FRONTIERS www.rsc.org/dalton | Dalton Transactions

Metal complexes in medicinal chemistry: new vistas and challengesin drug design

Katherine H. Thompson and Chris Orvig*

Received 26th September 2005, Accepted 26th October 2005First published as an Advance Article on the web 23rd November 2005DOI: 10.1039/b513476e

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 inmedicinal applications. Both the advantages and the challenges of this approach are outlined, withpossibilities for future developments accentuated.

Introduction

Medicinal inorganic chemistry is a fairly recent offshoot ofbioinorganic chemistry, itself a science still with much to learn. It isat the interface between medicine and inorganic chemistry, and in-cludes metal-based drugs, metal sequestering or mobilizing agents,metal-containing diagnostic aids, and the medicinal recruitment ofendogenous metal ions. The number of moderately comprehensivereviews of the topic can still be counted on the fingers of onehand;1–5 however, the field is growing exponentially.6 Rapid growthstems from some spectacular successes, most notably cisplatin fortreatment of testicular cancer, gadolinium complexes in magneticresonance imaging (MRI), and the rise of nuclear medicine, forboth therapy and diagnosis.

The use of metals in medical practice is certainly not in andof itself anything new. The lure of precious metals, such as goldand silver, attracted ancient Chinese, Egyptian, Greek and Indianhealers to use them in cures of various sorts. Copper and iron havealso been used since antiquity in metal-based therapies. Therehas always been a curious connection between the discovery of a

Medicinal Inorganic Chemistry Group, Department of Chemistry, Univer-sity of British Columbia, Vancouver, BC, Canada V6T 1Z1. E-mail:orvig@chem.ubc.ca; Fax: +1 604 822 2847; Tel: +1 604 822 4449

Katherine H. Thompson

Katherine Thompson studied at UBC (PhD, 1991), followed bypostdoctoral appointments at UBC, and then Western Human NutritionResearch Center, ARS-USDA (Presidio of San Francisco, CA), prior toher appointment as research associate in the Department of Chemistryat UBC in 1996. Her interests are in human trace mineral metabolismand metal-based prodrug development.

Chris Orvig earned his PhD at M.I.T. (1981) and after two yearsat UC Berkeley and one year at McMaster University, he joinedthe Department of Chemistry at the University of British Columbia(UBC), where he has been ever since. His interests are firmly planted inthe areas of medicinal inorganic chemistry, radiopharmaceuticals andcoordination chemistry.

Chris Orvig

new precious element and its quick movement into the medicinalarmamentarium.1

Today, therapeutic applications of inorganic chemistry inmedicine are varied, encompassing many aspects of the introduc-tion of metal ions into the body (or their intentional removal)for therapeutic or diagnostic effect.2 Cisplatin can be consideredthe archetypal inorganic drug, as it contains not one atom ofcarbon.7 Nonetheless, most metal-based pharmaceuticals todayare constructed with carbon-based ligands.

Design of ligands for metal-based pharmaceuticals

The importance of ligands in modifying the biological effectsof metal-based drugs cannot be overestimated.5 Ligands canmodify the oral/systemic bioavailability of metal ions, can assistin targeting specific tissues or enzymes; can deliver, protect, orsequester a particular metal ion, depending on the requirements,for therapy or diagnosis. Ligands can also ensure protection oftissues from toxic metal ions or, in a contrasting strategy, enhanceuptake of pharmacologically beneficial metal ions.8 Ligands can,of course, also serve in the traditional coordination chemistrycapacities of modifying reactivity and/or substitutional inertness.

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Addition of substitutents that either bind preferentiallyto membrane receptors (e.g., glycosyl moieties, see Fig. 1),or mimic naturally-occurring hormones (e.g. somatostatin-likeoligopeptides),9 assist in rendering ligands with designed targetspecificity, to yield far-reaching diagnostic and therapeutic impli-cations.

