Synthesis and Cytotoxicity Studies of New Morpholino-Functionalised and N-Heteroaryl-Substituted Titanocene Anticancer Drugs

M.      Tacke; M.      Hogan; J.      Claffey; C.      Pampillon

Abstract

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 TiCl4 resulting in morpholino-functionalised titanocenes 5a-c. When these titanocenes were tested against LLC-PK cells, the IC50 values obtained were of 24, 36, and 41 μM respectively. The most cytotoxic titanocene in this paper (5a) with an IC50 value of 24 μM is found to be almost ten times less cytotoxic than cis-platin, which showed an IC50 value of 3.3 μM 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 IC50 value obtained for titanocene 5a is approximately 100 times better than titanocene dichloride itself.

Keywords: Anti-cancer drugs, cis-platin, titanocene, fulvene, morpholino-functionalised metallocenes, nitrogen containing heteroaryl-substituted metallocenes, RCC, LLC-PK