Interaction of Antitumor Metallocenes with Nucleic Acids

Eberle, Rahel Patricia; Schürch, Stefan (6 June 2016). Interaction of Antitumor Metallocenes with Nucleic Acids. In: ASMS Conference on Mass Spectrometry and Allied Topics. USA: American Society for Mass Spectrometry

Introduction: Metallocenes Cp2M2+ (with M = Ti, V, Nb, Mo; Cp = cyclopentadienyl and derivatives) represent a promising class of antitumor agents. Evidence was found for the accumulation of the transition metals in the nucleus, thus implying DNA as a primary target. However, the characteristics of the interaction between different types of metallocenes and nucleic acids remain largely unknown. The development of novel metallodrugs requires the identification of the active compounds as well as precise knowledge of their interaction with the target. In the presented study, tandem mass spectrometry is applied to elucidate the patterns and specificities of metallocenes binding to nucleic acids.

Methods: Solutions of metallocene dichlorides (M=Ti, V, Nb, Mo, Hf, and W) were incubated with deoxyoligonucleotides of varying length and nucleotide composition. The resulting adducts were subsequently analyzed by ESI-MS and ESI-MS/MS (CID) in positive and negative ion mode on a LTQ Orbitrap XL instrument.

Preliminary Data or Plenary Speakers Abstract: Adduct formation was found to depend on the type of transition metal and the pH during incubation. ESI-MS data gave evidence for the formation of adducts that retained both cyclopentadienyl ligands as well as adducts that underwent ligand exchange (Cp- to OH-). The adducts were found to be remarkably stable upon CID and sets of fragment ions including the transition metal coordination center could be detected. Tandem mass spectrometric analysis of DNA adducts with first-row transition metals (Ti, V) gave evidence for the consecutive loss of the two Cp ligands. It is hypothesized that the adducts undergo an intramolecular rearrangement involving an adjacent phosphate group, which results in the ejection of the neutral ligands and a strengthened interaction with the oligonucleotide. This hypothesis is further supported by MS3 data, which revealed that product ions including the transition metal exhibit a minimum of three phosphate groups, thus reflecting the pivotal role of the phosphate linker in the fragmentation process. Second- and third-row transition metals (Nb, Mo, W) displayed a considerably altered behavior upon CID with backbone cleavage preferred over the loss of the ligands. Our data reveals that the nucleobase must be involved in the binding of the metallocenes, as base loss fragments carrying the intact metallocene were observed.

Novel Aspect: The elucidation of the binding motifs of metallocenes to nucleic acids is fundamental to the development of novel anticancer drugs.

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