1. Organometallic pharmaceuticals

Organometallic pharmaceuticals are part of the larger field of bioorganometallics. This broad field incorporates the use of organometallic compounds (compounds containing one or more bonds between metal and carbon atoms) in biologically relevant functions including bioimaging, biosensors, bioprobes, catalysis of biological reactions, synthesis of biological compounds, organometallic immunoassays, and use of organometallic compounds as direct therapeutic or diagnostic agents (1). It is this last use that describes the field of organometallic pharmaceuticals.

Interest in using organometallic compounds can be traced back to the 15^thcentury, with a shift in use of inorganic preparations of mercury or arsenic to organometallic compounds of these elements.(2) Ultimately, this interest has subsided given the truly toxic nature of mercury alkyls and arsenic alkyls.

Two mercury containing compounds still used today are mercurochrome and merthiolate. Mercurochrome (Merbromin), is an over-the-counter topical antiseptic that is no longer available in the United States of America due to its mercury content. Merthiolate (Thiomersal) has applications as an antifungal and antiseptic agent. This compound is also used as a vaccine preservative, in immunoglobulin preparations and nasal products. Once again, given the mercury content, its usage in childhood vaccines is being phased out in a variety of countries throughout the world.

The first important organometallic drug synthesized was an arsenic complex called Salvarsan (arsphenamine in the States); it was discovered in 1908 in the laboratory of Paul Ehrlich and used as an anti-syphilis medication as that disease was very prevalent at the time. The structure of Salvarsan came in a mixture of cyclic species, either a trimer or a pentamer. An unfortunate property of Salvarsan was that it was insoluble in water and therefore hard to deliver. However another derivative called Neosalvarsan was synthesized that was soluble allowing for improved efficacy of drug delivery. Both of these drugs were easily oxidized in air and had to be sealed constantly under inert atmospheres.²

Figure 1. Salvarsan Figure 2. Neosalvarsan

Fig. 1 Salvarsan² Fig. 2. Neosalvarsan² Fig. 3. Mapharsen²

Subsequently, in 1915 a new organoarsenic drug was created called Mapharsen which was much more stable in air and during the 1930s was the most widely used treatment against syphilis. Nowadays although these drugs no longer see much use with human patients, they are still used in veterinary medicine.²

3. Their Place in Today’s Society

Organometallic pharmaceuticals have come a long way from the discovery of Salvarsan and the now famous cisplatin in 1965 (5). Although still the most widely used anticancer treatment (1), cisplatin now has a host of other complexes with varying properties to treat diseases from parasites to damaged cardio tissue (6). These complexes are categorized by the way they are used in pharmaceutical applications.

3.1. Classification of Organometallic Pharmaceuticals (1)

3.1.1 Ligand Lability

Compounds where ligand lability plays a central role to the pharmaceuticals efficacy. One example of this class of compound is titanocene dichloride. Titanocene dichloride, Cp₂Ti Cl₂ has shown significant anticancer attributes. Ligand lability plays a central role in its efficacy as an anticancer agent. Loss of both Cp rings, and subsequent binding to the human blood iron-transport protein, transferrin, is significant²⁵ and permits delivery of the compound to cells in vivo. Given the high iron demand by cancer cells (which is normally satisfied by Fe³⁺ bound transferrin) and the relatively low pH inside these cells (which is significant in the release of Ti⁴⁺ from transferrin) delivery of of Ti⁴⁺ can be accomplished.

Figure 4. Titanocene dichlorode

Titanocene dichloride is an important organometallic pharmaceutical as it is able to overcome cisplatin resistance in ovarian cancers. It has also shown antiviral and insecticidal attributes.

3.1.2 Radioisotopes

Organometallics incorporating transition metal radioisotopes for treatment and/or imaging of cancers or other physiological processes.

a) preparation must be in physiological media

b) no purification should be required

c) time required to perform synthesis must be short

^99mTc is of particular importance in nuclear imaging as the nuclide is eluted in a saline solution, allowing convenient preparation as imaging agents.

One of the classic organometallic preparations incorporating a radiocentre is ^99mTc-Sestamibi. The radionuclides ¹⁸⁸Re and ^99mTc garner significant attention in the preparation of organometallic radiopharmaceuticals primarily due to their desirable decay attributes and availability from radionuclide generators. Given the radioactive decay of these transition metals, some prerequisites exist for utility as organometallic pharmaceuticals:³

Figure 5. Tc-Sestamibi

Prepared from a kit, and taken to reaction completion by microwave heating,⁴ this compound is easy and quick to prepare in any nuclear medicine department. This compound was originally used as a mycoradial perfusion imaging agent but has more recently been applied in tumour imaging and detection of multidrug resistance. The use of ^99mTc as a cardiac perfusion agent has been extended with a variety of arene ligands.⁹ Wester and co-workers prepared a series of substituted bis-arene compounds and showed significant myocardial uptake of these compounds. However, synthesis of these compounds required rigorous reaction conditions, limiting their widespread utility in a typical radiopharmacy.

