Synthesis, characterization and cytotoxicity studies of novel organo-metallic compounds

Despite the discovery of cis-platin in the treatment of cancer there hasbeen a considerable exploration on the antitumoral activity of othertransition metal complexes. One of the main problems about theapplication of transition metal complexes for chemotherapy is theirpotential toxicity. For instance, recently the attention has been focusedon titanium based complexes, which could have significant potentialeffect against solid tumor. The advantage of Ti(IV) complexes is theirrelative biological compatibility, which mostly leads to mild and revisableside effects. However, the hydrolytic instability of known Ti(IV)complexes and formation of various different species upon water additionmakes their therapeutic application problematic, and raises a stronginterest in the development of relatively stable Ti(IV) complexes with welldefined hydrolytic behavior that demonstrate appreciable cytotoxicactivity. Strong ligand binding is also of interest to avoid complete ligandstripping by transferrin, so that the ligand may be used as a target forstructure-activity relationship investigations.Titanocene dichloride (Cp2TiCl2) shows an average antiproliferativeactivity in vitro but promising results in vivo. Considerable work has beenperformed in developing therapeutic analogues of Cp2TiCl2 by varyingthe central metal, the labile ligands (Cl) and the bis-cyclopentadienylmoiety. In particular, small changes to the Cp ligand can strongly affectthe hydrolytic stability and water solubility properties of the metallocenesand have an impact on the cytotoxic activity.For a better exploration of the parameters affecting activity and itsmechanistic aspects, the synthesis and investigation of particularlydesigned complexes based on different strongly coordinating ligands hasbeen our main purposeWe synthesized novel titanocene and half-titanocene derivatives, havingsubstituted cyclopentadienyl ligands; all the complexes have been fullycharacterized by NMR, elemental analysis and MS. Additionally westudied the rate of hydrolysis of these complexes. Starting from thereflection that the different activities of the complexes could be related totheir different stabilities, the hydrolysis stability represents a firstpossible indication on the achievable cytotoxic effects of synthesizedcompounds.The synthesized compounds have been evaluated for their cytotoxicpotential against cancer cell lines. Most of these compounds showedsignificant anti-proliferative effects compared to cisplatin [edited by Author]