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

Medicinal inorganic chemistry has taken advantage ofcarbohydrate-appended (or derived) ligands to improve solubilityand molecular targeting of drug candidates. In the tricarbonyl-bound rhenium(VI) dipicolylamines, an asymmetric carbohydratesubstituent that is appended, rather than bound directly to themetal ion, permits tumour targeting without compromising metal–ligand binding stability. Other examples of metal-based glyco-conjugate medicinal agents include carbohydrate-linked cisplatinanalogues as anticancer agents,11 MRI agents targeting specificglycosyl receptors,12 and 99mTc-based single photon emissioncomputed tomography (SPECT) imaging agents.13,14

Synergistic ligands for enhanced functionality

Another type of ligand functionality can be achieved by utilizingligands that are pharmaceutically active in and of themselves,thus incorporating multifunctionality within a single molecule.Examples include ketoconazole and clotrimazole as ligands forCu(II), Ru(II) and Au(I) for more effective anti-malarial com-pounds, (compared to non-metal containing analogues) and anti-trypanosome therapeutics (Fig. 2).15 Other examples in develop-ment include vanadium-based thiazolidinedione compounds fordiabetes therapy16 and gold-based curcumin compounds as anti-arthritics.17

Appreciation is growing for the roles of the ligand(s) in metal-based therapeutic compounds, as distinct from those in metal-based diagnostic agents. Specifically, in diagnostic agents based onmetal ions which may be toxic when unprotected, substitutionalinertness 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 ofthe ligand may be designed to serve as targeting agents, eithertowards 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

Fig. 2 Molecular diagram (35% displacement ellipsoids) of the cationof Cu(CTZ)4]Cl2·2H2O, 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 theyremained intact indefinitely.

Oxidation state as a critical factor in bioavailability ofmetal-based drugs

Besides ligand choice, another critical factor in design of ametallopharmaceutical is oxidation state.21 The oxidation stateof the metal ion can be decisive in regulating the immediatein vivo response to metal-based pharmaceutical agents, oftenmaking the difference between a beneficial and a toxic response atthe same administered dose of a metal ion, and also directingtowards the metabolic pathways by which the compound willbe integrated. The oxidation state of the metal ion also dictatesparticular coordination geometries, hence limiting appropriatebinding for different ligand sets. By optimizing choice of ligand(s)and oxidation state, investigators can build in control of kineticand thermodynamic properties of metallopharmaceuticals forspecific therapeutic needs.

Interactions with serum proteins

The interaction of metallopharmaceuticals with serum proteinsis an important aspect of metal-based drug metabolism, capableof strongly affecting the distribution and biotransformation, andultimately the mechanism of action of the medicinal agent. Thetwo key proteins for metal ions in human serum are transferrin andalbumin. 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 ionssuch as group 13,22,23 vanadyl24 and lanthanide ions.25–28

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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 thatserves to transport hydrophobic metabolites, e.g. fatty acids, aswell as metal ions, including Cu(II) and Zn(II).29 HSA-bindingcan, in fact, be used to advantage for medicinal inorganicapplications. HSA-metal ion binding effects include delayingsystemic clearance, and prevention of redox conversion. Thus,HSA–binding of gadolinium-based pharmaceuticals was used toincrease the residence time of the latter in the blood, an advantagefor ensuring adequate time for enhanced MRI contrast.30 Serumprotein binding (especially HSA–vanadyl binding) may also becrucial to anti-diabetic efficacy of bis(maltolato)oxovanadium(IV)(BMOV) (vide infra), both for delaying systemic clearance and forinhibition of redox conversion of vanadyl to vanadate species.

Vanadium complexes in treatment of diabetes

The discovery, in 1985, that a simple vanadium salt, sodiumorthovanadate, added to drinking water, could reverse most ofthe diabetic symptomatology of experimentally-diabetic rats, wasexceptionally enticing.31 Diabetes mellitus (DM) is a very complexmetabolic disorder and, although injected insulin can alleviatemany of the symptoms in an intermittent fashion, there is nosimple cure that restores glucose homeostasis around the clock.32

The need for oral treatments for type 1 DM and new treatments fortype 2 DM is compelling with the explosive increase in new casesof diabetes, especially type 2 DM. Secondary complications, theresult of long-term excessive fluctuations in glucose and insulinlevels, are a major cause of morbidity in diabetes. Vanadium-containing compounds have shown considerable promise as orallyavailable prodrugs that alleviate most of the symptoms of diabetes:high blood sugar, elevated lipid levels, and increasingly damagingsecondary complications, including heart disease, cataracts, kid-ney disease and peripheral neuropathy.32

A crucial step in development of vanadium compounds fortreatment of diabetes was the discovery that modification of thevanadium core by chelation could improve biodistribution andtolerability.33 BMOV (Fig. 3) is the first (and so far unsurpassed)of a number of complexes that demonstrated superior activity overinorganic vanadium sources (e.g. VOSO4 or NaVO3) through bothin vivo and/or in vitro assays of biological effectiveness.34–36

Fig. 3 Bis(maltolato)oxovanadium(IV), BMOV, the first purpose-designed vanadium-based insulin enhancing pharmaceutical agent.

