Novel achiral titanocene anti-cancer drugs synthesised from bis-N,N-dimethylamino fulvene and lithiated heterocyclic compounds.

From the carbolithiation of 6-bis-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 TiCl(4) resulting in bis-N,N-dimethylamino-functionalised titanocenes 5a-c. When these titanocenes were tested against LLC-PK cells, the IC(50)-values obtained were of 240, and 270 microM for titanocenes 5b and 5c, respectively. The most cytotoxic titanocene in this paper, 5a with an IC(50)-value of 36 microM was found to be approximately six times less cytotoxic than its mono-N,N-dimethylamino substituted analogue Titanocene C (IC(50) = 5.5 microM) and almost ten times less cytotoxic than cisplatin, which showed an IC(50)-value of 3.3 microM, when tested on the LLC-PK cell line.