Lauren E. Scott

Medicinal Inorganic Chemistry Approaches to Passivation and Removal of Aberrant Metal Ions in Disease

The field of medicinal inorganic chemistry has evolved with three conceptual aims: the introduction of metal ions to the biological system, manipulation and redistribution of metal ions within the system, and removal of metal ions from the system. This review focuses on the latter two goals: binding of metal ions for redistribution or removal. Metal ions play a pivotal role in the development and pathology of a range of conditions and, in some cases, are implicated in redox chemistry leading to oxidative stress. This review places particular focus on Alzheimer’s disease (AD) with additional coverage of Parkinson’s disease (PD), Friedreich’s ataxia (FRDA), transfusion-related iron overload, and Wilson’s disease (WD). All of these conditions involve elevated levels of metal ions in particular tissues or cell compartments of the body and present challenges in the field of medicinal inorganic chemistry to present, among other possible interventions, new chelators for therapeutic application.

N-Aryl-substituted 3-(β-D-glucopyranosyloxy)-2-methyl-4(1H)-pyridinones as agents for Alzheimer's therapy

Molecules designed to sequester, redistribute and/or remove metal ions are attractive therapeutic agents in neurodegenerative diseases such as Alzheimers disease. The multifactorial nature of the condition and the generally poor target specificity associated with metal ion-binding therapy has led to the development of multifunctional 3-hydroxy-4-(1H)-pyridinone pro-ligands. The excellent qualities of the basic 3-hydroxy-4-pyridinone framework as a low toxicity metal chelator and an antioxidant, as well as its antibacterial and analgesic properties among other functions, inspired us to functionalize it with a framework derived from thioflavin-T, the well-known traditional dye used as a marker to detect amyloid deposits in tissue sections. Thus 2-methyl-3-hydroxy-1-(4-dimethylaminophenyl)-4(1H)-pyridinone (HL1), 2-methyl-3-hydroxy-1-(4-methylaminophenyl)-4(1H)-pyridinone (HL2), 1-(4-aminophenyl)-3-hydroxy-2-methyl-4(1H)-pyridinone (HL3), 1-(6-benzothiazolyl)-3-hydroxy-2-methyl-4(1H)-pyridinone (HL4), 1-(2-benzothiazolyl)-3-hydroxy-2-methyl-4(1H)-pyridinone (HL5) and 2-methyl-3-hydroxy-1-[4-(4-bromophenyl)-2-thiazolyl]-4(1H)-pyridinone (HL6) were obtained. Glycosylation, as well as incorporation of structures mimicking those of known amyloid imaging agents, may target drug action to the site of interest, the metal-overloaded amyloid plaques in the Alzheimers brain. The pro-ligands were assessed for their antioxidant activity, cytotoxicity and ability to interfere with metal ion-induced amyloid peptide aggregation to screen promising lead compounds. Finally, in a brain uptake study with a radiolabeled glucoconjugate pyridinone, 3-(β-D-glucopyranosyloxy)-1-[4-(4-[125I]iodophenyl)-2-thiazolyl]-2-methyl-4(1H)-pyridinone ([125I]-GL7) was shown to cross the blood–brain barrier using an in situ rat brain perfusion technique.

Altering pyridinone N-substituents to optimise activity as potential prodrugs for Alzheimer's disease

Selective design modifications of specifically substituted 3-hydroxy-4(1H)-pyridinones show possibly advantageous ring freedom while maintaining metal-binding ability and antioxidant capacity, moving toward an efficient potential treatment for Alzheimers disease.

Synthesis, characterization, and cytotoxicity studies of Cu(II), Zn(II), and Fe(III) complexes of N-derivatized 3-hydroxy-4-pyridiones

The deleterious role of metal ions in Alzheimers disease has inspired the study of various metal chelators. We previously showed the synthesis and in vitro activity of several bidentate hydroxypyridinone compounds, including 3-hydroxy-2-methyl-1-phenyl-4(1H)-pyridinone (1), 1-(4-aminophenyl)-3-hydroxy-2-methyl-4(1H)-pyridinone (2), and 1-(2-benzothiazolyl)-3-hydroxy-2-methyl-4(1H)-pyridinone (3). While the focus has been on the Cu(II) ion, the other biorelevant metals, Zn(II) and Fe(III) have been largely neglected. Herein, we report the synthesis of Zn(II) and Fe(III) complexes of ligands 1, 2, and 3, and their characterization by infrared (IR) spectroscopy, high resolution mass spectrometry (HR-MS), elemental analysis, and NMR, where applicable. Solid state structures of Zn(1)2, Fe(1)3, and Cu(3)2 are analyzed with X-ray crystallography. The cytotoxicity of pro-ligands 1, 2, and 3, and the three metal complexes of 2 are examined in a neuronal cell line to determine the effect of metal chelation on toxicity of the compounds.

3-Hydroxy-4-pyridinone derivatives designed for fluorescence studies to determine interaction with amyloid protein as well as cell permeability.

Finding a cure for Alzheimers disease is an urgent goal. Multifunctional metal binders are used to elucidate its pathological features and investigated as potential therapeutics. The use of physicochemical and TD-DFT calculations constituted successful strategy in the design of 1-(4-(benzo[d]oxazol-2-yl)phenyl)-3-hydroxy-2-methylpyridin-4(1H)-one (HL21) and 1-(4-(benzo[d]thiazol-2-yl)phenyl)-3-hydroxy-2-methylpyridin-4(1H)-one (HL22). We report the synthesis and full characterization of these compounds, including X-ray crystallography. Using fluorescent signal as the readout, it was determined that HL22 interacts with amyloid-beta protein fibrils, and permeates into bEnd.3 cells used as a mimic of the blood-brain barrier. This provides the first example of direct investigation of our hydroxypyridinone compounds within a biological setting.

Community-Based Interventions in Asthma

Community and public health interventions provide potentially powerful means of decreasing morbidity, hospitalizations, emergency room visits, and mortality from asthma. This chapter thus provides an overview of community-based interventions, which have been demonstrated to be effective-and/or ineffective-in reducing the burden of disease, including development of asthma coalitions, interventions for both provider and patient education, environmental controls to reduce exposure to asthma triggers, and institutional policy and systems change. Perhaps most important is the demonstrated effect of integrated, comprehensive approaches to asthma management and control. A multidisciplinary approach spanning T1 through T4 translational research, coupled with public health activities is promising and has already demonstrated success in reducing the burden of disease.