The World Health Organization estimates that ca. 11 million people worldwide have Alzheimer's disease (AD) and this population is expected to nearly double by 2030.1 This disease, which manifests in progressive neurodegeneration, is characterized by the presence of amyloid-β (Aβ) peptide aggregates.2 -4 The mechanism for the formation of Aβ aggregates is not entirely understood, though metal ions such as Cu II and Zn II have been shown to facilitate Aβ aggregation.2 -4 In particular, redox-active Cu II is implicated in the generation of reactive oxygen species (ROS), leading to an increase in oxidative stress, which is one proposed neuropathology of AD.2 -8 To elucidate Cu-mediated events in AD pathogenesis, Cu coordination to Aβ has been explored as well as effects on the removal of Cu from Cu-Aβ species using chelating agents.2 -13 These studies have demonstrated that the extent of metal-induced Aβ aggregation and ROS production can be modulated by metal chelators, which highlights metal-ion chelation therapy as a promising AD treatment.Many orthodox metal chelators show inhibition of metal-induced Aβ aggregation and ROS formation,2 -4 , 9 , 13 but they may not be suitable for AD therapeutics. Most of these chelators cannot cross the blood brain barrier (BBB) and are not able to specifically target metal ions in various Aβ forms without removing vital metals from other biological systems due to lack of an Aβ recognition ability. The metal chelator clioquinol (CQ) reveals decreased Aβ aggregate deposits and improved cognition in early clinical trials.14 The long-term use is, however, limited by an adverse side effect, subacute myelo-optic neuropathy.15 , 16 Our recent studies suggest that CQ assists, in part, in the disaggregation of Aβ aggregates, but could not completely prevent Aβ aggregation.17 Therefore, rational design of chelating agents capable of targeting metal ions in Aβ species followed by modulation of Aβ aggregation in the brain is essential toward metal-ion chelation therapy for AD. Only limited efforts have been made toward this goal.3 , 10 -12 Herein we present the preparation of bifunctional metal chelators (1 and 2) and their interaction with Cu-induced Aβ aggregates. Both chelators exhibit modulation of Cu-associated Aβ aggregation, which is more effective than that by the well-known metal chelating agents CQ, EDTA, and phen in this study.18Our strategy for developing metal chelators as potential AD therapeutics is to create bifunctional molecules that contain structural moieties for metal ion chelation and Aβ recognition (Figure 1). For the latter purpose, the basic frameworks of 1 and 2 are based on the Aβ aggregate-imaging probes 125 IMPY and p-125 I-stilbene,18 respectively, which show strong binding affinity to Aβ aggregates.19 These compounds are small, neutral, lipophilic, and thus able to penetrate the BBB. Furthermore, they are easily removed from normal brain mhlim@umich.edu . Supporting Information Available: Experimental procedures, preparation and characterization of 1 and 2, Ta...
Metals are essential cellular components selected by nature to function in several indispensable biochemical processes for living organisms. Metals are endowed with unique characteristics that include redox activity, variable coordination modes, and reactivity towards organic substrates. Due to their reactivity, metals are tightly regulated under normal conditions and aberrant metal ion concentrations are associated with various pathological disorders, including cancer. For these reasons, coordination complexes, either as drugs or prodrugs, become very attractive probes as potential anticancer agents. The use of metals and their salts for medicinal purposes, from iatrochemistry to modern day, has been present throughout human history. The discovery of cisplatin, cis-[PtII(NH3)2Cl2], was a defining moment which triggered the interest in platinum(II)- and other metal-containing complexes as potential novel anticancer drugs. Other interests in this field address concerns for uptake, toxicity, and resistance to metallodrugs. This review article highlights selected metals that have gained considerable interest in both the development and the treatment of cancer. For example, copper is enriched in various human cancer tissues and is a co-factor essential for tumor angiogenesis processes. However the use of copper-binding ligands to target tumor copper could provide a novel strategy for cancer selective treatment. The use of nonessential metals as probes to target molecular pathways as anticancer agents is also emphasized. Finally, based on the interface between molecular biology and bioinorganic chemistry the design of coordination complexes for cancer treatment is reviewed and design strategies and mechanisms of action are discussed.
