Specific Interactions of Antitumor Metallocenes with Deoxydinucleoside Monophosphates

Abstract

Bent metallocenes CpMCl (M = Ti, V, Nb, Mo) are known to exhibit cytotoxic activity against a variety of cancer types. Though the mechanism of action is not fully understood yet, the accumulation of the metal ions in the nucleus points towards DNA as one of the primary targets. A set of eight deoxydinucleoside monophosphates was used to study the adduct yields with metallocenes and cisplatin. The binding affinities are reflected by the relative intensities of the adducts and were found to follow the order of Pt > V > Ti > Mo (no adducts were detected with Nb). High-resolution tandem mass spectrometry was applied to locate the binding patterns in the deoxydinucleoside monophosphates. Whereas cisplatin binds to the soft nitrogen atoms in the purine nucleobases, the metallocenes additionally interact with the hard phosphate oxygen, which is in good agreement with the hard and soft (Lewis) acids and bases (HSAB) concept. However, the binding specificities were found to be unique for each metallocene. The hard Lewis acids titanium and vanadium predominantly bind to the deprotonated phosphate oxygen, whereas molybdenum, an intermediate Lewis acid, preferentially interacts with the nucleobases. Nucleobases comprise alternative binding sites for titanium and vanadium, presumably oxygen atoms for the first and nitrogen atoms for the latter. In summary, the intrinsic binding behavior of the different metallodrugs is reflected by the gas-phase dissociation of the adducts. Consequently, MS/MS can provide insights into therapeutically relevant interactions between metallodrugs and their cellular targets. Graphical Abstract ᅟ.

Fine-tuning the cytotoxicity of ruthenium(ii) arene compounds to enhance selectivity against breast cancers

“…This behavior indicates that 11Cl influences the fragmentation behavior of the oligonucleotides, supporting the stabilization of DNA by the ruthenium complex through an interaction with its secondary structure. Additionally, the lack of an apparent nucleotide selectivity or sequence binding preference, 83,84 and the promotion of base-loss pathways, 85 while retaining the backbone and sugar fragments, are coherent with the absence of covalent interactions between the nucleobases and 11Cl , further confirming its interaction with the phosphate backbone in the DNA grooves.…”