Synthesis and MALDI MS/MS characterization of a cis-diaminocyclohexyl Pt(II)-vitamin B12 complex potentially useful for targeted drug delivery

The water-soluble vitamin B12 is essential for most organisms despite being produced by only a few bacteria. The demand for vitamin B12 is particularly high at sites of enhanced proliferation, such as cancer cells, making it particularly attractive as targeting agent. Indeed, the use of vitamin B12 for selectively delivering radioisotopes or various cytotoxic agents into cancer cells has already been actively investigated [1-3]. To these purposes vitamin B12 needs to be derivatized by the introduction of modifiers, such as ligands or receptor binding molecules. Coordination to the ribose ring and oxidative alkylation are the most common synthetic routes. Interestingly, vitamin B12 has been used to form adducts with Tc and Re complexes linked to the axial positions of the cobalt center [1], demonstrating that its Co(III)-CN moiety tends to bridge a second metal (M) ion to form a {Co-CN- M} unit. Cisplatin (cis-diammine-dichloro-Pt(II)) is one of the most potent agents against a wide variety of solid tumors, its cytotoxicity being mediated by formation of DNA adducts [4]. Thus the possibility of using vitamin B12 as a ligand for cisplatin (and its analogues) would be highly desirable in view of a targeted delivering of anticancer drugs [2]. In this communication, we demonstrate that Co-CN in vitamin B12 bridges to Pt(II) center yielding stable complexes with the central structural feature {Co-CN-Pt}. The formation of the cis-Pt(II) complex with vitamin B12 (m/z 1663.647) was investigated by matrix assisted laser desorption/ionization mass spectrometry, MALDI MS in positive ion mode, using 4-chloro-α-cyanocinnamic acid as a matrix [5]. Structural characterization was accomplished by collision-induced dissociation (ToF/ToF) MS analysis.