3.1.3 Exploitation of Ligand Properties

Exploiting attributes of a organometallic ligand, with known properties, for use in biological systems is a key aspect in the efficacy of organometallic compounds. A good example of this use is the combination of antibacterial compounds with metal centres. Pioneering work on organometallic complexes with organic ligands of known antibacterial properties began with the work of E I Edwards in the 1970s.⁸ Utilizing the ferrocenyl group as the relevant organometallic centre, this work outlines derivatization of one Cp ring with either penicillin, cephalosporin, or hyrids including both these b-lactam antibiotics.^10-12 The impetus in this work is undoubtedly to combat acquired antibiotic resistance by the general population. These compounds act as b-lactamase inhibitors, restricting the activity of this enzyme in the cleavage of the four-membered b-lactam ring.

Figure 6.

3.1.4 Biomolecules

Organometallic groups attached to bio-molecules (e.g. proteins, peptides) of known function. Examples of this classification of drug include substitution of a phenyl ring for an organometallic cluster in the anticancer compound tamoxifen (see Section 3.2.1) or ferrocenyl derivatives of the antimalarial compound, chloroquine.

3.1.5 Coordination Complexes

Organometallic groups attached to coordination complexes with known therapeutic attributes.

3.2 Anticancer Treatment

Many organometallic compounds play a key role in cancer treatment among today’s society. For example, cisplatin is a common drug used in chemotherapy (used to treat 70% of all cancer patients¹) which destroys cancer cells by cross-linking their DNA^.7 This is a common mechanism in anticancer drugs because DNA replication is integral to the cancer’s progression¹. Many other organometallic anticancer drugs exist including titanocene dichloride, (Cp)₂V(NCSe)₂ ¹, and carboplatin. Although platinum based drugs (such as cisplatin and carboplatin) are successful, they also carry unfavorable side effects and are unable to treat some types of cancer¹. For this reason, ruthenium compounds are now being studied extensively for their anticancer abilities¹. Important properties of these compounds include their ligand exchange kinetics, their variety of accessible oxidation states under physiological conditions, and their ability mimic iron and reduce toxicity by binding to certain biomolecules¹. Below is a general overview of some of the most important organometallic anticancer agents examined in the last 12 years.

3.2.1. Selective Estrogen Receptor Modulators (SERMs) – Tamoxifen derivatives

Tamoxifen is an organic compound used to treat hormone-depended cancers by controlling estrogen production (13).

Figure 7. (a) hydroxytamoxifen (b) tamoxifen

As one-third of hormone-dependent tumors acquire resistance to tamoxifen (13), and one-third do not even respond (13), a number of organometallic tamoxifen derivatives have been designed to augment the estrogen-inhibiting properties of the organic compound.

3.2.1.i. Titanium

A titanocene-type tamoxifen derivative is formed by the substitution of the aromatic β-ring of tamoxifen by a Cp2TiCl2 entity, shown below.

Figure 8. Cp2TiCl2 derivative of tamoxifen

This compound has a strong affinity for the estradiol receptor (relative binding affinity (RBA) = 8.5%) and exhibits estrogenic effects on hormone-dependent breast cancer cells (13). The Cp2TiCl2 entity also exhibits this estrogenic activity in the absence of tamoxifen, indicating that it plays a key role in the observed estrogenic effects (13).

3.2.1.ii. Rhenium

In place of Cp2TiCl2, the rhenium tamoxifen derivative has a CpRe(CO)3 group incorporated into the tamoxifen framework (14).

Figure 9. CpRe(CO)3 derivative of tamoxifen

The anti-proliferative effect observed for this rhenium derivative is slightly higher than that for the active tamoxifen compound, hydroxytamoxifen (13). The length of the side chains were originally varied to allow for specialization, but were found to have no effect on the anti-proliferative properties. Additionally, the isomeric form also has no effect on the compound’s efficacy.

3.2.1.iii. Iron

Ferrocenyl derivatives of OH-Tam are called ferrocifens (13).

