Synthesis and cytotoxicity studies of new morpholino-functionalised and N-heteroaryl-substituted titanocene anticancer drugs.

From the carbolithiation of 6-morpholino fulvene (3) and different lithiated nitrogen containing heterocycles (2-N-methylimidazolyl, 2-N-(N,N-dimethylamino)methyl-imidazolyl, and 2-N-methylindolyl), the corresponding lithium cyclopentadienide intermediate (4a-c) was formed. These three lithiated intermediates underwent a transmetallation reaction with TiCl(4) resulting in morpholino-functionalised titanocenes 5a-c. When these titanocenes were tested against LLC-PK cells, the IC(50) values obtained were of 24, 36, and 41 microM respectively. The most cytotoxic titanocene in this paper (5a) with an IC(50) value of 24 microM is found to be almost ten times less cytotoxic than cis-platin, which showed an IC(50) value of 3.3 microM when tested on the epithelial pig kidney LLC-PK cell line, and approximately 2 times less cytotoxic than its dimethylamino-functionalised analogue. Encouragingly however, the IC(50) value obtained for titanocene 5a is approximately 100 times better than titanocene dichloride itself.

Substituted titanocenes induce caspase-dependent apoptosis in human epidermoid carcinoma cells in vitro and exhibit antitumour activity in vivo.

Titanocene compounds are a novel series of agents that exhibit cytotoxic effects in a variety of human cancer cells in vitro and in vivo. In this study, the antiproliferative activity of two titanocenes (Titanocenes X and Y) was evaluated in human epidermoid cancer cells in vitro. Titanocenes X and Y induce apoptotic cell death in epidermoid cancer cells, with IC50 values that are comparable to cisplatin. Characterisation of the cell death pathway induced by titanocene compounds in A431 cells revealed that apoptosis is preceded by cell cycle arrest and the inhibition of cell proliferation. The induction of apoptosis is dependent on the activation of caspase-3 and -7 but not caspase-8. Furthermore, the antitumour activity of Titanocene Y was tested in an A431 xenograft model of epidermoid cancer. Results indicate that Titanocene Y significantly reduced the growth of A431 xenografts with an antitumour effect similar to cisplatin. These results suggest that titanocenes represent a novel series of promising antitumour agents.