Selective 20S proteasomal inhibition and apoptosis induction were observed when several lines of cancer cells were treated with a series of copper complexes described as [Cu((2), and [Cu(HL I )(L I )]OAc (3), where HL I is the ligand 2,4-diiodo-6-((pyridine-2-ylmethylamino) methyl)phenol. These complexes were synthesized, characterized by means of ESI spectrometry, infrared, UV-visible and EPR spectroscopies, and X-ray diffraction when possible. After full characterization species 1-3 were evaluated for their ability to function as proteasome inhibitors and apoptosis inducers in C4-2B and PC-3 human prostate cancer cells and MCF-10A normal cells. With distinct stoichiometries and protonation states, this series suggests the assignment of species [CuL I ] + as the minimal pharmacophore needed for proteasomal chymotryspin-like activity inhibition and permits some initial inference of mechanistic information.Three well characterized discrete copper complexes with asymmetric phenol-substituted ligands are able to inhibit the proteolytic activity of the 20s proteasome. Evidence for a minimal pharmacophore suggests a potential basis for new cancer therapies with tunable and cost-effective metallodrugs.
Amyloid-beta (Abeta) plaques are largely associated with the neuropathogenesis of Alzheimer's disease (AD). Metal ions such as Cu(II) and Zn(II) have been implicated as contributors to their formation and deposition. Metal chelators have been used to modulate metal-induced Abeta aggregation. The bidentate ligand clioquinol (CQ) presents an effective influence on metal-involved Abeta aggregation, which has been explained through its metal chelation and is generally monitored by fluorescence and turbidity assays in vitro. The studies herein, however, suggest that the effects of CQ on metal-driven Abeta aggregation may not be visualized accurately by both assays. Subsequently, the present work demonstrates that CQ is able to chelate metal ions from metal-Abeta species and to assist, in part, in the disaggregation of Abeta aggregates, but it could not completely hinder the progression of Abeta aggregation.
In this study, we compare the proteasome inhibition capabilities of two anticancer candidates, [Ni(LIA)2] (1) and [Zn(LIA)2] (2), where LIA- is the deprotonated form of the ligand 2,4-diiodo-6-(((2-pyridinylmethyl)amino)methyl)phenol. Species 1 contains nickel(II), a considerably inert ion that favors covalency, whereas 2 contains zinc(II), a labile transition metal ion that favors predominantly ionic bonds. We report on the synthesis and characterization of 1 and 2 using various spectroscopic, spectrometric, and structural methods. Furthermore, the pharmacological effects of 1 and 2, along with the salts NiCl2 and ZnCl2, were evaluated in vitro and in cultured human cancer cells in terms of their proteasome-inhibitory and apoptotic cell death-inducing capabilities. It is shown that neither NiCl2 nor 1 have the ability to inhibit the proteasome activity at any sustained levels. However, ZnCl2 and 2 showed superior inhibitory activity to the chymotrypsin-like activity of both 26S proteasome (IC50 = 5.7 and 4.4 μmol/L, respectively) and purified 20S proteasome (IC50 = 16.6 and 11.7 μmol/L, respectively) under cell-free conditions. Additionally, inhibition of proteasomal activity in cultured prostate cancer cells by 2 was associated with higher levels of ubiquitinated proteins and apoptosis. Treatment with either the metal complex or the salt was relatively non-toxic toward human normal cells. These results strengthen the current working hypothesis that fast ligand dissociation is required to generate an [MLIA]+ pharmacophore, capable of interaction with the proteasome. This interaction, possibly via N-terminal threonine aminoacids present in the active sites, renders the proteasome inactive. Our results present a compelling rationale for 2, along with its gallium(III) and copper(II) congeners to be further investigated as potential anticancer drugs that act as proteasome inhibitiors.