Figure 10. FeCp2 derivative of OH-Tam

The anti-proliferative effect of ferrocifens is due to two major factors: 1. the antihormonal effect of tamoxifen mediated by the estradiol receptor and 2. a cytotoxic effect from the presence of the ferrocenyl substituent (13).

3.2.1.iv. Ruthenium

Ruthenium complexes, or ruthenocifens, are very similar to ferrocifens in structure. In figure 10 above Fe is replaced with Ru. These complexes act as antiestrogens, having an anti-proliferative effect slightly higher than OH-Tam on hormone-dependent breast cancer cells and no effect on hormone-independent cells (13).

3.2.1.v. Triosmium and Dicobalt Clusters(18)

Given difficulties in synthesis of triosmium clusters of Tamoxifen, focus has shifted to structural analogues of the Tamoxifen ligand. Lipophilicity, which is often evaluated to determine relative transport in blood and cell penetrating ability, of these compounds is considerable in the triosmium cluster analogues. However, receptor binding affinity is very low in these compounds.

Figure 11. Triosmium and Dicobalt clusters

Dicobalt derivitized Tamoxifen shows some receptor binding affinity, as well as significant lipophilicity.

3.2.2. Iron-derivative polymer compounds

Ferrocene derivatives with non-SERM mechanisms have also been evaluated as anticancer agents. The ferricenium salts ferricenium picrate and ferricenium trichloroacetate are better suited to permeating cell membranes and thus display greater anti-proliferative activity compared to ferrocene (15). Also, studies (16, 17) have been conducted to impart similar properties by adding functional groups to ferrocene, most notably polyaspartamide groups.

Figure 12. Polyaspartamide-ferrocene anticancer compounds

The amino group being protonated at physiological pH could facilitate cellular uptake of the ferrocene-containing polymers. These have been found to be effective in vitro against intestinal cancers known to resist chemotherapeutic treatment (13).

3.2.3. Titanium and Molybdenum Derivatives

Titanium and molybdenum derivatives mainly take the form of metallocene-type complexes. Titanocene dichloride, mentioned previously, is a very important organometallic compound and even entered clinical trials (13). However, trials were discontinued due to formulation problems despite titanocene dichloride’s exhibiting greater activity towards certain cancers than other established drugs (19). Modifications and studies are still being conducted on this class of compound to hopefully improve it for therapeutic anticancer treatment. For instance, the chloride ligands of Ti(η5-C5H5)2Cl2 have been substituted by a variety of anionic and neutral ligands to improve its poor water solubility (20,21).

As mentioned in 3.1.1 titanocene dichloride is also known for its labile-ligand use. Known organic anticancer drugs have been coordinated to the titanium centre in the place of the chloride ligands (22). The chloride ligands of molybdenocene dichloride are also substituted, but thiol ligands are the main substituents (13).

Figure 13. Molybdenocene dichloride thiol derivative

3.2.4. Ruthenium Arene Compounds

Some examples of ruthenium based anticancer drugs are Ru(η⁶-C₆H₆)Cl₂(metronidazole) and Ru(η⁶-C₆H₆)Cl₂(DMSO) ¹. Ru(η⁶-C₆H₆)Cl₂(DMSO) has been shown to inhibit topoisomerase II, an important target in chemotherapy (13). Another Ru-arene compound with anticancer attributes contains a iodido ligand and a s-donor/p-acceptor phenylazopyridine ligand.⁸

Figure 14. [(h⁶-arene)Ru(az-py)I]⁺

This set of compounds has shown superior inertness with respect to ligand substitution, but high cytoxicity to human ovarian (A2780) and human lung (A549) cancer cells.

3.3 Antimicrobials

3.3.1 Bacterial

Organometallic pharmaceuticals have entered the realm of antibacterials in restoring activity to organic antibiotics that have become ineffective due to drug resistance (13). Attaching an organometallic fragment (such as ferrocene) to a known antibacterial agent (penicillin and cephalosporin) has been shown to greatly alter antibacterial activity compared to the initial compound (10) (discussed in 3.1.3, figure 5).

A tungsten tetracarbonyl unit linked to the antibacterial drug norfloxacin shows excellent activity against three different strains of bacteria (23).

Figure 15. Tungsten tetracarbonyl derivative with norfloxacin

Organometallic complexes of rhodium, iridium and ruthenium have also been found to exhibit antibacterial properties (13).

3.3.2 Viral

The tetraruthenium cluster, [H4Ru4(η6-C6H6)4]2+, is extremely water soluble and is active against the polio virus type 1 while exhibiting little toxicity in healthy cells (24).

