Synthesis and cytotoxicity studies of methoxy benzyl substituted titanocenes

Abstract

From the reaction of 6(2-methoxy-phenyl)fulvene ( 1a), 6(3-methoxy-phenyl)fulvene ( 1b), 6(3,4-dimethoxy-phenyl)fulvene ( 1c) and 6(3,4,5-trimethoxy-phenyl)fulvene ( 1d) with LiBEt 3H, lithiated cyclopentadienide intermediates 2a– d were synthesised. These intermediates were then transmetallated to titanium with TiCl 4 to give benzyl substituted titanocenes bis-[(2-methoxy-benzyl)cyclopentadienyl]titanium(IV) dichloride ( 3a), bis-[(3-methoxy-benzyl)cyclopentadienyl]titanium(IV) dichloride ( 3b), bis-[(3,4-dimethoxy-benzyl)cyclopentadienyl]titanium(IV) dichloride ( 3c) and bis-[(3,4,5-trimethoxy-benzyl)cyclopentadienyl]titanium(IV) dichloride ( 3d). The three titanocenes 3a– c were characterised by single crystal X-ray diffraction, while the structure of the fourth titanocene 3d was elucidated through a DFT calculation. All four titanocenes had their cytotoxicity investigated through preliminary in vitro testing on the LLC-PK (pig kidney epithelial) cell line in order to determine their IC 50 values. Titanocenes 3a– d were found to have IC 50 values of 97, 159, 88 and 253 μM, respectively. All four titanocene derivatives show significant cytotoxicity improvement when compared to unsubstituted titanocene dichloride.