Interactions of organometallic anticancer agents with nucleotides and DNA

This Perspective will focus on recent developments in the field of antitumour metallocenes structurally related to titanocene dichloride. Despite extensive testing of titanocene dichloride which culminated in phase I and II clinical trials, further trials have been abandoned. While DNA has been implicated as the major target related to anticancer activity, identification of the active species and mechanism of action has been poorly understood and hence the design of second generation titanocene derivatives has not been possible. Recent mechanistic studies have provided a plausible mechanism for delivery of Ti to cancer cells via transferrin mediated endocytosis. This mechanism requires the presence of labile Cp–Ti bonds that hydrolyse on a time scale to deliver Ti to transferrin. A large range of titanocene derivatives in which the cyclopentadienyl rings have been substituted by both electron withdrawing and donating groups, including aromatic, alkyl and cyclic amines, have been prepared and tested for activity in the last 5 years. These results have shown that subtle structural effects can have a significant effect on biological activity and that biological activity is highly cell line dependent. However, the biological chemistry and cellular studies required to determine the mechanism of action of these new titanocenes have not been reported. In contrast, the bioorganometallic chemistry and cellular studies of molybdocene dichloride have implicated interaction with cellular thiols as the key reaction related to biological activity. Tailoring of the pseudohalide ligands by tuning the strength of the Mo–S bonds provides the opportunity to enhance cell uptake. Further research is required to establish the origin of antitumour activity.

Antitumour bis(cyclopentadienyl) metal complexes: titanocene and molybdocene dichloride and derivatives.

Cyclopentadienyl metal complexes are organometallic compounds which exhibit antiproliferative properties in vivo and in vitro. They are represented by compounds of various structural type. The metallocene diacido complexes (C5H5)2MX2 contain early transition metal atoms such as titanium(IV) and vanadium(IV), the ionic metallicenium salts [(C5H5)2M]+X− include medium transition metals, e.g. iron(III), whereas the uncharged decasubstituted metallocenes (C5R5)2M comprise the main group elements tin(II) and germanium(II) as central metal atoms M. A variety of biological data are available about metallocene diacido complexes, especially titanocene dichloride. These substances exhibit antitumor properties against numerous experimental tumors, e.g. Ehrlich ascites tumor, B 16 melanoma, colon 38 carcinoma, Lewis lung carcinoma, as well as against various human tumors heterotransplanted to athymic mice. Biological experiments using (C5H5)2TiCl2 and (C5H5)2VCl2 pointed to the nucleic acids as a probable target for metallocene diacido complexes within the cells, revealed a main accumulation of titanium or vanadium in the liver and the intestine and unfolded a pattern of organ toxicity which fundamentally differs from that of other cytostatic drugs. These biological features confirm the cyclopentadienyl metal complexes to be an independent group of non-platinum-group metal antitumor agents being characterized by unusual biological properties. They represent interesting candidates for future biological and clinical investigations.

Transition and main-group metal cyclopentadienyl complexes: Preclinical studies on a series of antitumor agents of different structural type

Tumor inhibition by metallocenes: ultrastructural localization of titanium and vanadium in treated tumor cells by electron energy loss spectroscopy.

In this paper we overview our studies on amine–phenolato TiIV complexes as cytotoxic agents, in the context of the results reported thus far with titanocene dichloride, budotitane and derivatives. In particular, we emphasize the studies about the structure–activity relationship performed and important insights gained with the known compounds and our complexes, in regards to their hydrolytic behavior and cytotoxic activity, while pointing to potential mechanistic aspects. Titanocene dichloride and budotitane show cytotoxic activity towards cells that are resistant to cisplatin with reduced side effects. Their main drawback is their hydrolytic instability that has impeded mechanistic investigations and pharmaceutical use. Our new family of cytotoxic complexes was designed to include a single highly electron-donating chelating ligand to afford octahedral TiIV complexes of relatively high hydrolytic stability, with the aim to retain ligand binding throughout the biological activity for achieving controlled processes and allowing mechanistic evaluation. The effect of several parameters on hydrolysis and cytotoxicity were investigated, including those relating to the tetradentate ligand and those relating to the labile groups. Overall we observed high cytotoxic activity that is strongly dependent on the ligand, and which is strongly correlated to the complex hydrolytic behavior. Additional mechanistic studies provide insights regarding the time frame of activity and cell penetration. Some comparisons to titanocene dichloride, budotitane and analogues are highlighted.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

D. Krahl

Papers

Intracellular distribution of titanium after treatment with the antitumor agent titanocene dichloride: on electron energy loss spectroscopic study.