In vitro reactions of a cyanocobalamin–cisplatin conjugate with nucleoside monophosphates

Abstract

Rationale Cisplatin (CP) is a widely used anticancer drug characterized by toxic side effects that could be alleviated using novel delivery systems including CP prodrugs. The in vitro incubation of a putative prodrug, obtained from cyanocobalamin (CNCbl) and cis‐diamminemonochloroplatinum(II) (mCP), with nucleoside monophosphates (NMPs) was investigated. Methods The in vitro reactions between the putative prodrug CNCbl‐mCP and the NMPs of adenosine (AMP), guanosine (GMP), cytidine (CMP) and uridine (UMP) were carried out in slightly acidic water–methanol solutions at 37°C for 24 h. Each sample was examined using reversed‐phase liquid chromatography coupled with electrospray ionization in positive ion mode and tandem mass spectrometry (RPLC/ESI‐MS/MS) by collision‐induced dissociation in a linear ion‐trap mass spectrometer. Results Seven adducts were recognized as formed by substitution reactions of the chloride ligand in planar CP. Comparison between observed and theoretical isotopic patterns together with MS/MS fragmentation pathways revealed the presence of single or multiple binding sites depending on the NMP involved. The CNCbl‐mCP conjugate was found to interact with N7 or O4 atoms of GMP and UMP, respectively, generating single adducts, while two isomeric adducts were observed for CMP. Finally, AMP gave rise to three isomeric adducts. Conclusions In agreement with literature data relevant to the interaction between CP and NMPs, the most reactive nucleotides were AMP and GMP. The present RPLC/ESI‐MS/MS approach is very promising for investigation of the reactions of CP conjugates with ribonucleotides not only in vitro but also in vivo.

Ligand-Tuning of the Stability of Pd(II) Conjugates with Cyanocobalamin

“…By using CblCN as a carrier, inorganic cytostatic agents can also be selectively accumulated in cancer cells, so that the side effects of traditional chemotherapy are significantly reduced. For obvious reasons, most of the studies reported have focused on cisplatin and related complexes [ 23 , 25 , 26 , 27 , 31 , 32 ]. Efficient inhibition of DNA replication and transcription abilities, requires a drug release within the cell that is enabled by CN bridging, which is prone to the action of both intracellular enzymes [ 23 ] and visible light inducing photo-decay of the cobalt-carbon bond [ 33 ].…”