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.