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Metal complexes in medicinal chemistry: new vistas and challenges in drug design
Katherine H. Thompson and Chris Orvig*
Received 26th September 2005, Accepted 26th October 2005 First published as an Advance Article on the web 23rd November 2005 DOI: 10.1039/b513476e An overview is presented of selected metal-based pharmaceuticals, either diagnostic or therapeutic, with emphasis on specic 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.

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Introduction
Medicinal inorganic chemistry is a fairly recent offshoot of bioinorganic chemistry, itself a science still with much to learn. It is at the interface between medicine and inorganic chemistry, and includes metal-based drugs, metal sequestering or mobilizing agents, metal-containing diagnostic aids, and the medicinal recruitment of endogenous metal ions. The number of moderately comprehensive reviews of the topic can still be counted on the ngers of one hand;15 however, the eld is growing exponentially.6 Rapid growth stems from some spectacular successes, most notably cisplatin for treatment of testicular cancer, gadolinium complexes in magnetic resonance imaging (MRI), and the rise of nuclear medicine, for both therapy and diagnosis. The use of metals in medical practice is certainly not in and of itself anything new. The lure of precious metals, such as gold and silver, attracted ancient Chinese, Egyptian, Greek and Indian healers to use them in cures of various sorts. Copper and iron have also been used since antiquity in metal-based therapies. There has always been a curious connection between the discovery of a
Medicinal Inorganic Chemistry Group, Department of Chemistry, University of British Columbia, Vancouver, BC, Canada V6T 1Z1. E-mail: orvig@chem.ubc.ca; Fax: +1 604 822 2847; Tel: +1 604 822 4449

new precious element and its quick movement into the medicinal armamentarium.1 Today, therapeutic applications of inorganic chemistry in medicine are varied, encompassing many aspects of the introduction of metal ions into the body (or their intentional removal) for therapeutic or diagnostic effect.2 Cisplatin can be considered the archetypal inorganic drug, as it contains not one atom of carbon.7 Nonetheless, most metal-based pharmaceuticals today are constructed with carbon-based ligands.

Design of ligands for metal-based pharmaceuticals The importance of ligands in modifying the biological effects of metal-based drugs cannot be overestimated.5 Ligands can modify the oral/systemic bioavailability of metal ions, can assist in targeting specic tissues or enzymes; can deliver, protect, or sequester a particular metal ion, depending on the requirements, for therapy or diagnosis. Ligands can also ensure protection of tissues from toxic metal ions or, in a contrasting strategy, enhance uptake of pharmacologically benecial metal ions.8 Ligands can, of course, also serve in the traditional coordination chemistry capacities of modifying reactivity and/or substitutional inertness.

Katherine Thompson studied at UBC (PhD, 1991), followed by postdoctoral appointments at UBC, and then Western Human Nutrition Research Center, ARS-USDA (Presidio of San Francisco, CA), prior to her appointment as research associate in the Department of Chemistry at UBC in 1996. Her interests are in human trace mineral metabolism and metal-based prodrug development. Chris Orvig earned his PhD at M.I.T. (1981) and after two years at UC Berkeley and one year at McMaster University, he joined the Department of Chemistry at the University of British Columbia (UBC), where he has been ever since. His interests are rmly planted in the areas of medicinal inorganic chemistry, radiopharmaceuticals and coordination chemistry. Katherine H. Thompson Chris Orvig

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Addition of substitutents that either bind preferentially to membrane receptors (e.g., glycosyl moieties, see Fig. 1), or mimic naturally-occurring hormones (e.g. somatostatin-like oligopeptides),9 assist in rendering ligands with designed target specicity, to yield far-reaching diagnostic and therapeutic implications.

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Fig. 1 Model of (2-(bis(2-pyridinylmethyl)amino)ethyl-b-D-glucoypyranosyl)-tricarbonylrhenium chloride, a metal-based prodrug functionalized with a pendant carbohydrate for improved tissue targeting. (Reprinted with permission from ref. 10 C 2005, ACS).