The stabilization of a bivalent oxidation state in cobalt complexes of phenolate-based asymmetric tridentate ligands with iodo and bromo substituents is studied. The complexes [CoII(LIA)2].2CH3OH (1) and [CoII(LBrA)2].CH3OH (2) were characterized by means of several spectroscopic and spectrometric techniques. The molecular structure of 1 was determined by diffractometric analysis and reveals the cobalt(II) ion in a distorted-octahedral geometry. The centrosymmetric metal ion adopts a local D2h symmetry and is surrounded by facially coordinated ligands. Equivalent donor sets in both ligands are trans to each other, and DFT calculations suggest that the fac-trans configuration is favored by a small margin when compared to the fac-cis isomers. Both DFT calculations and EPR spectroscopy agree with a high-spin S=3/2 electronic configuration given by [ag1, b1g1, ag1, b2g2, b3g2]. This oxidation state was indirectly observed by the lack of a ppiphenolate-->dsigma*cobalt(III) charge-transfer band, which is found between 430 and 470 nm for similar cobalt(III) species. On the basis of the geometrical preferences and the oxidation state of archetypical 1 and 2, two metallosurfactants [CoII(LI-ODA)2] (3) and [CoII(LI-NOBA)2].CH2Cl2 (4) were obtained. The redox chemistry of 1-4 is marked by metal- and ligand-centered activity with several follow up processes and film formation on the electrode. Both metallosurfactants exhibit amphiphilic properties and organization, as shown by compression isotherms and Brewster angle microscopy but exhibit dissimilar collapse mechanisms; whereas 3 collapses at constant pressure, 4 exhibits a constant-area collapse. Langmuir-Blodgett films are readily obtained and were characterized by equilibrium contact angle and atomic force microscopy.
Hydrolysis of the asymmetric pyridine- and phenol-containing ligand HL (1) (2-hydroxy-4-6-di- tert-butylbenzyl-2-pyridylmethyl)imine) led to the use of bis-(3,5-di -tert-butyl-2-phenolato-benzaldehyde)copper(II), [Cu (II)(L (SAL)) 2] ( 1) as a precursor for bis-(2,4-di- tert-butyl-6-octadecyliminomethyl-phenolato)copper(II), [Cu (II)(L (2)) 2] ( 3), bis-(2,4-di- tert-butyl-6-octadecyl aminomethyl-phenolato)copper(II), [Cu (II)(L (2A)) 2] ( 3'), and bis-(2,4-di- tert-butyl-6-[(3,4,5-tris-dodecyloxy-phenylimino)-methyl]-phenolato)copper(II), [Cu (II)(L (3)) 2] ( 4). These complexes exhibit hydrophilic copper-containing head groups, hydrophobic alkyl and alkoxo tails, and present potential as precursors for redox-responsive Langmuir-Blodgett films. All systems were characterized by means of elemental, spectrometric, spectroscopic, and electrochemical techniques, and their amphiphilic properties were probed by means of compression isotherms and Brewster angle microscopy. Good redox activity was observed for 3 with two phenoxyl radical processes between 0.5 and 0.8 V vs Fc (+)/Fc, but this complex lacks amphiphilic behavior. To attain good balance between redox response and amphiphilicity, increased core flexibility in 3' and incorporation of alkoxy chains in 4 were attempted. Film formation with collapse at 14 mN.m (-1) was observed for the alkoxy-derivative but redox-response was seriously compromised. Core flexibility improved Langmuir film formation with a higher formal collapse and showed excellent cyclability of the ligand-based processes.
(9) were synthesized to model the stoichiometric, coordination, and protonation chemistry in the waxy metallosurfactants 1-4. Detailed data analysis and comparison between 1-4 and 5-9 involved mass spectrometric and spectroscopic methods along with crystallographic determination of 5 (P2 1 /c), 6 (P1), 7 (P2 1 /c), 8Ј (the analogue of 8 with tetraphenylborate counterions, P2 1 /c), and 9 (P1). DFT calculations were used to identify the frontier orbitals, polarizability, and dipole moments. Species 1-4 had their
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