In vitro studies of 3-hydroxy-4-pyridinones and their glycosylated derivatives as potential agents for Alzheimer's disease.

Glycosides of 3-hydroxy-4-pyridinones were synthesized and characterized by mass spectrometry, elemental analysis, (1)H and (13)C NMR spectroscopy, and in one case by X-ray crystallography. The Cu(2+) complex of a novel 3-hydroxy-4-pyridinone was synthesized and characterized by IR and X-ray crystallography, showing the ability of these compounds to chelate potentially toxic metal ions. An MTT cytotoxicity assay of a selected glycosylated compound showed a relatively low toxicity of IC(50) = 570 +/- 90 microM in a human breast cancer cell line.

Glycosylated tetrahydrosalens as multifunctional molecules for Alzheimer's therapy.

The tetrahydrosalens N,N'-bis(2-hydroxybenzyl)-ethane-1,2-diamine ((2)(1)), N,N'-bis(2-hydroxybenzyl)-(-)-1,2-cyclohexane-(1R,2R)-diamine ((2)(2)), N,N'-bis(2-hydroxybenzyl)-N,N'-dimethyl-ethane-1,2-diamine ((2)(3)), N,N'-bis(2-hydroxybenzyl)-N,N'-dibenzyl-ethane-1,2-diamine ((2)(4)), and N,N'-bis(2-(4-tert-butyl)hydroxybenzyl)-ethane-1,2-diamine ((2)(5)), as well as their prodrug glycosylated forms, (1-5), have been prepared and evaluated in vitro for their potential use as Alzheimer's disease (AD) therapeutics. Dysfunctional interactions of metal ions, especially those of Cu, Zn, and Fe, with the amyloid-beta (Abeta) peptide are hypothesised to play an important role in the aetiology of AD, and disruption of these aberrant metal-peptide interactions via chelation therapy holds considerable promise as a therapeutic strategy. Tetrahydrosalens such as (2)(1-5) have a significant affinity for metal ions, and thus should be able to compete with the Abeta peptide for Cu, Zn, and Fe in the brain.

Vanadium treatment of type 2 diabetes: a view to the future.

3-Hydroxy-2-methyl-4-pyrone and 2-ethyl-3-hydroxy-4-pyrone (maltol and ethyl maltol, respectively) have proven especially suitable as ligands for vanadyl ions, in potential insulin enhancing agents for diabetes mellitus. Both bis(maltolato)oxovanadium(IV) (BMOV), and the ethylmaltol analog, bis(ethylmaltolato)oxovanadium(IV) (BEOV), have the desired intermediate stability for pro-drug use, and have undergone extensive pre-clinical testing for safety and efficacy. Pharmacokinetic evaluation indicates a pattern of biodistribution consistent with fairly rapid dissociation and uptake, binding to serum transferrin for systemic circulation and transport to tissues, with preferential uptake in bone.

One and two dimensional pulsed electron paramagnetic resonance studies of in vivo vanadyl coordination in rat kidney.

The biological fate of a chelated vanadium source is investigated by/n vivo spectroscopic methods to elucidate the chemical form in which the metal ion is accumulated. A pulsed electron paramagnetic resonance study of vanadyl ions in kidney tissue, taken from rats previously treated with bis(ethylmaltolato)oxovanadium(IV) (BEOV) in drinking water, is presented. A combined approach using stimulated echo (3-pulse) electron spin echo envelope modulation (ESEEM) and the two dimensional 4-pulse hyperfine sublevel correlation (HYSCORE) spectroscopies has shown that at least some of the VO(2+) ions are involved in the coordination with nitrogen-containing ligands.

Lanthanide containing compounds for therapeutic care in bone resorption disorders.

Lanthanide ions, Ln(III), are known functional mimics of Ca(II) ions and have been shown to affect the bone remodeling cycle. Exploiting this disruption to the bone remodeling cycle has potential for the treatment of bone density disorders, such as osteoporosis. In an effort to find new orally active agents for these disorders, a series of Ln(III) containing complexes incorporating small, non-toxic, bidentate pyrone and pyridinone ligands have been synthesized and characterized (LnL(3), Ln = La, Eu, Gd, Tb, Yb, L = 3-oxy-2-methyl-4-pyrone (ma(-)), 3-oxy-2-ethyl-4-pyrone (ema(-)), 3-oxy-1,2-dimethyl-4-pyridinone (dpp(-)) and 3-oxy-2-methyl-4(1H)-pyridinone (mpp(-))).

