Titanium (IV) complexes of thianthrene and dibenzodioxin as possible antitumour agents

Abstract

This study involves the synthesis and characterization of new organometallic complexes of Ti(IV). Such complexes are designed to act as possible antitumour agents and thus include ligands with specific functions. As target for biological activity, the DNA double helix was identified. These complexes include (i) a labile halogen ligand which is capable of forming a covalent bond with DNA, (ii) a planar condensed 3-membered ring system which may act as intercalator in the major groove of DNA and (iii) two bulky, non-labile stopper ligands which will control the degree of intercalation. The complexes represent two groups, namely those where the transition metal is bonded directly to the planar ring system and those where a sulphur atom is located between the metal and the ring system. The sulphur acts as a spacer and causes the ring system to be out of the plane of the metal fragment. New complexes [TiCpi(R)Cl], [TiCpi(R)2], [TiCpi(SR)Cl] and [TiCpi{SR)2 ] (R = thianthrene, dibenzodioxin) were prepared by adding the lithiated rings or the metallated thiolates to titanocene dichloride. Also studied was the insertion of titanocene dichloride into ring-opened, dilithiated thianthrene. The composition of the new complexes were determined by using NMR studies, mass spectrometry and micro analysis. The structure of [TiCpi(Db )Cl] was confirmed by a single crystal X-ray diffraction study. Since the molecular geometries of the complexes are of utmost importance for their interaction with DNA, their three-dimensional structures were also studied using computer generated spacefill models. From these results, the structures of the complexes were obtained and together with their physical features, the complexes [TiCpi(Db )Cl] and [TiCpi(DbS)Cl] were selected as the best candidates for in vivo and in vitro tests. The latter did not form part of this study.