Medicinal inorganic chemistry has taken advantage of carbohydrate-appended (or derived) ligands to improve solubility and molecular targeting of drug candidates. In the tricarbonylbound rhenium(VI) dipicolylamines, an asymmetric carbohydrate substituent that is appended, rather than bound directly to the metal ion, permits tumour targeting without compromising metal ligand binding stability. Other examples of metal-based glycoconjugate medicinal agents include carbohydrate-linked cisplatin analogues as anticancer agents,11 MRI agents targeting specic glycosyl receptors,12 and 99m Tc-based single photon emission computed tomography (SPECT) imaging agents.13,14 Synergistic ligands for enhanced functionality Another type of ligand functionality can be achieved by utilizing ligands that are pharmaceutically active in and of themselves, thus incorporating multifunctionality within a single molecule. Examples include ketoconazole and clotrimazole as ligands for Cu(II), Ru(II) and Au(I) for more effective anti-malarial compounds, (compared to non-metal containing analogues) and antitrypanosome therapeutics (Fig. 2).15 Other examples in development include vanadium-based thiazolidinedione compounds for diabetes therapy16 and gold-based curcumin compounds as antiarthritics.17 Appreciation is growing for the roles of the ligand(s) in metalbased therapeutic compounds, as distinct from those in metalbased diagnostic agents. Specically, in diagnostic agents based on metal ions which may be toxic when unprotected, substitutional inertness can be a valuable property.18,19 For therapeutic agents, on the other hand, biomolecular rearrangement can be expected, and even be considered an advantage.8 In both cases, portions of the ligand may be designed to serve as targeting agents, either towards a particular tissue, or an enzyme.20 In diagnostic agents, the whole molecule can usually be expected to remain intact, from administration through to excretion. Not so in metal-based
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Fig. 2 Molecular diagram (35% displacement ellipsoids) of the cation of Cu(CTZ)4 ]Cl2 2H2 O, where CTZ = 1-[[(2-chlorophenyl)diphenyl]methyl]-1H -imidazole (clotrimazole). (Reprinted with permission from ref. 15 C 2001, ACS.).

therapeutics, some of which would not even function if they remained intact indenitely.

Oxidation state as a critical factor in bioavailability of metal-based drugs Besides ligand choice, another critical factor in design of a metallopharmaceutical is oxidation state.21 The oxidation state of the metal ion can be decisive in regulating the immediate in vivo response to metal-based pharmaceutical agents, often making the difference between a benecial and a toxic response at the same administered dose of a metal ion, and also directing towards the metabolic pathways by which the compound will be integrated. The oxidation state of the metal ion also dictates particular coordination geometries, hence limiting appropriate binding for different ligand sets. By optimizing choice of ligand(s) and oxidation state, investigators can build in control of kinetic and thermodynamic properties of metallopharmaceuticals for specic therapeutic needs.

Interactions with serum proteins The interaction of metallopharmaceuticals with serum proteins is an important aspect of metal-based drug metabolism, capable of strongly affecting the distribution and biotransformation, and ultimately the mechanism of action of the medicinal agent. The two key proteins for metal ions in human serum are transferrin and albumin. Apo-transferrin (apo-Tf), a bilobal single chain protein, is capable of tight reversible binding of two equivalents of Fe(III), and has been shown to bind a wide variety of other metal ions such as group 13,22,23 vanadyl24 and lanthanide ions.2528 This journal is The Royal Society of Chemistry 2006

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The other important protein, human serum albumin (HSA), is present at a considerably higher concentration (0.65 mM) than is apo-Tf (0.025 mM).29 It is a large globular protein that serves to transport hydrophobic metabolites, e.g. fatty acids, as well as metal ions, including Cu(II) and Zn(II).29 HSA-binding can, in fact, be used to advantage for medicinal inorganic applications. HSA-metal ion binding effects include delaying systemic clearance, and prevention of redox conversion. Thus, HSAbinding of gadolinium-based pharmaceuticals was used to increase the residence time of the latter in the blood, an advantage for ensuring adequate time for enhanced MRI contrast.30 Serum protein binding (especially HSAvanadyl binding) may also be crucial to anti-diabetic efcacy of bis(maltolato)oxovanadium(IV) (BMOV) (vide infra), both for delaying systemic clearance and for inhibition of redox conversion of vanadyl to vanadate species. Vanadium complexes in treatment of diabetes The discovery, in 1985, that a simple vanadium salt, sodium orthovanadate, added to drinking water, could reverse most of the diabetic symptomatology of experimentally-diabetic rats, was exceptionally enticing.31 Diabetes mellitus (DM) is a very complex metabolic disorder and, although injected insulin can alleviate many of the symptoms in an intermittent fashion, there is no simple cure that restores glucose homeostasis around the clock.32 The need for oral treatments for type 1 DM and new treatments for type 2 DM is compelling with the explosive increase in new cases of diabetes, especially type 2 DM. Secondary complications, the result of long-term excessive uctuations in glucose and insulin levels, are a major cause of morbidity in diabetes. Vanadiumcontaining compounds have shown considerable promise as orally available prodrugs that alleviate most of the symptoms of diabetes: high blood sugar, elevated lipid levels, and increasingly damaging secondary complications, including heart disease, cataracts, kidney disease and peripheral neuropathy.32 A crucial step in development of vanadium compounds for treatment of diabetes was the discovery that modication of the vanadium core by chelation could improve biodistribution and tolerability.33 BMOV (Fig. 3) is the rst (and so far unsurpassed) of a number of complexes that demonstrated superior activity over inorganic vanadium sources (e.g. VOSO4 or NaVO3 ) through both in vivo and/or in vitro assays of biological effectiveness.3436

Fig. 3 Bis(maltolato)oxovanadium(IV), BMOV, the rst purposedesigned vanadium-based insulin enhancing pharmaceutical agent.

