Morpholino-functionalized and heteroaryl-substituted titanocene anti-cancer drugs: Synthesis and Cytotoxicity studies

摘要

From the carbolithiation of 6-morpholino fulvene (3a) and different ortho-lithiated heterocycles (furan, thiophene and Nmethylpyrrole), 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 58, 63 and 115 tM for titanocenes 5a-c respectively. The most cytotoxic titanocene 5a with an IC50 value of 58 mu M is found to be approximately 20 times less cytotoxic than cis-platin, which showed an IC50 value of 3.3 mu M, when tested on the LLC-PK cell line, and 10 times less cytotoxic than its dimethylamino-functionalised analogue (Titanocene C, IC50 = 5.5 mu M).