Chris Orvig

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.

Coordination chemistry of vanadium in metallopharmaceutical candidate compounds

Abstract The discovery of vanadiums insulin-like behaviour in vitro, and later of the orally available glucose- and lipid-lowering capability of these same compounds in vivo, has stimulated renewed interest in vanadium coordination chemistry. Besides the anti-diabetic effects for which it is now so well known, vanadium also exhibits a number of other therapeutic effects including anti-tumour and anti-inflammatory activities. In this review, emphasis will be on the most recent developments in the coordination chemistry of vanadium(III), (IV) and (V), as related to development of these compounds for pharmaceutical use. How best to measure bioactivity and the pharmaceutical relevance of accompanying increased oxidative stress will also be considered.

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.

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 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.

Tumour targeting with radiometals for diagnosis and therapy

Use of radiometals in nuclear oncology is a rapidly growing field and encompasses a broad spectrum of radiotracers for imaging via PET (positron emission tomography) or SPECT (single-photon emission computed tomography) and therapy via α, β(-), or Auger electron emission. This feature article opens with a brief introduction to the imaging and therapy modalities exploited in nuclear medicine, followed by a discussion of the multi-component strategy used in radiopharmaceutical development, known as the bifunctional chelate (BFC) method. The modular assembly is dissected into its individual components and each is discussed separately. The concepts and knowledge unique to metal-based designs are outlined, giving insight into how these radiopharmaceuticals are evaluated for use in vivo. Imaging nuclides (64)Cu, (68)Ga, (86)Y, (89)Zr, and (111)In, and therapeutic nuclides (90)Y, (177)Lu, (225)Ac, (213)Bi, (188)Re, and (212)Pb will be the focus herein. Finally, key examples have been extracted from the literature to give the reader a sense of breadth of the field.

Acyclic Chelate with Ideal Properties for 68Ga PET Imaging Agent Elaboration

We have investigated novel bifunctional chelate alternatives to the aminocarboxylate macrocycles NOTA (N(3)O(3)) or DOTA (N(4)O(4)) for application of radioisotopes of Ga to diagnostic nuclear medicine and have found that the linear N(4)O(2) chelate H(2)dedpa coordinates (67)Ga quantitatively to form [(67)Ga(dedpa)](+) after 10 min at RT. Concentration-dependent coordination to H(2)dedpa of either (68)Ga or (67)Ga showed quantitative conversion to the desired products with ligand concentrations as low as 10(-7) M. With (68)Ga, specific activities as high as 9.8 mCi nmol(-1) were obtained without purification. In a 2 h competition experiment against human apo-transferrin, [(67)Ga(dedpa)](+) showed no decomposition. Two bifunctional versions of H(2)dedpa are also described, and these both coordinate to (67)Ga at RT within 10 min. Complete syntheses, characterizations, labeling studies, and biodistribution profiles of the (67)Ga complexes are presented for the new platform chelates. The stability of these platform chelates is higher than that of DOTA.

Glucose-lowering properties of vanadium compounds: Comparison of coordination complexes with maltol or kojic acid as ligands

Bis(kojato)oxovanadium(IV) [abbreviated VO(ka)2], a close chemical analog of the insulin-mimetic lead compound bis(maltolato)oxovanadium(IV)--abbreviated BMOV or VO(ma)2--is reported and its reaction chemistry and insulin-mimetic properties are presented. VO(ka)2 [log K1 = 7.61(10), log K2 = 6.89(6), log beta 2 = 14.50(16)] has a reaction chemistry which directly parallels that of VO(ma)2. In aqueous solution it is more slowly oxidized by molecular oxygen to [VO2(ka)2]- than is VO(ma)2 to [VO2(ma)2]-. Variable pH electrochemistry and variable pH 51V NMR of solutions of VO(ka)2 are presented and contrasted with the corresponding results for VO(ma)2. Time course studies (24 hr) in STZ-diabetic rats following the oral or i.p. administration of VO(ka)2, VO(ma)2, VO2+ (vanadyl) as vanadyl sulfate (VOSO4), and [VO2(ma)2]- as its [NH4]+ salt have been performed, as have chronic oral studies comparing VO(ka)2 and VO(ma)2 over a six week period. In all studies, the most potent form of vanadium was the neutrally charged, water soluble, complex VO(ma)2.

Cellular Transport Mechanisms of Cytotoxic Metallodrugs: An Overview beyond Cisplatin

The field of medicinal inorganic chemistry has grown consistently during the past 50 years; however, metal-containing coordination compounds represent only a minor proportion of drugs currently on the market, indicating that research in this area has not yet been thoroughly realized. Although platinum-based drugs as cancer chemotherapeutic agents have been widely studied, exact knowledge of the mechanisms governing their accumulation in cells is still lacking. However, evidence suggests active uptake and efflux mechanisms are involved; this may be involved also in other experimental metal coordination and organometallic compounds with promising antitumor activities in vitro and in vivo, such as ruthenium and gold compounds. Such knowledge would be necessary to elucidate the balance between activity and toxicity profiles of metal compounds. In this review, we present an overview of the information available on the cellular accumulation of Pt compounds from in vitro, in vivo and clinical studies, as well as a summary of reports on the possible accumulation mechanisms for different families of experimental anticancer metal complexes (e.g., Ru Au and Ir). Finally, we discuss the need for rationalization of the investigational approaches available to study metallodrug cellular transport.

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.