With regard to serum protein binding differences, in the case of apo-Tf, no discernable differences are seen, comparing BMOV to VOSO4 , while for HSA binding, formation of a BMOV HSA adduct may represent an important difference between hydroxypyrone-chelated vanadyl and an inorganic vanadyl source. Provision of a chelated vanadyl source may lead to an inadvertent targeting effect, in that the presence of the chelating ligand augments the binding ability of the endogenous albumin. Ternary complex formation (i.e. one maltolato ligand and one vanadyl ion, bound to HSA) does not necessarily take place in vivo, where several low molecular weight bioligands (e.g. citrate, oxalate, nucleotides) are present, but it is at least feasible biochemically. Albumin binds one equivalent of VO2+ in the Cu(II) site at the Nterminus, likely through an imidazole, and several equivalents, via non-specic interactions with carboxylate side chains of surface amino acids. Adduct formation with HSA could also protect the complex from oxidation, while at the same time increasing relative efcacy by slowing transit time through the bloodstream.39 The rst human clinical (Phase I) trial was completed recently of a designed vanadium-based antidiabetic prodrug, bis(ethylmaltolato)oxovanadium(IV) (BEOV), the ethylmaltol analogue of BMOV (Fig. 3).37 The overall objective of this Phase I trial, carried out by Medeval Ltd. in Manchester, UK, was to assess the safety and tolerability of BEOV. Specic objectives were to: (1) assess the health effects of single, escalating doses of orally administered BEOV; (2) determine the pharmacokinetics of modest doses of BEOV from measured plasma, urinary and fecal [V]total ; (3) compare the bioavailability of a well-tolerated dose of oral BEOV and an equivalent molar dose of oral VOSO4 ; and (4) compare uptake in the fasted, compared to the fed, state. The outcome of this initial clinical trial were that there were no adverse health affects observed in any of the [nondiabetic] volunteers; gastrointestinal, liver and kidney function, and blood parameters all remained within normal levels throughout the study. Pharmacokinetic analysis showed a clear, non-proportional, dose-dependence in vanadium uptake from BEOV, along with a more rapid and efcient uptake compared to that from vanadyl sulfate.40 Fasted subjects absorbed more vanadium from BEOV than did fed subjects (by a large margin!). Lastly, the relative bioavailability of vanadium from BEOV was estimated to be three times that of an equivalent dose of vanadium from VOSO4 , corroborating earlier results in experimental animals.41 These results illustrate some of the unique challenges of developing metal-based pharmaceutical agents for treatment of chronic disease. Vanadium will never be a one-size-ts-all drug, as it requires titrating the dose to the individual patient, ensuring patient compliance, and monitoring metal ion accumulation; however, in a post-genomic environment of tailoring the drug (and the dose) of a prodrug to a particular patient, there may well be room for further development of vanadium-based antidiabetic agents as pharmaceuticals. Outlook Rapid advances in the eld of bioinorganic chemistry are increasingly making it possible to purposely design and synthesize metalbased pharmaceutical agents that serve valuable roles as diagnostic or therapeutic agents. Beyond choosing the correct metal ion for a particular application, the key to this process is nding a Dalton Trans., 2006, 761764 | 763

Rapid dissociation following an oral dose of chelated vanadyl maltol complexes seems to be required for oral activity.37 ESEEM evaluation of bone vanadium derived from oral BEOV (the ethylmaltol analogue of BMOV, vide infra) as well as other analytical evaluations, have shown that the complex is dissociated prior to tissue uptake.38 This journal is The Royal Society of Chemistry 2006

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suitable ligand for the job, whether to enhance uptake, to target a particular biomolecule, or to ensure that the metal ion remains securely sequestered, out of harms way. Many exciting developments currently in medicinal inorganic chemistry are in areas of imaging research,42 in which the nuclear and electronic properties of the metal ions are key factors in being able to visualize their presence in vivo, whether by uorescence, electronic properties, positron emission, or gamma emission. In all instances, secure binding of the metal ion, with appropriate targeting functionalities, is critical to the success of these agents.43 Some of the newest modalities being explored permit use of these molecules as reporters, e.g. for intracellular pH, O2 or Ca2+ concentration, or even specic enzyme activities.20,44 A new frontier in pharmaceutical research, glycobiology, that is also starting to have profound affects on research directions in medicinal inorganic chemistry, includes use of glycosyl substituents for enhanced tissue targeting, as outlined above. Pro-ligands for recruitment of endogenous metal ions, and an increasing variety of dual-use imaging/therapeutic agents, are some of the ground-breaking new applications being explored.

Acknowledgements
This research has been supported for many years by the Natural Sciences and Engineering Research Council of Canada and the Canadian Institutes of Health Research, as well as by numerous companies. The authors thank Dr Tim Storr for useful discussions in the preparation of this review.

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