Vanadocene complexes, such as the one below, have potential in preventing HIV transmissions (13).

Figure 16. Vanadocene acetylacetonate

3.3.3 Parasites

Drug resistance to antiparasitic drugs has been overcome in many cases similarly to antibiotic resistance in incorporation of organometallic entities (13). Because of the popularity of ferrocene, antimalarial drugs have been particularly well studied (13). Ferroquine, a combination of ferrocene and chloroquinine, is one of these.

Figure 17. Ferroquine

Ferrocene derivatized carbohydrate compounds have shown potential as an antimalarial compound. Given the elevated glucose consumption by infected erythrocytes, this strategy of specific targeting infected cells is attractive.

Figure 18. Ferrocenyl carbohydrate conjugate

Other antiparasitic drugs have been prepared from iridium, platinum, rhodium, palladium, antimony, and osmium to target a variety of parasites including L. donovani, T. brucei, T. cruzi, and the helminth worms, among many others (13).

References

P.J. Dyson et al. Appl. Organometal. Chem. 2005, 19: 1 – 10
G. Jaouen. Bioogranometallics: Biomolecules, Labeling, Medicine. (Wiley-VCH Verlag GmbH & Co.: KGaA, Weinheim). 2006, 5-7.
Schibli R., Schubiger P.A., European Journal of Nuclear Medicine, 2002, 29, Issue 11.
Hung et al., J Nucl Med 1991, 32, 2162-2168
Rosenberg B., Van Camp L, Krigas T. Nature, 1965, 205, 698.
Johnson TR, Mann BE, Clark JE, Foresti R, Green CJ, Motterlini R. Angew. Chem. Int. Ed. 2003, 42, 3722.
R.A. Alderden, M.D. Hall, T.W. Hambley. “The Discovery and Development of Cisplatin" J. Chem. Ed. 2006, 83, 728–724.
S.J. Dougan et al; Proc. Nat. Acad. Sci. USA, 2008, 105, 11628.
Wester D.W., J. Med. Chem. 1991, 34, 3284-3290
E. I. Edwards, R. Epton, G. Marr, J. Organomet. Chem. 1975, 85, C23–C25
E. I. Edwards, R. Epton, G. Marr, J. Organomet. Chem. 1976, 122, C49–C53
E. I. Edwards, R. Epton, G. Marr, J. Organomet. Chem. 1979, 168, 259–272
Jaouen, G.; Dyson, P.J., Medicinal Organometallic Chemistry. Comprehensive Organometallic Chemistry III. Vol 12. Elsevier, Ltd.: Switzerland. 2007, 445-464.
Top, S.; Vessières, A.; Pigeon, P.; Rager, M.N.; Huché, M.; Salomon, E.; Cabestaing, C.; Vaisserman, J.; Jaoun, G. ChemBioChem. 2004, 5, 1104.
Pigeon, P.; Top, S.; Vessières, A.; Huché, M.; Hillard, E.A.; Salomon, E.; Jaouen, G.J. J. Med. Chem. 2005, 48, 2814.
Neuse, E.W. J. Inorg. Organomet. Polym. 2005, 15, 3.
Grimes, R.N. Coord. Chem. Rev. 2000, 200-202, 773.
K.H. Chan et al. Journal of Organometallic Chemistry. 2006, 691, 9–19
Köpf-Maier, P. Anticancer Res. 1999, 19, 493.
Mokdsi, G.; Harding, M.M. J. Organomet. Chem. 1998, 565, 29.
Meléndez, E. Crit. Rev, Onc. Hematol. 2002, 42. 309.
Meléndez, E.; Marrero, M.; Rivera, C. Inorg. Chim. Acta, 2000, 298, 178.
Chen, X.-B.; Ye, Q.; Wu, Q.; Song, Y.-M.; Xiong, R.-G.; You, X.-Z. Inorg. Chem. Commun. 2004. 7, 1302.
Allardyce, C.S.; Dyson, P.J.; Ellis, D.J.; Salter, P.A.; Scopelliti, R. J. Organomet. Chem. 2003, 668, 35.
Sadler P.J.; Biochemistry, 2000, 39, 10023-10033
Ferreira, C. et al., Inorg. Chem. 2006, 45, 20, 8414-8422

Authors:

1. Rebecca Dixon (U)

2. Krista Morrow (U)

3. Corey Sanz (U)

4. Mike Woods (U)

Introduction

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Organometallic pharmaceuticals

Contents:

1. Introduction

2. History

3. Organometallics Today

3.1. Classification

3.2. Anticancer Treatment