Synthesis, characterization, and metal coordinating ability of multifunctional carbohydrate-containing compounds for Alzheimer's therapy.

Dysfunctional interactions of metal ions, especially Cu, Zn, and Fe, with the amyloid-beta (A beta) peptide are hypothesized to play an important role in the etiology of Alzheimer's disease (AD). In addition to direct effects on A beta aggregation, both Cu and Fe catalyze the generation of reactive oxygen species (ROS) in the brain further contributing to neurodegeneration. Disruption of these aberrant metal-peptide interactions via chelation therapy holds considerable promise as a therapeutic strategy to combat this presently incurable disease.

Vanadium in diabetes: 100 years from Phase 0 to Phase I.

A little over one hundred years ago, a vanadium-containing compound was assessed clinically for use in treatment of human diabetic patients. The results were somewhat ambiguous, but nonetheless, intriguing. In 2000, the first Phase I clinical trial of a designed vanadium-based pharmaceutical agent (bis(ethylmaltolato)oxovanadium(IV), BEOV), was completed by Medeval Ltd.

Metal complexes of maltol and close analogues in medicinal inorganic chemistry.

The family of hydroxypyrones and close congeners, the hydroxypyridinones, is a particularly versatile class of ligands. The most widely investigated for medicinal applications are the 3-hydroxy-4-pyrones and the 1,2- 3,2- and 3,4-hydroxypyridinones. Key features of these ligands are: a six-membered ring, with a ring N or O atom either ortho or para to a ketone group, and two ortho exocyclic oxygen atoms.

Design of targeting ligands in medicinal inorganic chemistry.

This tutorial review will highlight recent advances in medicinal inorganic chemistry pertaining to the use of multifunctional ligands for enhanced effect. Ligands that adequately bind metal ions and also include specific targeting features are gaining in popularity due to their ability to enhance the efficacy of less complicated metal-based agents. Moving beyond the traditional view of ligands modifying reactivity, stabilizing specific oxidation states, and contributing to substitution inertness, we will discuss recent work involving metal complexes with multifunctional ligands that target specific tissues, membrane receptors, or endogenous molecules, including enzymes.

Editorial: lanthanide compounds for therapeutic and diagnostic applications.

The medical applications of lanthanides are diverse: MRI contrast agents, hypophosphatemic agents for kidney dialysis patients, luminescent probes in cell studies, and for palliation of bone pain in osteosarcoma.

Metal complexes in medicinal chemistry: new vistas and challenges in drug design.

An overview is presented of selected metal-based pharmaceuticals, either diagnostic or therapeutic, with emphasis on specific attributes and in vivo interactions of these compounds relevant to their use in medicinal applications. Both the advantages and the challenges of this approach are outlined, with possibilities for future developments accentuated.

Synthesis and characterization of dual function vanadyl, gallium and indium curcumin complexes for medicinal applications.

Novel bis[4-hydroxy-3-methoxyphenyl]-1,6-heptadiene-3,5-dione (curcumin) complexes with the formula, ML(3), where M is Ga(III) or In(III), or of the formula, ML(2) where M is [VO](2+), have been synthesized and characterized by mass spectrometry, infrared and absorption spectroscopies, and elemental analysis. A new ligand, bis[4-acetyl-3-hydroxyphenyl]-1,6-heptadiene-3,5-dione (diacetylbisdemethoxycurcumin, DABC) was similarly characterized; an X-ray structure analysis was performed. Vanadyl complexes tested in an acute i.

Coordination chemistry and insulin-enhancing behavior of vanadium complexes with maltol C6H6O3 structural isomers.

Syntheses of vanadium complexes using the naturally occurring ligands isomaltol (Hima) and allomaltol (Hama), as well as a newly synthesized, potentially tetradentate diaminodipyrone [H(2)(en(ama)(2)], are reported. Complete characterization of the resulting compounds [trans-VO(ima)(2)(H(2)O), VO(ama)(2), V(ima)(3), V(ama)(3) and VO(en(ama)(2))], including X-ray crystallography analyses for trans-VO(ima)(2)(H(2)O) and V(ima)(3), are presented herein. Potentiometric titrations (25 degrees C, I = 0.

Vanadium complexes with mixed O,S anionic ligands derived from maltol: synthesis, characterization, and biological studies.

