies report the metal-chelating ability of β-keto
enol-functionalized curcuminoids that were synthesized to overcome some criticisms and doubts on the real efficacy of curcumin as a pharmaceutical.74 The presence of a substituent in α position to the two carbonyl groups alters several processes, among which the keto
enol tautomeric equilibrium—a fundamental feature of curcumin cytoprotection102—metal-chelating ability, stability, and bioavailability. The insertion of an aliphatic chain with a terminal ester group leads to a family of curcuminoids with improved chemical stability in physiological conditions,80 and valuable metal chelating properties.103,104 When the substituent is an aliphatic chain (i.e., 2 (CH2)nCOOC(CH3)3 n 5 1,2) (Fig. 15.9A), the predominant tautomer in aqueous solution is the DK one; however, complexation with metal ions like Cu21 or Fe31 shifts the equilibrium toward the KE tautomer as demonstrated by NMR data. The high affinity of these ligands for hard metal ions—that is, Fe31 and Cu21—accounts for an anticipated dissociation of the β-keto
enol moiety, that is therefore able to coordinate the metal ion even in acid condition. At physiological pH of 7.4, the formation of 1:2 metal-to-ligand complex species is observed for Fe31, while a mixture of a 1:1 and 1:2 metal-toligand complex species is observed for Cu21.103 In addition to metal chelating ability, these derivatives are able to interfere with Aβ1
40 peptide during fibrillization and inhibit formation of fibrils in a concentration-dependent manner. IC50 values are comparable with that of curcumin, suggesting that this structural modification preserves Aβ disaggregating ability, as well as radical scavenging ability,105 and superoxide dismutase activity.103 In the past decades, labile ester

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OH

R=

R R2

-(CH2)n-COOC(CH3)3

n = 1, 2

(A)

-(CH2)n-COOCH

n = 1, 2

(B)

n = 1, 2

(C)

R2

O

R1

R1

H3C n

N

O O

O R1 HN

n

NH O

N

R2

CH3

N H

N

N

n = 1, 2 ,4

H3C

(D)

N

(E)

N CH3

NH N

N

OH

R HO

OH O

H3C

(F)

O H3C

FIGURE 15.9 Chemical structures of β-keto
enol modified curcumin ligands: (A) KE substituted esters; (B) KE substituted acids; (C) phthalimide-based curcuminoids; (D) tacrine-derived curcuminoids; (E) donepezil-derived curcumin; (F) Curcumin derived Schiff base.

groups have been exploited to large extent in the manufacture of prodrugs.106 The cleavage of the ester sets the carboxylic group free (Fig. 15.9B). The presence of the carboxylate group on the one hand increases water solubility and on the other adds an additional ligating site. These carboxylic curcuminoids behave as tridentate chelators with OOO donor set, particularly selective for Fe31 and Cu21. At physiological pH (7.4), 1:2 metal-to-ligand complex species are formed for both metal ions with high value of overall stability constants (log β); in addition, derivatives with OH groups on the aromatic rings exert radical scavenging activity that is not perturbed by metal coordination, an important feature in neurodegeneration prevention and therapy.107 Recently, Thalidomide derivatives have gained a renewed attraction for the development of therapeutics,108 and phthalimide-based curcuminoids (KF) (Fig. 15.9C) are an interesting example. They are characterized by the insertion of phthalimide-functionalized chain in α position to the two carbonyl groups of β-diketo moiety that is still able to bind metal ions. Computational and experimental studies demonstrated that the perturbation and destruction of amyloid aggregates due to KF compounds is a consequence of several effects, but unfortunately, the ligand binding is nonspecific, the Aβ fibrils display

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several partially or not overlapping binding sites, in which dispersion interactions (vdW) act as the driving force. In addition, KF compounds exert a protective function in nonreceptor-mediated oxidative glutamate toxicity in mouse hippocampal HT-22 cells and reduce inducible NO synthase transcript levels even better than curcumin.100 In the search for a molecule with multiple pharmacological effects able to fight the many different facets of neurological diseases, Liu et al. combined the pharmacophores of curcumin with tacrine, a potent acetylcholinesterase inhibitor (AChEI), to form new multitarget drugs (Fig. 15.9D).109 In these derivatives, the β-keto
enol moiety is transformed into a β-oxo-amide group, capable to bind metal ion by the formation of a six-membered ring. The chelators demonstrated by UV
vis spectroscopy have high affinity for copper(II) rather than iron (II), a reasonable result due to the presence of borderline Lewis base N in the chelating site. In addition to metal chelating ability, the compounds showed positive inhibitory effects both on acetylcholine esterase and butyrylcholine esterase and also exhibited pronounced oxygen radical absorbance capacity. Lack of chelating effect in monodentate ligands usually decreases the thermodynamic stability as entropy variation diminishes and kinetic inertness since metal ion is not closely bound. Nevertheless, some examples of interesting monodentate curcumin derivative are reported in literature, such as those proposed by Chen et al.110 These molecules, particularly compound named A4 (Fig. 15.9E), showed affinity for Cu21 and Fe21 rather than Zn21, in addition their impact on metal-induced Aβ1
42 aggregation was investigated. All three metal ions (Cu21, Fe21, and Zn21) accelerated the aggregation in the order Cu21DZn21 . Fe21, but compound A4 clearly decreased fibrils build up in the presence of Cu21 and Fe21 compared with the potent copper chelator clioquinol, its effect was instead weak on the Zn21-promoted fibrils, consistently with low affinity for this metal ion. Finally, with the aim to increase chelating ability, a curcumin derived Schiff base ligand was synthesized by condensation of curcumin with amino ethylene piperazine (Fig. 15.9F).111 The compound strongly binds Cu21 and Zn21 in a square planar and distorted octahedral geometry, respectively.

CONCLUDING REMARKS In the past decades, the “golden spice” curcumin stood out for a wide range of biological properties, including antioxidant and antiinflammatory activities that are closely connected to its metal chelating ability. The keto
enol moiety behaves as an OO donor set with high

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affinity for copper and iron, both involved in the development of neurological disorders. The relationship between the metal ion, cognitive impairment, and the development of the ailment is still largely obscure but several factors should be taken into account: (1) metal-dependent deposition and aggregation of misfolded proteins, (2) Fenton and Haber
Weiss reactions, (3) redox cycling, and (4) metal dyshomeostasis. Despite its pharmaceutical properties, the use of curcumin was slowed down by its high instability and bioavalilability. To overcome this drawback, many derivatives were designed, synthesized, and investigated, but only few with retained or improved metal-chelating ability. Particularly, the presence of the β-keto
enol moiety is of utmost importance in all curcumin derivatives, in order to form typically 1:2 metalto-ligand complexes with both Fe31 and Cu21. The effect of the new curcuminoids on metal-induced protein aggregation seems promising, but only few manuscripts are reported. There is still lack of knowledge on the most talented derivatives and medicinal inorganic chemistry has to face broad challenges from several frontiers, especially as it concerns the effect of the new curcuminoids on metal chelation, radical scavenging ability, protein disaggregation upon metal-induction in vitro and possibly in vivo.

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