Benzyl-substituted titanocene dichloride anticancer drugs: From lead to hit

Through the reaction of Super Hydride (LiBEt3H) with 6-phenyl-substituted fulvenes followed by transmetallation to TiCl4 ten novel benzyl-substituted titanocene dichloride derivatives were synthesised. 6(4-morpholinomethyl-phenyl) fulvene (6g) and (bis-[(4-methoxymethyl-benzyl)cyclopentadienyl]titanium(IV) dichloride) (8a) were characterised by single crystal X-ray diffraction. All of the titanocenes had their cytotoxicity investigated through preliminary in vitro testing on the LLC-PK (pig kidney epithelial) cell line and CAKI-1 human kidney cell human carcinoma cell line in an MTT based assay in order to determine their IC50 values. The titanocenes synthesised were found to have IC50 values ranging from 2.3 (±0.3) μM (comparable to cisplatin) to others which show no anti-proliferative activity on this cell line in standard DMSO formulations on LLC-PK cell line. Eight of the titanocenes were found to be completely water-soluble and had IC50 values of 6.5 (±0.7) μM to no activity when using medium only for formulation. On the CAKI-1 cell line, IC50 values of 7.8 (±1.4) μM to no activity were found using DMSO formulation, while IC50 values of 0.55 (±0.32) μM to no activity were measured using just medium as the formulation reagent. Some of the titanocenes show significant cytotoxicity improvement when compared directly to the lead compound Titanocene Y (bis-[(p-methoxybenzyl)cyclopentadienyl] titanium(IV) dichloride) and are more cytotoxic than cisplatin. Bis-[(4-diethylaminomethyl-benzyl)cyclopentadienyl]titanium(IV) dichloride (8d) at this preliminary stage seems to be the most promising of the ten compounds prepared and exhibits nanomolar activity against CAKI-1.

Within the synthesis of several benzyl-substituted titanocene dichlorides is reported starting from 6-phenyl-substituted fulvenes. This synthesis has led to the discovery of new water-soluble benzyl-substituted titanocenes. Each compound had MTT-based cytotoxicity tests on pig kidney epithelial (LLC-PK) cells and human CAKI-1 renal cancer cells completed, which show promising cytotoxic behaviour for some compounds comparable to or better cytotoxicities than cisplatin.Figure optionsDownload as PowerPoint slide