Highly selective apoptotic cell death induced by halo-salane titanium complexes.

Following the accidental discovery of cisplatin by Rosenberg and co-workers and its enormous success as chemotherapeutic agent, there has been a growing interest in the investigation of other platinum-based compounds as well as nonACHTUNGTRENNUNGplatinum metal-based systems. Among these, titanium(IV) complexes showed encouraging antitumor activity in various cell lines. Nearly all complexes investigated were derivatives of either titanocene dichloride or budotitane, the only titanium complexes reaching clinical trials so far. Titanocene dichloride showed promising results in phase I trials and was further investigated in phase II studies. Unfortunately, no objective clinical responses were observed. The main disadvantages of titanocene complexes are their fast hydrolysis under physiological conditions and the formation of unidentified metabolites. The hydrolysis of the first chloride of titanocene dichloride occurs within seconds and the cyclopentadienyl ligands are hydrolyzed after 2–3 days. This hampers identification of the active species and the investigation of mechanistic detail. Furthermore, little is known about the cellular uptake of titanium complexes or their exact mechanism of action. It has been shown that titanocene dichloride is enriched in areas near the nuclear chromatin, covalently binds to DNA and inhibits DNA synthesis. Interestingly, the binding to DNA occurs via the phosphate backbone rather than the nucleobases. Titanocene dichloride was also reported to inhibit human topoisomerase II. Concerning the cellular uptake, it seems that transferrin, as well as albumin, plays a role in transferring Ti into the cell. While stripping of the ligands is required for trafficking of Ti via transferrin, a route via albumin could leave the complexes intact. An adduct of the complex stabilized by albumin might then enter the cell. This would promote a more active role for these drugs in contrast to the prodrug role proposed for the transferrin delivery mechanism. Consistent with these findings, two methyl substituted titanium salane complexes were recently reported to be cytotoxic independent of transferrin. We herein report the synthesis of halogen-substituted titanium salane complexes 2a–d and their detailed biochemical evaluation in two different tumor cell lines. The salane ligands 1a–d were accessible by simple refluxing the appropriate phenol, N,N’-dimethylethylenediamine and formaldehyde in methanol. Metalation with titanium tetraisopropoxide (TiACHTUNGTRENNUNG(OiPr)4) finally gave the racemic C2 symmetrical complexes [23,24] (Scheme 1), which could be recrystallized from n-hexane or ACHTUNGTRENNUNGtoluene.