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., Manchester, UK. Results here, too, were promising, but not without some difficult remaining questions. In this review, we look back at the many questions asked and answered regarding vanadium's glucose-enhancing potential, its biodistribution and biomolecular transformation, and its mechanism(s) of action, and consider some of the newest developments in the field, including novel delivery methods for vanadium in diabetes treatment.

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.p. testing protocol in STZ-diabetic rats showed a lack of insulin enhancing potential. Vanadyl complexes were, however, more cytotoxic than were the ligands alone in standard MTT (3-[4,5-dimethylthiazole-2-yl]ate, -2,5-diphenyl-tetrazolium bromide) cytotoxicity testing, using mouse lymphoma cells. With the exception of DABC, that was not different from VO(DABC)(2), the complexes were not significantly different from one another, with IC(50) values in the 5-10 microM range. Gallium and indium curcumin complexes had IC(50) values in the same 5-10 microM range; whereas Ga(DAC)(3) and In(DAC)(3) (where DAC=diacetylcurcumin) were much less cytotoxic (IC(50)=20-30 microM). Antioxidant capacity was decreased in VO(DAC)(2), Ga(DAC)(3), and In(DAC)(3), compared to vanadyl, gallium and indium curcumin, corroborating the importance of curcumin's free phenolic OH groups for scavenging oxidants, and correlated with reduced cytotoxic potential.

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. In this study, we kept the ligand and dose the same, varying instead the metal ion bound to the maltolato ligand in a series of binary complexes of neutral charge. A requirement for vanadyl ion as the metal ion of choice was apparent; no other metal ion tested served as a suitable substitute. Amongst [MoO(2)](2+), Co(II), Cu(II), Cr(III), and Zn(II), only [MoO(2)](2+) and Co(II) showed any hypoglycemic activity at the ED(50) dose for bis(maltolato)oxovanadium(IV), 0.6 mmolkg(-1) by oral gavage in streptozotocin (STZ)-diabetic rats within 72 h of administration of compound.

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. In both acute and chronic screening tests, VO(cur)2 was ineffective as an insulin mimetic agent; however, it also proved to be exceptionally non-toxic, with no evidence of negative symptomatology during a month-long treatment period, at doses up to and including 2.0 mmol kg(-1) day(-1).

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. A secondary objective was to compare the effects of vanadium complexation and oxidation state on tissue iron, copper, and zinc. Wistar rats were fed either ammonium metavanadate (AMV), VS, or BMOV (1.2 mM each in the drinking water). Tissue uptake of V following 12 wk of BMOV or AMV was higher than that from VS (p < 0.05). BMOV led to decreased tissue Zn and increased bone Fe content. The same three compounds were compared in a cellular model of absorption (Caco-2 cells). Vanadium uptake from VS was higher than that from BMOV or AMV at 10 min, but from BMOV (250 microM only, 60 min), uptake was far greater than from AMV or VS. These results show that neither complexation nor oxidation state alone are adequate predictors of relative absorption, tissue accumulation, or trace element interactions.

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. The pyridinone glycosides could be cleaved by a broad specificity beta-glycosidase, Agrobacterium sp.beta-glucosidase, and for one compound k(cat) and K(m) were determined to be 19.8 s(-1) and 1.52 mM, respectively. Trolox Equivalent Antioxidant Capacity (TEAC) values were determined for the free pyridinones, indicating the good antioxidant properties of these compounds. Metal-Abeta(1-40) aggregates with zinc and copper were resolubilized by the non-glycosylated pyridinone ligands.

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. These bis-ligand oxovanadium(IV) (VOL(2)) compounds have a clear advantage over inorganic vanadyl sulfate in terms of bioavailability and pharmaceutical efficacy. BEOV has now completed Phase I and has advanced to Phase II clinical trials. In the Phase I trial, a range of doses from 10 mg to 90 mg BEOV, given orally to non-diabetic volunteers, resulted in no adverse effects; all biochemical parameters remained within normal limits. In the Phase IIa trial, BEOV (AKP-020), 20 mg, daily for 28 days, per os, in seven type 2 diabetic subjects, was associated with reductions in fasting blood glucose and %HbA1c; improved responses to oral glucose tolerance testing, versus the observed worsening of diabetic symptoms in the two placebo controls.

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. This activity was assayed in vitrovia a turbidity assay; (2)(1) and (2)(3) were found to attenuate Abeta(1-40) aggregation after exposure to Cu(2+) and Zn(2+). In addition, (2)(1-5) were determined to be potent antioxidants on the basis of an in vitro antioxidant assay. (1-5) were prepared as metal binding prodrugs; glycosylation is intended to prevent systemic metal binding, improve solubility, and enhance brain uptake. Enzymatic (beta-glucosidase) deprotection of the carbohydrate moieties was facile, with the exception of (4), demonstrating the general feasibility of this prodrug approach. Finally, a representative prodrug, (3), was determined to be non-toxic over a large concentration range in a cell viability assay.

