Morpholino‐Functionalized and Heteroaryl‐Substituted Titanocene Anti‐Cancer Drugs: Synthesis and Cytotoxicity Studies

From the carbolithiation of 6‐morpholino 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 morpholino‐functionalised titanocenes 5a – c . When these titanocenes were tested against LLC‐PK cells, the IC₅₀ values obtained were of 58, 63 and 115 μM for titanocenes 5a – c respectively. The most cytotoxic titanocene 5a with an IC₅₀ value of 58 μM is found to be approximately 20 times less cytotoxic than cis‐platin, which showed an IC₅₀ value of 3.3 μM, when tested on the LLC‐PK cell line, and 10 times less cytotoxic than its dimethylamino‐functionalised analogue (Titanocene C , IC₅₀ = 5.5 μM).