The quest for alternative drugs to the well-known cisplatin and its derivatives, which are still used in more than 50% of the treatment regimes for patients suffering from cancer, is highly needed.1,2 Despite their tremendous success, these platinum compounds suffer from two main disadvantages: they are inefficient against platinum-resistant tumors, and they have severe side effects such as nephrotoxicity. The latter drawback is the consequence of the fact that the ultimate target of these drugs is ubiquitous: It is generally accepted that Pt anticancer drugs target DNA, which is present in all cells.3,4 Furthermore, as a consequence of its particular chemical structure, cisplatin in particular offers little possibility for rational improvements to increase its tumor specificity and thereby reduce undesired side effects.

In this context, organometallic compounds, which are defined as metal complexes containing at least one direct, covalent metal−carbon bond, have recently been found to be promising anticancer drug candidates. Organometallics have a great structural variety (ranging from linear to octahedral and even beyond), have far more diverse stereochemistry than organic compounds (for an octahedral complex with six different ligands, 30 stereoisomers exist!), and by rational ligand design, provide control over key kinetic properties (such as hydrolysis rate of ligands). Furthermore, they are kinetically stable, usually uncharged, and relatively lipophilic and their metal atom is in a low oxidation state. Because of these fundamental differences compared to “classical coordination metal complexes”, organometallics offer ample opportunities in the design of novel classes of medicinal compounds, potentially with new metal-specific modes of action. Interestingly, all the typical classes of organometallics such as metallocenes, half-sandwich, carbene-, CO-, or π-ligands, which have been widely used for catalysis or biosensing purposes, have now also found application in medicinal chemistry (see Figure ​Figure11 for an overview of these typical classes of organometallics).



Figure 1

Summary of the typical classes of organometallic compounds used in medicinal chemistry.



In this Perspective, we report on the recent advances in the discovery of organometallics with proven antiproliferative activity. We are emphasizing those compounds where efforts have been made to identify their molecular target and mode of action by biochemical or cell biology studies. This Perspective covers more classes of compounds and in more detail than a recent tutorial review by Hartinger and Dyson.(5) Furthermore, whereas recent reviews and book contributions attest to the rapid development of bioorganometallic chemistry in general,6,7 this Perspective focuses on their potential application as anticancer chemotherapeutics. Another very recent review article categorizes inorganic anticancer drug candidates by their modes of action.(8) It should be mentioned that a full description of all currently investigated types of compounds is hardly possible anymore in a concise review. For example, a particularly promising class of organometallic anticancer compounds, namely, radiolabeled organometallics, has been omitted for space limitations. Recent developments of such compounds have been reviewed in detail by Alberto.(9)

http://pubs.acs.org/doi/pdf/10.1021/jm100020w

Organometallic Anticancer Compounds

Multimetallic catalysis based on heterometallic complexes and clusters.

Transition-metal nanocluster stabilization for catalysis: A critical review of ranking methods and putative stabilizers

Naked metal nanoparticles from metal carbonyls in ionic liquids: Easy synthesis and stabilization

Highly efficient synthesis of graphene/MnO2 hybrids and their application for ultrafast oxidative decomposition of methylene blue

The six-membered heavy atom heterocycles [Re2(CO)8(μ-SbPh2)(μ-H)]2, 5, and Pd[Re2(CO)8(μ-SbPh2)(μ-H)]2, 7, have been prepared by the palladium-catalyzed ring-opening cyclo-dimerization of the three-membered heterocycle Re2(CO)8(μ-SbPh2)(μ-H), 3. The palladium atom that lies in the center of the heterocycle 7 was removed to yield 5. The palladium removal was found to be partially reversible leading to an unusual example of host–guest behavior. A related dipalladium complex Pd2Re4(CO)16(μ4-SbPh)(μ3-SbPh2)(μ-Ph)(μ-H)2, 6, was also formed in these reactions of palladium with 3.

Tetrarhena-heterocycle from the palladium-catalyzed dimerization of Re2(CO)8(μ-SbPh2)(μ-H) exhibits an unusual host-guest behavior.

New highly dispersed bimetallic nanoscale catalysts based on rhenium combined with antimony or bismuth have been shown to be highly effective for the ammoxidation of 3-picoline to nicotinonitrile (precursor for vitamin B3) under mild conditions in the liquid phase.

New Catalytic Liquid-Phase Ammoxidation Approach to the Preparation of Niacin (Vitamin B3)

Facile synthesis and catalytic properties of single crystalline β-MnO2 nanorods

Facile cleavage of a phenyl group from SbPh3 by dirhenium carbonyl complexes

The reaction of Re(2)(CO)(8)[mu-eta(2)-C(H)=C(H)Bu(n)](mu-H) with BiPh(3) in heptane solvent at reflux yielded three new compounds Re(2)(CO)(8)(mu-BiPh(2))(2), 1 (14% yield), [Re(CO)(4)(mu-BiPh(2))](3), 2 (5% yield), and Re(2)(eta(6)-C(6)H(5)Ph)(CO)(7), 3, 4.7 mg (7% yield). Compound 1 contains two Re(CO)(4) groups joined by two bridging BiPh(2) ligands in a four-membered ring. There is no Re-Re bond in 1, Re...Re = 4.483(1) A. Compound 2 contains a six-membered Re(3)Bi(3) ring in a twist-boat conformation. When heated to 110 degrees C in toluene, compound 1 was transformed into the heterocycle 2 (8% yield), the known compound Re(CO)(5)Ph, 4 (25% yield), and the new compound Re(2)(CO)(8)(mu-BiPh)(2), 5 (4% yield). Compound 5 contains two Re(CO)(4) groups joined by two bridging BiPh ligands and a Re-Re bond, Re-Re = 3.1006(18) A. When compound 2 was heated to reflux in an octane solution, it was converted to two new compounds: cis-Re(4)(CO)(16)(mu-BiPh(2))(2)(mu(4)-BiPhBiPh), cis-6 and trans-Re(4)(CO)(16)(mu-BiPh(2))(2)(mu(4)-BiPhBiPh), trans-7 and a small amount of 1 (3% yield). cis-6 and trans-7 are isomers. Both compounds contain two fused Re(2)Bi(3) rings that share a quadruply bridging BiPhBiPh ligand that contains a Bi-Bi bond; Bi-Bi = 3.0237(7) A in cis-6 and Bi-Bi = 2.9765(3) A in trans-7. The phenyl groups on the bridging BiPhBiPh ligand in cis-6 have a cis-orientation and in trans-7 they have a trans-orientation. In the presence of visible light, cis-6 and trans-7 are transformed into yet another isomer Re(4)(CO)(16)(mu-BiPh(2))(2)(mu-BiBiPh(2)), 8, by a shift of one of the phenyl ligands on the bridging BiPhBiPh ligand to the neighboring bismuth atom. Compound 8 contains two fused rings, one five-membered Re(2)Bi(3) ring, and one four-membered Re(2)Bi(2) ring.

William C. Pearl

Papers

Tetrarhena-heterocycle from the palladium-catalyzed dimerization of Re2(CO)8(μ-SbPh2)(μ-H) exhibits an unusual host-guest behavior.

New Catalytic Liquid-Phase Ammoxidation Approach to the Preparation of Niacin (Vitamin B3)

Facile synthesis and catalytic properties of single crystalline β-MnO2 nanorods

Facile cleavage of a phenyl group from SbPh3 by dirhenium carbonyl complexes

Rhenium-bismuth carbonyl cluster compounds.