Metal-based antitumor drugs play a relevant role in antiblastic chemotherapy. Cisplatin is regarded as one of the most effective drugs, even if severe toxicities and drug resistance phenomena limit its clinical use. Therefore, in recent years there has been a rapid expansion in research and development of novel metal-based anticancer drugs to improve clinical effectiveness, to reduce general toxicity and to broaden the spectrum of activity. The variety of metal ion functions in biology has stimulated the development of new metallodrugs other than Pt drugs with the aim to obtain compounds acting via alternative mechanisms of action. Among non-Pt compounds, copper complexes are potentially attractive as anticancer agents. Actually, since many years a lot of researches have actively investigated copper compounds based on the assumption proposal that endogenous metals may be less toxic. It has been established that the properties of copper-coordinated compounds are largely determined by the nature of ligands and donor atoms bound to the metal ion. In this review, the most remarkable achievements in the design and development of copper(I, II) complexes as antitumor agents are discussed. Special emphasis has been focused on the identification of structure-activity relationships for the different classes of copper(I,II) complexes. This work was motivated by the observation that no comprehensive surveys of copper complexes as anticancer agents were available in the literature. Moreover, up to now, despite the enormous efforts in synthesizing different classes of copper complexes, very few data concerning the molecular basis of the mechanisms underlying their antitumor activity are available. This overview, collecting the most significant strategies adopted in the last ten years to design promising anticancer copper(I,II) compounds, would be a help to the researchers working in this field.

Copper complexes as anticancer agents

Complexes of heterocyclic thione donors

Complexes of heterocyclic thionates. Part 1. Complexes of monodentate and chelating ligands

Metallothioneins (MTs) define a superfamily of ubiquitous cysteine-rich low molecular weight proteins or polypeptides that contain polynuclear metalsulfur coordination sites formed by metal ions with d10 configuration. The most prominent characteristics of these biomolecules, which have been discovered as a cadmium and zinc containing protein in horse kidney by Margoshes and Vallee in 1957,1 are their extremely high metal and sulfur contents (up to 10% w/w). Although MTs have been known as long as about half a century, their precise physiological function is still under debate. According to Kägi and Schäffer, they are thought to play roles both in the intracellular fixation of the essential trace elements zinc and copper, in controlling the concentrations of the free ions of these elements, in regulating their flow to their cellular destinations, in neutralizing the harmful influences of exposure to toxic elements such as cadmium and mercury, and in the protection from a variety of stress conditions.2 More recently, it was concluded by Maret and Vallee that the long sought role of MT lies in the control of the cellular zinc distribution as a function of the energy state of the cell and not in the widely held belief that MT primarily scavenges radicals or detoxifies metals.3 As can be learned by these speculations, investigations directed to explore the structure and chemistry of metallothioneins in greater detail are extremely important taking into account that nature makes use of them as multipurpose proteins. Several reviews covering this issue are available in the literature.4 Today, MTs are known to occur in all animal phyla examined so far as well as in certain fungi, plants, and cyanobacteria. Characterized by a low molecular mass of 6.000-7.000 amu, by 20 totally conserved cysteines out of a total of 61 or 62 amino acid residues (according to ca. 30% by number), without aromatic amino acids such as tyrosine or histidine, the apoprotein from rat liver (thionein) is able to bind a total of seven equivalents of divalent metal ions with d10 configuration such as Zn2+ or Cd2+ in two noninteracting domains. After demetalation, these proteins can be loaded with up to six Cu1+ ions in each domain.5 * To whom correspondence should be addressed. (G.H.) Tel +495251-60-2494. Fax +49-5251-60-3423. E-mail biohenkel@ uni-paderborn.de. (B.K.) Tel +49-251-833-3131. Fax +49-251-8338366. E-mail krebs@uni-muenster.de. † Universität Paderborn. ‡ Universität Münster. 801 Chem. Rev. 2004, 104, 801−824

Metallothioneins: zinc, cadmium, mercury, and copper thiolates and selenolates mimicking protein active site features--structural aspects and biological implications.

Eric S. Raper

Papers

Complexes of heterocyclic thione donors

Complexes of heterocyclic thionates. Part 1. Complexes of monodentate and chelating ligands

Complexes of heterocyclic thionates Part 2: complexes of bridging ligands

Copper complexes of heterocyclic thioamides and related ligands

Copper(I) halide-complexes of imidazole thiones: crystal structure of dimeric monochloro bis (1-methylimidazoline-2-thione) copper(I)