Cyanocobalamin conjugates of cisplatin and diaminocyclohexane-platinum(II): Matrix-assisted laser desorption ionization mass spectrometry characterization using 4-chloro-α-cyanocinnamic acid as the matrix

Abstract

cis-Diamminedichloroplatinum(ii), also known as cisplatin, is a widely used chemotherapeutic agent to treat several malignant tumours, but unfortunately it causes serious side effects, especially nausea, vomiting and nephrotoxicity. Enhancing the selectivity to cancer cells using other compounds combined with cisplatin may overcome these issues. Here, cisplatin and oxaliplatin derivatives bearing a cyanocobalamin (CNCbl) unit were prepared and investigated by matrix-assisted laser desorption/ionization (MALDI) mass spectrometry (MS). A 4-chloro-α-cyanocinnamic acid (ClCCA) matrix was very effective to explore the formation of CNCbl-Pt(ii) conjugates. In the case of cisplatin, the conjugate is formed by the elimination of one easily leaving anionic ligand (i.e., Cl-) from the complex, whereas the cyano group (CN) that is axially coordinated to Co(iii) in CNCbl (M) becomes bound to the Pt(ii) of monochloro cisplatin, thus yielding a heterobimetallic derivative with the most intense peak of the ion cluster at m/z 1619.55 ([M + cis-PtII (NH3)2Cl]+) and an empirical formula of [C63H94ClCoIIIN16O14PPtII]+. Its identity was revealed by tandem MS (CID ToF/ToF) and the subsequent recognition of the most intense product ions. Likewise, the chelating (1R,2R)-1,2-diaminocyclohexane (R,R-DACH) non-leaving group ligand of oxaliplatin, in the form of cis-sulfoaquo R,R-DACH-Pt(ii), produces two different conjugates with CNCbl in MALDI-MS ([M + PtII(R,R-DACH)]+) at m/z 1663.64 and 1664.63, both singly-positively charged, with suggested compositions of [C69H101CoIIIN16O14PPtII]+ and [C69H102CoIIIN16O14PPtII]+, respectively. By properly relying on tandem MS data, it has been possible to propose a detailed description of these two CNCbl-Pt(ii) drug conjugates. This investigation sets the stage for future MALDI MS studies on platinum anticancer drugs.