Synthesis, Molecular Structure (X-ray and DFT), and Solution Behavior of Titanium 4-Acyl-5-pyrazolonates. Correlations with Related Antitumor β-Diketonato Derivatives

Previously reported structure−activity relationships have shown two features for effective antitumor activity of titanium β-diketone complexes:  (a) ligand asymmetry and (b) the presence of planar substitutents on the ligand. Mono- and dinuclear derivatives, studied with diffraction and DFT methods show that (a) is consistent with different Ti−O(β-diketonato) bond lengths, which are longer than Ti−O(oxo) and Ti−O(alkoxy) ones. π−π features observed in dinuclear derivatives correlate with strong reactivity of related complexes with DNA and support DNA intercalation by such planar groups, in agreement with (b). Large variation for Ti−O bond lengths and Ti−O−C bond angles in the ethoxy moiety is associated with the titanium withdrawing effect and oxygen bonding s character; it is confirmed through exploration of the Cambridge crystallographic database. This ethoxy geometrical flexibility also suggests versatile accommodation in protein pockets and/or other biological targets. Electrospray ionization mass spectrometry (ESI-MS) spectra show formation of di- and trinuclear Ti-4-acyl-5-pyrazolonato cationic oligomers. Hydrolysis/oligomerization is also described by NMR results.