Rapid dissociation following an oral dose of chelated vanadylmaltol complexes seems to be required for oral activity.37 ESEEMevaluation of bone vanadium derived from oral BEOV (theethylmaltol analogue of BMOV, vide infra) as well as otheranalytical evaluations, have shown that the complex is dissociatedprior to tissue uptake.38

With regard to serum protein binding differences, in the case ofapo-Tf, no discernable differences are seen, comparing BMOVto VOSO4, while for HSA binding, formation of a BMOV–HSA adduct may represent an important difference betweenhydroxypyrone-chelated vanadyl and an inorganic vanadyl source.Provision of a chelated vanadyl source may lead to an inadvertenttargeting effect, in that the presence of the chelating ligandaugments the binding ability of the endogenous albumin. Ternarycomplex formation (i.e. one maltolato ligand and one vanadylion, 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 N-terminus, likely through an imidazole, and several equivalents, vianon-specific interactions with carboxylate side chains of surfaceamino acids. Adduct formation with HSA could also protect thecomplex from oxidation, while at the same time increasing relativeefficacy by slowing transit time through the bloodstream.39

The first human clinical (Phase I) trial was completed re-cently of a designed vanadium-based antidiabetic prodrug,bis(ethylmaltolato)oxovanadium(IV) (BEOV), the ethylmaltolanalogue of BMOV (Fig. 3).37 The overall objective of this PhaseI trial, carried out by Medeval Ltd. in Manchester, UK, wasto assess the safety and tolerability of BEOV. Specific objectiveswere to: (1) assess the health effects of single, escalating doses oforally administered BEOV; (2) determine the pharmacokinetics ofmodest doses of BEOV from measured plasma, urinary and fecal[V]total; (3) compare the bioavailability of a well-tolerated dose oforal 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 wereno adverse health affects observed in any of the [nondiabetic]volunteers; gastrointestinal, liver and kidney function, and bloodparameters all remained within normal levels throughout thestudy. Pharmacokinetic analysis showed a clear, non-proportional,dose-dependence in vanadium uptake from BEOV, along with amore rapid and efficient uptake compared to that from vanadylsulfate.40 Fasted subjects absorbed more vanadium from BEOVthan did fed subjects (by a large margin!). Lastly, the relativebioavailability of vanadium from BEOV was estimated to bethree 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 ofdeveloping metal-based pharmaceutical agents for treatment ofchronic disease. Vanadium will never be a ‘one-size-fits-all’ drug,as it requires ‘titrating’ the dose to the individual patient, ensuringpatient 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 wellbe room for further development of vanadium-based antidiabeticagents as pharmaceuticals.

Outlook

Rapid advances in the field of bioinorganic chemistry are increas-ingly making it possible to purposely design and synthesize metal-based pharmaceutical agents that serve valuable roles as diagnosticor therapeutic agents. Beyond choosing the correct metal ionfor a particular application, the key to this process is finding a

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suitable ligand for the job, whether to enhance uptake, to targeta particular biomolecule, or to ensure that the metal ion remainssecurely sequestered, out of harm’s way.

Many exciting developments currently in medicinal inorganicchemistry are in areas of imaging research,42 in which the nuclearand electronic properties of the metal ions are key factors in beingable to visualize their presence in vivo, whether by fluorescence,electronic properties, positron emission, or gamma emission. Inall instances, secure binding of the metal ion, with appropriatetargeting functionalities, is critical to the success of these agents.43

Some of the newest modalities being explored permit use of thesemolecules as “reporters”, e.g. for intracellular pH, O2 or Ca2+

concentration, or even specific enzyme activities.20,44

A new frontier in pharmaceutical research, glycobiology,that is also starting to have profound affects on researchdirections in medicinal inorganic chemistry, includes use ofglycosyl substituents for enhanced tissue targeting, as out-lined above. Pro-ligands for recruitment of endogenous metalions, and an increasing variety of dual-use imaging/therapeuticagents, are some of the ground-breaking new applications beingexplored.

Acknowledgements

This research has been supported for many years by the NaturalSciences and Engineering Research Council of Canada and theCanadian Institutes of Health Research, as well as by numerouscompanies. The authors thank Dr Tim Storr for useful discussionsin the preparation of this review.

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