Budotitane

Abstract: Cisplatin, cis-diamminedichloroplatinum(II), and carboplatin, cis-diammine(cyclobutane-1,1-dicarboxylato)platinum(II), are the first drugs from inorganic chemistry to have come under routine clinical use in medical oncology. Their antitumor activity ranges from testicular carcinomas, ovarian carcinomas, and tumors of the head and neck to bladder tumors. However, the spectrum of indication is fairly limited. There is no or only insufficient antitumor activity in tumors which account for the major share of cancer mortality today, e.g. lung tumors and gastrointestinal tumors. Direct derivatives of cisplatin such as carboplatin have only led to a limited reduction or change in drug toxicity. In most cases, the toxicity pattern has changed from nephrotoxicity to myelotoxicity. New metal complexes are now being developed which are designed to supplement the spectrum of indication of platinum complexes. Among non-platinum complexes, budotitane (INN), cis-diethoxybis(1-phenylbutane-1,3-dionato)titanium(IV), is among the most advanced. It is undergoing clinical trials today. Extensive investigations into structure-activity relations have clearly shown a dependence of the activity on the central metal and the diketonato ligand. The tumor-inhibiting effect decreases in the order titanium > zirconium > hafnium > molybdenum > tin > germanium. Antitumor activity is also highly dependent on the nature of the diketonate used. Ligands substituted with planar aromatic ring systems such as the phenyl groups in budotitane are advantageous. Most of the tumor-inhibiting bis(β-diketonato) complexes are cis-configurated. The cis-configurated compounds with an unsymmetrically substituted β-diketonate as ligand are in an equilibrium between three possible cis-isomers in solution at room temperature, due to the fact that the diketonate can rotate via a twist mechanism. The easily hydrolizable group in these complexes does not play a major role in antitumor activity, but it is important for the galenic formulation in the clinic. The ethoxy group as leaving group in budotitane hydrolizes at a slower rate than the corresponding halides.

Abstract: Carefully design your ligand! A new family of highly cytotoxic TiIV complexes demonstrates strong dependence of activity on the particular ligand employed, in which small structural modifications dramatically affect both hydrolytic behavior and biological activity (see picture). Different structure-dependence patterns are observed for hydrolysis and cytotoxicity, which are, nonetheless, strongly related. We recently introduced a new class of bis(isopropoxo)–TiIV complexes with diamine bis(phenolato) ligands that possess antitumor activity against colon HT-29 and ovarian OVCAR-1 cells that is higher than that of the known TiIV compounds titanocene dichloride and budotitane as well as that of cisplatin. Herein, we elaborate on this family of compounds; we discuss the effect of structural parameters on the cytotoxic activity and hydrolytic behavior of these complexes, seeking a relationship between the two. Whereas complexes with small steric groups around the metal center possess high activity and lead mostly to formation of O-bridged polynuclear complexes with bound bis(phenolato) ligand upon water addition, bulky complexes hydrolyze to release all free ligands and are inactive. Slightly increasing the size of the N-donor substituents probably weakens the ligand binding in solution, and, thus, rapid hydrolysis is observed, leading to a lack of cytotoxicity, supporting the requirement for ligand inertness. Replacing the two isopropoxo ligands with a single catecholato unit gives a complex with a different geometry that exhibits slower hydrolysis and reduced cytotoxicity, suggesting some participation of labile ligand hydrolysis in the cytotoxicity mechanism. A crystallographically characterized O-bridged polynuclear species obtained from a biologically active bis(isopropoxo) complex upon water addition is inactive, which rules out its participation as the active species, yet suggests some role of the particular steric and electronic requirements allowing its formation in the activity mechanism. Additional measurements support rapid formation of the active species in the presence of cells prior to O-bridged TiIV cluster formation.

Abstract: 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 (Scheme 1), which could be recrystallized from n-hexane or ACHTUNGTRENNUNGtoluene.

Abstract: Titanium(IV) coordination complexes represent attractive alternatives to platinumbased anticancer drugs. The advantage of the titanium metal lies in its low toxicity, and the hydrolysis of titanium(IV) coordination complexes in biological water-based environment to the safe and inert titanium dioxide is an enormous benefit. On the other hand, the rapid hydrolysis of titanium(IV) complexes in biological environment and their rich aquatic chemistry hampered the exploration and the development of effective compounds. Titanium(IV) complexes were the first to enter clinical trials for cancer treatment following the success of platinum-based chemotherapy, with the pioneering compounds titanocene dichloride and budotitane. Despite the high efficacy and low toxicity observed in vivo, the compounds failed the trials due to insufficient efficacy to toxicity ratio and formulation complications. The rapid hydrolysis of the complexes led to formation of multiple undefined aggregates and difficulties in isolating and identifying the particular active species and its precise cellular target. Numerous derivatives with different labile ligands or substitutions on the inert ones contributed to improve the complex anticancer features, and the best ones were comparable with, and occasionally better than cisplatin. Hydrolytic stability was improved in some cases but remained challenging. The following generation of phenolato-based complexes that came three decades later exhibited high activity and markedly improved stability, where no dissociation was observed for weeks in biological solutions. Complexes of no labile ligands whatsoever that remain intact in solution demonstrated in vitro and in vivo efficacy, with no signs of toxicity to the treated animals. Mechanistic insights gained for the different complexes analyzed include, among others, possible interaction with DNA and induction of apoptosis. Such complexes are highly promising for future exploration and clinical development.