Investigation of the cyclopentadienyl loss of titanocene-DNA adducts in negative ESI-MS/MS

Metallocenes and their derivatives have been found to be a promising alternative to the widely used platinum-based anticancer drugs. Same as platinum-based agents, metallocenes, such as Titanocene dichloride (Cp2TiCl2, Cp = cyclopentadienyl), bind to nuclear DNA, inhibiting the cell replication and, therefore, reducing the growth of the cancer cells. Current investigations with positive ESI-MS/MS on the binding mechanism of titanocene have revealed the phosphate group adjacent to a thymine nucleobase as favored binding site. In contrast to the backbone fragmentation occurring after CID of cationic adducts ([M+Cp2Ti]n+), CID of cationic titanocene-DNA adducts ([M+Cp2Ti]n-) lead to the loss of the cyclopentadienyl ligands and only minor backbone scission. On closer consideration, the resulting ion was identified as the odd-electron titanium-DNA adduct [M+Ti]n-•. This implies that one cyclopentadienyl is lost as C5H5•, whereas the other is released as C5H6. High-resolution tandem Mass Spectrometry has been used to further investigate this unusual electron transfer during the ligand loss as well as the localization of the remaining unpaired electron