Titanocene, anticancer activity

Other metal complexes also have promising anticancer activity. Two Ti(IV) complexes are on clinical trial, an acetylacetonate derivative (budotitane) and titanocene dichloride, and the antimetastic activity of octahedral Ru(III) complexes is attracting attention, one of which is now on clinical trial. Ru(III), like several other metal ions, can be delivered to cells via the iron transport protein transferrin. 

Titanocene dichloride, [TiIV(q5-C5H5)2Cl2], will be remembered in the history of metal-based drugs as a pioneer in the field of organometallic complexes with anticancer activity. 

Sun H, Li H, Weir RA, Sadler PJ (1998) The first specific TiIV-protein complex potential relevance to anticancer activity of titanocenes. Angew Chem Int Ed Engl 37 1577-1579... 

Kelter G, Sweeney NJ, Strohfeldt K, Fiebig H-H, Tacke M (2005) In-vitro anti-tumor activity studies of bridged and unbridged benzyl-substituted titanocenes. Anticancer Dmgs 16 1091-1098... 

Metallocenes are examples of metal complexes that have little activity in the normal first-line screens for anticancer activity P388 and L1210 leukemias. In contrast, titanocene (23), vanadocene complexes... 

As mentioned in the introduction, metallocene-type complexes based on the early transition metals were evaluated as anticancer compounds shortly after the discovery of cisplatin. While the biological activity of each of the metallocene dihalides is unique, titanocene dichloride 7 has been the subject of a number of studies and even entered clinical evaluation, although evaluation was discontinued (not due to its anti-proliferative properties), principally due to formulation problems, despite showing superior activity to certain cancers than other established drugs. This class of compound continues to be modified and studied for anticancer activity, for example, the titanocene-type derivative of tamoxifen 1, described above, and other developments described below. 

Substituted titanocene dichlorides have potential application as metal-based anticancer drugs, and therefore, the cytotoxic activity of members of all four... 

We published the first potential anticancer early—late complexes in 2010 (Fig. 1) [91]. The chosen combination was Ti-Ru. The ruthenium was bound to a titanocene dichloride via a phosphane introduced on a modified Cp. AU the heterobimetaUic complexes 37 were found to be considerably more active than the parent mononuclear titanocene dichloride and [(arene)RuCl2PR3] complexes or than the mixture of both of them. Moreover, the results suggested no cross-resistance with cisplatin. Cathepsin B inhibition was hypothesized as a possible mechanism of action. 

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