Transition Metal-based Anticancer Drugs Targeting Nucleic Acids: A Tandem Mass Spectrometric Investigation

Abstract

The search for effective drugs against cisplatin-resistant tumors resulted in a large number of organometallic compounds that are evaluated for their antiproliferative activity. Among the most promising candidates are bent metallocenes based on various transition metal ions and ligands. The elucidation of structural features and the characterization of the interaction of a drug candidate with its target require accurate and sensitive analytical tools. Tandem mass spectrometry is applied to the investigation of the adduct sites and binding patterns of metallodrugs bound to single-stranded oligonucleotides and higher-order nucleic acids. Results reveal the binding specificities of the different metallodrugs and demonstrate the influence they exert on the dissociation pathways of the adducts in the gas-phase.

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

“…Tandem mass spectrometry was used to investigate the binding mode interaction of 11Cl with single-(ss) and doublestrand (ds) DNA oligomers. 77,78 After incubation, 43 and 23% of the identified ssDNA and dsDNA ions contained ruthenium, respectively, with [Ru(η 6 -toluene)(PPh 3 )] 2+ as the main ruthenium adduct in the gas phase (in agreement with the fragmentation behavior observed during the characterization of the complexes, see above). The interaction between the oligonucleotides and 11Cl is non-covalent in nature (in agreement with fluorescence and circular dichroism data) as loss of the ruthenium from the isolated adduct can be observed even when no collision-induced dissociation energy (to fragment the ions) is applied.…”

The multifaceted roles of mass spectrometric analysis in nucleic acids drug discovery and development

“…In particular, the covalent attack to the N7 nucleophilic position of purines is known to weaken the corresponding N‐glycosidic bond, which promotes depurination and strand cleavage at the ensuing abasic site. This effect has been observed for a wide range of electrophilic agents including metal‐based therapeutics (Eberle et al, 2017; Iannitti‐Tito et al, 2000; Nyakas et al, 2011; Wickham et al, 1995; Zeng et al, 2019) and alkylating drugs, such as oxirans (Iannitti et al, 1997; Wickham et al, 1995), nitrogen mustards (E. Yu & Fabris, 2003; Q. Zhang et al, 2006), bis‐3‐chloropiperidines (Carraro et al, 2019; Sosic et al, 2017; Sosic et al, 2021), and many others (Scheme 1). This observation has spurred the systematic exploration of alternative activation techniques to identify possible solutions for minimizing base losses in favor of backbone fragmentation (reviewed in depth in Silvestri & Brodbelt, 2013).…”

“…In particular, the covalent attack to the N7 nucleophilic position of purines is known to weaken the corresponding N-glycosidic bond, which promotes depurination and strand cleavage at the ensuing abasic site. This effect has been observed for a wide range of electrophilic agents including metal-based therapeutics (Eberle et al, 2017;Iannitti-Tito et al, 2000;Nyakas et al, 2011;Zeng et al, 2019) and alkylating drugs, such as oxirans (Iannitti et al, 1997;, nitrogen mustards (E. Yu & Fabris, 2003;Q. Zhang et al, 2006), bis-3chloropiperidines (Carraro et al, 2019;Sosic et al, 2017;, and many others (Scheme 1).…”

Bent DNA Bows as Sensing Amplifiers for Detecting DNA-Interacting Salts and Molecules

“…On the other hand, we would like to emphasize that such limitation does not prevent the bent DNA bows from being good sensing amplifiers in certain applications. Just like a light sensor that does not distinguish colors could be useful in applications where uniform responses to a wide spectrum are desired (e.g., monochromatic CCD cameras in fluorescence microscopy), the bent DNA bows could be great sensing amplifiers for screening a pool of molecules and identifying the candidates that interact with DNA in pharmaceutical applications [81,82].…”