Chelate stabilization of a titanium(IV)-salan alkoxide by ligand exchange with 2,6-pyridinedicarboxylic acid (dipic) resulted in heptacoordinate complex 3 which is not redox-active, stable on silica gel and has increased aqueous stability. 3 is highly toxic in HeLa S3 and Hep G2 and has enhanced antitumor efficacy in a mouse cervical-cancer model.

To discover chemical probes to further under-stand the function of individual DNA polymerases, we established a generally applicable high-throughput screening. By applying this technique we discovered three novel inhibitor classes of human DNA polymerase λ (DNA Pol λ), a key enzyme to maintain the genetic integrity of the genome. The rhodanines, classified as an excellent drug scaffold, were found to be the most potent inhibitors for DNA Pol λ. Importantly, they are up to 10 times less active against the highly similar DNA polymerase β. We investigated basic structure activity relationships. Furthermore, the rhodanines showed pharmacological activity in two human cancer cell lines. So the here reported small molecules could serve as useful DNA Pol λ probes and might serve as starting point to develop novel therapeutic agents.

The synthesis, biochemical evaluation, and hydrolysis studies of a wide selection of alkyl- and halogen-substituted titanium salan alkoxides are presented herein. A systematic change in the employed alkoxides revealed that both the bulk of the salan ligands and the steric demand of the labile ligands are of great importance for the obtained biological activity. Surprisingly, these two factors are not independent from each other; lowering the steric demand of the alkoxide of a hitherto nontoxic complex renders it cytotoxic. Therefore, our data suggest that the overall size of the complex exerts a strong influence on its biological activity. To decide whether the correlation between the cytotoxicity and the steric demand of the whole complex is merely based on an altered hydrolysis or on the interaction with biomolecules, the behavior of selected complexes under hydrolytic conditions and the influence of transferrin were investigated. Complexes differing only in their labile alkoxy ligands gave the same hydrolysis products with similar hydrolysis rates but displayed cytotoxicities that differed in the range of one order of magnitude. Thus, it seems that the hydrolysis product is not the active species but rather that the unhydrolysed complex is important for the first interaction with a biomolecule. This promoted the idea of hydrolysis being a detoxification pathway. In accordance with the above conclusion, chloro-substituted complex [Ti(Ph(Cl)N(Me))(2)(O(iPr))(2)] displayed a high cytotoxicity (IC(50) approximately 5 microM) and surprisingly high hydrolytic stability (t(1/2)=108 h). These findings, together with the observed cytotoxicity in a cisplatin-resistant cell line, make halo-substituted salan complexes an interesting target for further studies.

The anticancer activity of titanium complexes has been known since the groundbreaking studies of Köpf and Köpf-Maier on titanocen dichloride. Unfortunately, possibly due to their fast hydrolysis, derivatives of titanocen dichloride failed in clinical studies. Recently, the new family of titanium salan complexes containing tetradentate ONNO ligands with anti-cancer properties has been discovered. These salan complexes are much more stabile in aqueous media. In this study we describe the biological activity of two titanium salan complexes in a mouse model of cervical cancer. High efficiency of this promising complex family was demonstrated for the first time in vivo. From these data we conclude that titanium salan complexes display very strong antitumor properties exhibiting only minor side effects. Our results may influence the chemotherapy with metallo therapeutics in the future.

Metal‐based antitumor agents: Halogen‐substituted titanium salane complexes showed IC50 values comparable to cisplatin. In contrast to their alkyl‐substituted congeners, they almost exclusively induced apoptotic cell death. This unique combination of very low IC50 values and pronounced preference for apoptosis makes them promising therapeutic agents.magnified image

Titanocene difluorides can be obtained by halide metathesis of the respective titanocene dichlorides with trimethyltin fluoride (Me(3)SnF), giving access to a new class of cytotoxic active substances. Furthermore, an improved method for the synthesis of diaryl-substituted titanocene dichlorides is presented.

Seven heptacoordinate titanium(IV) complexes were synthesized based on the concept of hetero-bis-chelate stabilization of salan (ONNO) and thiosalan (OSSO) titanium(IV)alkoxides with 2,6-pyridinedicarboxylic acid (dipic) and derivatives thereof. The resulting compounds were investigated in a solid by X-ray diffraction and in solution by NMR spectroscopy. A thiosalan (OSSO) titanium(IV) complex could be isolated and its conformational stabilization by dipic was shown by (1)H NMR spectroscopy to lead to nonfluxional behavior even at room temperature. The stability of selected complexes was assessed at pH 1.9, 6.8, and 12.1 by an UV-vis monitored hydrolysis study with >5 Mio. equivalents of water. Even at pH 12.1 [L(1)Ti(dipic)(1)] showed t1/2 of more than 2 days. The cytotoxicity of all compounds was investigated in two human carcinoma cell lines. IC50-values in the range of cisplatin were achieved by all tested compounds except for [L(4)Ti(dipic)(1)], which was proven to be nontoxic. The functionalization of dipic was thus well tolerated and did neither interfere with the stability nor the cytotoxicity of the heteroleptic complexes.

Controlled hydrolysis of donor-substituted titanium-salan complexes led to the formation of well-defined dinuclear complexes. Structure determination by means of X-ray and NMR-studies revealed the presence of a single μ-oxo bridge and one labile alkoxide ligand per titanium center. Concomitant cytotoxicity assays of the isolated dinuclear complexes showed cytotoxicities in the low micro-molar region, surpassing in this respect even their monomeric ancestors, thus making them possible highly active metabolites of titanium-salan anti-cancer drugs.