Four mixed O,S binding bidentate ligand precursors derived from maltol (3-hydroxy-2-methyl-4-pyrone) have been chelated to vanadium to yield new bis(ligand)oxovanadium(IV) and tris(ligand)vanadium(III) complexes. The four ligand precursors include two pyranthiones, 3-hydroxy-2-methyl-4-pyranthione, commonly known as thiomaltol (Htma), and 2-ethyl-3-hydroxy-4-pyranthione, commonly known as ethylthiomaltol (Hetma), as well as two pyridinethiones, 3-hydroxy-2-methyl-4(H)-pyridinethione (Hmppt) and 3-hydroxy-1,2-dimethyl-4-pyridinethione (Hdppt). Vanadium complex formation was confirmed by elemental analysis, mass spectrometry, and IR and EPR (where possible) spectroscopies.

New insights into the interactions of serum proteins with bis(maltolato)oxovanadium(IV): transport and biotransformation of insulin-enhancing vanadium pharmaceuticals.

Significant new insights into the interactions of the potent insulin-enhancing compound bis(maltolato)oxovanadium(IV) (BMOV) with the serum proteins, apo-transferrin and albumin, are presented. Identical reaction products are observed by electron paramagnetic resonance (EPR) with either BMOV or vanadyl sulfate (VOSO4) in solutions of human serum apo-transferrin. Further detailed study rules out the presence of a ternary ligand-vanadyl-transferrin complex proposed previously.

Complementary inhibition of synoviocyte, smooth muscle cell or mouse lymphoma cell proliferation by a vanadyl curcumin complex compared to curcumin alone.

A novel vanadyl curcumin complex (VO(cur)2) has been synthesized and and its physicochemical properties characterized. Biological characterization included in vitro testing for anti-rheumatic activity in synoviocytes, angiogenesis inhibition in smooth muscle cells and anti-cancer potential in mouse lymphoma cells; as well as in vivo testing for hypoglycemic activity by oral gavage in streptozotocin (STZ)-diabetic rats. VO(cur)2 was more effective as an anti-cancer agent, compared to uncomplexed curcumin or vanadyl ion alone, was more than twice as effective as curcumin alone as an anti-arthritic agent, and was more than four times as effective as curcumin alone in inhibiting smooth muscle cell proliferation.

Comparison of anti-hyperglycemic effect amongst vanadium, molybdenum and other metal maltol complexes.

A wide variety of vanadium-containing complexes have been tested, both in vivo and in vitro, as possible therapeutic agents for the oral treatment of type 2 diabetes mellitus. None so far has surpassed bis(maltolato)oxovanadium(IV) (BMOV) for glucose- and lipid-lowering in an orally available formulation. Ligand choice is clearly an important factor in pharmacological efficacy of vanadium compounds as insulin enhancing agents.

Boon and bane of metal ions in medicine.

In biological systems metal ions promote responses that range from deficiency to toxicity. Some, such as iron and zinc, have a known optimal intake range for normal, healthy individuals. Metal ions contained within well-designed molecules already constitute a great boon for the medicinal pharmacopoeia.

Vanadyl-thiazolidinedione combination agents for diabetes therapy.

A series of vanadium compounds, chelated by ligands containing a thiazolidinedione moiety as an additional insulin-enhancing component, were produced in this study to create potentially synergistic compounds. A set of four bifunctional ligand precursors were synthesized: (+/-)-5-[4-[(5-hydroxy-4-oxo-4H-pyran-2-ylmethyl)amino]benzyl]thiazolidine-2,4-dione (HL(1)), (+/-)-5-[4-[(5-hydroxy-1-methyl-4-oxo-1,4-dihydro-pyridin-2-ylmethyl)amino]benzyl]thiazolidine-2,4-dione (HL(2)), 5-[4-(5-hydroxy-4-oxo-4H-pyran-2-ylmethoxy)benzylidene]thiazolidine-2,4-dione (HL(3)), and (+/-)-5-[4-(5-hydroxy-4-oxo-4H-pyran-2-ylmethoxy)benzyl]thiazolidine-2,4-dione (HL(4)), each containing a metal chelating portion as well as a thiazolidinedione moiety. From this set of ligand precursors, air-stable VO(L(1))(2), VO(L(3))(2), and VO(L(4))(2) were prepared.

Influence of chelation and oxidation state on vanadium bioavailability, and their effects on tissue concentrations of zinc, copper, and iron.

Today, vanadium compounds are frequently included in nutritional supplements and are also being developed for therapeutic use in diabetes mellitus. Previously, tissue uptake of vanadium from bis(maltolato)oxovanadium(IV) (BMOV) was shown to be increased compared to its uptake from vanadyl sulfate (VS). Our primary objective was to test the hypothesis that complexation increases vanadium uptake and that this effect is independent of oxidation state.