Clioquinol, a Drug for Alzheimer's Disease Specifically Interfering with Brain Metal Metabolism:  Structural Characterization of Its Zinc(II) and Copper(II) Complexes

Vaira, Massimo Di; Bazzicalupi, Carla; Orioli, Pierluigi; Messori, Luigi; Bruni, B; Zatta, Paolo

doi:10.1021/ic0494051

Cited by 273 publications

(180 citation statements)

References 22 publications

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“…Indeed, no subsequent clinical trials have observed SMON in participants treated with clioquinol. Clioquinol has a moderate affinity for iron, copper, and zinc (Kd Cu is 1.2×10 -10 M, Kd Zn is 7×10 -8 M) [197], and for this reason it was explored as a drug for AD. Although it was initially considered a chelator [198][199][200][201], it has more recently been characterized as a copper/zinc ionophore, which functions to redistribute these metals into cells [196,[202][203][204][205][206].…”

Section: Clioquinol and Pbt2mentioning

confidence: 99%

Biometals and Their Therapeutic Implications in Alzheimer's Disease

2015

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No disease modifying therapy exists for Alzheimer's disease (AD). The growing burden of this disease to our society necessitates continued investment in drug development. Over the last decade, multiple phase 3 clinical trials testing drugs that were designed to target established disease mechanisms of AD have all failed to benefit patients. There is, therefore, a need for new treatment strategies. Changes to the transition metals, zinc, copper, and iron, in AD impact on the molecular mechanisms of disease, and targeting these metals might be an alternative approach to treat the disease. Here we review how metals feature in molecular mechanisms of AD, and we describe preclinical and clinical data that demonstrate the potential for metal-based drug therapy.

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Section: Clioquinol and Pbt2mentioning

confidence: 99%

Biometals and Their Therapeutic Implications in Alzheimer's Disease

2015

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“…Based on these results we employed the same functional and 378 basis set to investigate the structures of Cu(8-HQH) 2 and Cu(8-HQS) 2 , and compared 379 the results to the reported 1:2 metal:ligand structure for Cu(CQ) 2 . 87 The X-ray metricals 380 for Cu(CQ) 2 and the computed values are shown in Table 4. The predicted coordination 381 0.06 Å of the reported data for Cu(CQ) 2 .…”

Section: Theoretical Calculations Of the Cu II Complexes 372mentioning

confidence: 99%

8-Hydroxyquinoline Schiff-base compounds as antioxidants and modulators of copper-mediated Aβ peptide aggregation

Gomes

Vieira

Jones

et al. 2014

Journal of Inorganic Biochemistry

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“…Clioquinol is a lipohilic compound that is able to form stable complexes with copper (II) ions (135). To test this, we mixed CQ and CuCl 2 in a 1:1 molar ratio and an observable color change occurred, indicating that a chemical reaction had taken place (136).…”

Section: Clioquinolmentioning

confidence: 99%

New applications of old metal-binding drugs in the treatment of human cancer

Dou¹

2012

Front Biosci

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Significant advances in the use of metal complexes, precipitated by platinum, have fostered a renewed interest in harnessing their rich potential in the treatment of cancer. In addition to platinum-based complexes, the anticancer properties of other metals such as ruthenium have been realized, and ruthenium-based compounds are currently being investigated in clinical trials. Since the process of drug development can be expensive and cumbersome, finding new applications of existing drugs may provide effective means to expedite the regulatory process in bringing new drugs to the clinical setting. Encouraging findings from laboratory studies reveal significant anticancer activity from different classes of metal-chelating compounds, such as disulfiram, clioquinol, and dithiocarbamate derivatives that are currently approved for the treatment of various pathological disorders. Their use as coordination complexes with metals such as copper, zinc, and gold that target the ubiquitin-proteasome pathway have shown significant promise as potential anticancer agents. This review discusses the unique role of several selected metals in relation to their anti-cancer properties as well as the new therapeutic potential of several previously approved metal-chelating drugs. In vitro and in vivo experimental evidence along with mechanisms of action (e.g., via targeting the tumor proteasome) will also be discussed with anticipation of strengthening this exciting new concept. KeywordsDisulfiram; Clioquinol; Dithiocarbamates; Copper; Zinc; Ubiquitin-Proteasome Pathway; Proteasome Inhibitor; Chymotrypsin-Like Activity; Review INTRODUCTION The use of metal complexes for cancer treatmentThe development of metal-based complexes for the treatment of cancer began with the discovery of the anti-cancer properties of cisplatin in the early 1960s (Figure 1). Over 90% of testicular cancer cases have been cured by cisplatin, and it has also been important in the treatment of several other types of cancer, including ovarian, cervical, bladder, head and neck, melanoma, and lymphomas (1). Cisplatin interacts with DNA and forms adducts which interfere with the replication and transcription processes, and ultimately triggers apoptosis (2). These cisplatin-DNA interactions have been extensively studied, and it has been clearly shown that a (Pt)-GG intrastrand cross-link is responsible for the cytotoxicity of Send correspondence to: Qing Ping Dou, The Developmental Therapeutics Program, Barbara Ann Karmanos Cancer Institute, and Departments of Oncology, Pharmacology and Pathology, School of Medicine, Wayne State University, Detroit, Michigan 48201, USA, doup@karmanos.org. NIH Public Access Author ManuscriptFront Biosci (Schol Ed). Author manuscript; available in PMC 2013 May 07. Published in final edited form as:Front Biosci (Schol Ed). ; 4: 375-391. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript cisplatin (3). However, the toxicities associated with cisplatin, coupled with intrinsic and acquired drug resistance, ha...

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Clioquinol, a Drug for Alzheimer's Disease Specifically Interfering with Brain Metal Metabolism: Structural Characterization of Its Zinc(II) and Copper(II) Complexes

Cited by 273 publications

References 22 publications

Biometals and Their Therapeutic Implications in Alzheimer's Disease

Biometals and Their Therapeutic Implications in Alzheimer's Disease

8-Hydroxyquinoline Schiff-base compounds as antioxidants and modulators of copper-mediated Aβ peptide aggregation

New applications of old metal-binding drugs in the treatment of human cancer

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