This paper is aimed at introducing the organometallic chemist to the fascinating area of organometallic pharmaceuticals. It commences by identifying the properties of organometallic (transition metal) compounds that lend themselves to medical applications. Next, the specialized techniques and methods that are used to assess the medicinal properties of compounds are summarized, and although these techniques are not restricted to organometallic compounds, all examples are concerned with organometallic compounds. The design and evaluation of organometallic compounds for medicinal applications are described in context with the diseases they have been evaluated against, and areas are identified that may have most potential for organometallic pharmaceuticals. Some new results, including the first example of an organo-osmium compound that might exhibit effective anticancer properties, are also described.

A series of ruthenium(II) and osmium(II) p-cymene dichloride complexes with either a pta (1,3,5-triaza-7-phosphatricyclo[3.3.1.1]decane) or [pta-Me]Cl ligand which exhibit anticancer activity have been prepared and characterized by 1 H and 31 P NMR spectroscopy and mass spectrometry. Three of the complexes, viz. [Os(η 6 -p-cymene)Cl 2 (pta)] and [M(η 6 -pcymene)Cl 2 (pta-Me)]Cl (M ) Ru, Os), have also been characterized by single-crystal X-ray diffraction. The pta complexes are selective anticancer agents, whereas the pta-Me + complexes are indiscriminate and damage both cancer and healthy cells but represent models for the protonated pta adduct which has been implicated in drug activity. To establish a link between their biological activity and the effect they have on DNA (a likely in vivo target), the reactivity of the complexes toward a 14-mer oligonucleotide (5′-ATACATGGTACATA-3′) was studied using electrospray ionization mass spectrometry. It was found that the complexes bind to the oligonucleotide with loss of chloride and in some cases loss of the arene. Loss of arene appears to be most facile with the ruthenium-pta complexes but also takes place with the ruthenium-pta-Me complexes, whereas arene loss is not observed for the osmium complexes. In addition, as pH is reduced, increased binding to the oligonucleotide is observed, as evidenced from mass spectrometric relative intensities. Binding energies between the metal centers and the surrounding ligands were calculated using density functional theory (DFT). The calculated energies rationalize the experimentally observed tendencies for arene loss and show that the pta ligands are relatively strongly bound. Exchange of metal center (ruthenium versus osmium), methylation or protonation of the pta ligand, or change of the arene (p-cymene versus benzene) results in significant differences in the metal-arene binding energies while leaving the metal-phosphine bond strength essentially unchanged. Significantly lower binding energies and reduced hapticity are predicted for the exchange of arene by nucleobases. The latter show higher binding energies for nitrogen σ-bonding than for π-bonding.

Reaction of the dimer [(η5-C5Me5)RhCl(μ2-Cl)]2 with 2 or 4 equiv of the water-soluble phosphine 1,3,5-triaza-7-phosphatricyclo[3.3.1.1]decane (pta) affords [Rh(η5-C5Me5)(pta)Cl2] and [Rh(η5-C5Me5)(pta)2Cl]Cl, respectively. Both complexes have been characterized in solution by NMR spectroscopy and in the solid state by single-crystal X-ray diffraction, the latter as the chloride and BPh4 - salts. In addition, the rhodium(I) complexes [Rh(η5-C5Me5)(CO)(pta)] and [Rh(η5-C5H5)(pta)2] have been prepared from [Rh(η5-C5Me5)(CO)2] and [Rh(η5-C5H5)(PPh3)2], respectively, by reaction with pta. An in vitro evaluation of these compounds, together with [Os(η6-C10H14)(pta)Cl2] and the well-characterized antimetastasis drug [Ru(η6-C10H14)(pta)Cl2], RAPTA-C, was undertaken using HT29 colon carcinoma, A549 lung carcinoma, and T47D breast carcinoma cells. In the HT29 cell line, the two nearest congeners to [Ru(η6-C10H14)(pta)Cl2], viz., [Rh(η5-C5Me5)(pta)Cl2] and [Os(η6-C10H14)(pta)Cl2], demonstrated very similar cytotoxicity profiles. [Rh(η5-C5Me5)(pta)Cl2] proved significantly more cytotoxic in A549 cells and [Rh(η5-C5Me5)(pta)2Cl]Cl 3-fold more cytotoxic in T47D cells, both relative to RAPTA-C. These data suggest that the development of organometallic anticancer drugs based on the neighboring elements to ruthenium should not be overlooked.

A new series of organometallic ruthenium(II)-arene compounds of the type RuCl2(η6-arene)(phosphine) (phosphine = 1,3,5-triaza-7-phosphaadamantane, PTA, and 3,7-diacetly-1,3,7-triaza-5-phosphabicyclo[3.3.1]nonane, DAPTA) with different potential hydrogen-bonding functionalities on the arene ligand have been prepared and studied for their antitumor activity. Cell viability studies using the TS/A mouse adenocarcinoma cancer cell line and the nontumorigenic HBL-100 human mammary cell line, combined with uptake determinations, are compared to the nonfunctionalized analogues, previously shown to be active on solid metastasizing tumors. The reactivity of the functionalized RAPTA compounds with a 14-mer oligonucleotide (established by mass spectrometry) has been rationalized by DFT calculations, which indicate that environmental factors are important.