Synthesis and cytotoxicity studies of new dimethylamino-functionalised and heteroaryl-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 μM for titanocenes 5a and 5b, respectively. The most cytotoxic titanocene 5c with an IC50 value of 5.5 μM is found to be almost as cytotoxic as cis-platin, which showed an IC50 value of 3.3 μM, when tested on the LLC-PK cell line, and titanocene 5c is approximately 400 times better than titanocene dichloride itself.

Bis-(N,N-dimethylamino-2(N-methylpyrrolyl)methylcyclopentadienyl) titanium (IV) dichloride is the most cytotoxic titanocene synthesised so far. It was synthesised starting from 2-(N-methylpyrrolyl) lithium and 6-N,N-dimethylamino fulvene. Herein, we present the synthesis and DFT structure of the titanocene and two further derivatives followed by MTT-based cytotoxicity tests on LLC-PK cells.Figure optionsDownload as PowerPoint slide