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(-))). Preliminary biological analysis included cytotoxicity, cell uptake and bidirectional transport studies in Caco-2 cells and in vitro hydroxyapatite (HA) binding studies. The proportion of intact compounds bound to HA was calculated based on determination of Ln(III) concentration by ICP-MS and by UV-vis spectrophotometric assay of the proligand in solution. The LnL(3) species were found to have IC(50) values at least 6 times greater than that of cisplatin, >or= 98% HA-binding capacity, and permeability coefficients in the moderate range. La(dpp)(3) was ascertained to be the lead compound for the treatment of bone density disorders with the highest percentage cell uptake of 9.07 +/- 2.33% and the highest preliminary P(app) value of 3.54 +/- 2.86 x 10(-6) cm s(-1) compared to the other LnL(3) complexes tested.

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. To this end, we developed two multifunctional carbohydrate-containing compounds N,N'-bis[(5-beta-D-glucopyranosyloxy-2-hydroxy)benzyl]-N,N'-dimethyl-ethane-1,2-diamine (H2GL1) and N,N'-bis[(5-beta-D-glucopyranosyloxy-3-tert-butyl-2-hydroxy)benzyl]-N,N'-dimethyl-ethane-1,2-diamine (H2GL2) for brain-directed metal chelation and redistribution. Acidity constants were determined by potentiometry aided by UV-vis and 1H NMR measurements to identify the protonation sites of H2GL1,2. Intramolecular H bonding between the amine nitrogen atoms and the H atoms of the hydroxyl groups was determined to have an important stabilizing effect in solution for the H2GL1 and H2GL2 species. Both H2GL1 and H2GL2 were found to have significant antioxidant capacity on the basis of an in vitro antioxidant assay. The neutral metal complexes CuGL1, NiGL1, CuGL2, and NiGL2 were synthesized and fully characterized. A square-planar arrangement of the tetradentate ligand around CuGL2 and NiGL2 was determined by X-ray crystallography with the sugar moieties remaining pendant. The coordination properties of H2GL1,2 were also investigated by potentiometry, and as expected, both ligands displayed a higher affinity for Cu2+ over Zn2+ with H2GL1 displaying better coordinating ability at physiological pH. Both H2GL1 and H2GL2 were found to reduce Zn2+- and Cu2+- induced Abeta1-40 aggregation in vitro, further demonstrating the potential of these multifunctional agents as AD therapeutics.

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.

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.

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. Readily functionalizable, the hydroxypyrones and hydroxypyridinones allow one to achieve a range of di- and trivalent metallocomplex stabilities and can include tissue or molecular targeting features by design. Research over the past several decades has greatly expanded the array of ligands that are the subject of this critical review. Ligand applications as diverse as iron removal or supplementation, contrast agents in imaging applications, and mobilization of undesirable excess metal ions will be surveyed herein.

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. By contrast, differences in reaction products are observed for the interactions of BMOV and VOSO4 with human serum albumin (HSA), wherein adduct formation between albumin and BMOV is detected. In BMOV-albumin solutions, vanadyl ions are bound in a unique manner not observed in comparable solutions of VOSO4 and albumin. Presentation of chelated vanadyl ions precludes binding at the numerous nonspecific sites and produces a unique EPR spectrum which is assigned to a BMOV-HSA adduct. The adduct species cannot be produced, however, from a solution of VOSO4 and HSA titrated with maltol. Addition of maltol to a VOSO4-HSA solution instead results in formation of a different end product which has been assigned as a ternary complex, VO(ma)(HSA). Furthermore, analysis of solution equilibria using a model system of BMOV with 1-methylimidazole (formation constant log K1 = 4.5(1), by difference electronic absorption spectroscopy) lends support to an adduct binding mode (VO(ma)2-HSA) proposed herein for BMOV and HSA. This detailed report of an in vitro reactivity difference between VOSO4 and BMOV may have bearing on the form of active vanadium metabolites delivered to target tissues. Albumin binding of vanadium chelates is seen to have a potentially dramatic effect on pharmacokinetics, transport, and efficacy of these antidiabetic chelates.

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. The X-ray structure of oxobis(thiomaltolato)vanadium(IV),VO(tma)(2), was also determined; both cis and trans isomers were isolated in the same asymmetric unit. In both isomers, the two thiomaltolato ligands are arranged around the base of the square pyramid with the V=O linkage perpendicular; the vanadium atom is slightly displaced from the basal plane [V(1) = 0.656(3) A, V(2) = 0.664(2) A]. All of the new complexes were screened for insulin-enhancing effectiveness in streptozotocin-induced diabetes in rats, and VO(tma)(2) was profiled metabolically for urinary vanadium and ligand clearance by GFAAS and ESIMS, respectively. The new vanadium complexes did not lower blood glucose levels acutely, possibly because of rapid dissociation and excretion.

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 = 0.16 M NaCl) were used to measure stability constants in the V(IV)-Hima system; these data were compared to previous data collected on the V(IV)-L (L = Hma, Hama) systems. The in vivo efficacy of these compounds to lower the blood glucose levels of STZ-diabetic rats was tested; all but VO(en(ama)(2)) produced significant decreases in plasma glucose levels. The results were compared to those of the benchmark compound BMOV [VO(ma)(2), bis(maltolato)oxovanadium(IV)], a known insulin-enhancing agent.

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. However, whether essential or not, the threshold for toxicity can be very low. One of the challenges of designing metal-based drugs is to balance the potential toxicity of an active formulation with the substantial positive impact of these increasingly common therapeutic and diagnostic aids.