Synthesis and cytotoxicity studies of new dimethylamino-functionalised and hetero aryl-substituted titanocene anti-cancer drugs

From the carbolithiation of N,N-dimethylamino fulvene (3a) and different ortho-lithiated heterocycles (furan, thiophene and N-methylpyrrole), the corresponding lithium cyclopentadienide intermediate (4a-c) was formed. These three lithiated intermediates underwent a transmetallation reaction with TiCl4 resulting in dimethylamino-functionalised titanocenes 5a-c. When these titanocenes were tested against LLC-PK cells, the IC50 values obtained were of 240, and 28 mu M for titanocenes 5a and 5b, respectively. The most cytotoxic titanocene 5c with an IC50 value of 5.5 mu M is found to be almost as cytotoxic as cis-platin, which showed an IC50 value of 3.3 mu M, when tested on the LLC-PK cell line, and titanocene 5c is approximately 400 times better than titanocene dichloride itself. (c) 2007 Elsevier B.V. All rights reserved.