Top-down mass spectrometry reveals multiple interactions of an acetylsalicylic acid bearing Zeise\u2019s salt derivative with peptides

Monika Cziferszky,Ronald Gust

doi:10.1007/s00775-020-01760-9

Monika Cziferszky, Ronald Gust

Open Access

https://doi.org/10.1007/s00775-020-01760-9

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Abstract

Synergistic effects and promising anticancer activities encourage the combination of non-steroidal anti-inflammatory drugs with metallodrugs. Here, we discuss the interactions of an organometallic complex consisting of an acetylsalicylic acid (ASA) moiety attached to a PtII center via an alkenol linker in a Zeise’s salt-type coordination (ASA–buten–PtCl3) with model peptides angiotensin 1 (AT), substance P (Sub P), and ubiquitin (UQ). Top-down mass spectrometry experiments show that the amino acid involved in the initial binding to the metal complex controls the coordination sphere of PtII in the adducts. The strong trans labilizing effect of the coordinating sulfur atom in Met causes fast release of the organic moiety and leads to the formation of dimers and oligomers in the case of Sub P. In contrast, interactions with nitrogen donors in AT result in stable adducts containing the intact ASA–buten–PtII complex. UQ forms two sets of PtII adducts, only one of them retains the ASA moiety, which is presumably the result of an unexpected binding geometry. Importantly, UQ is additionally acetylated at various Ser and Lys residues by the ASA–buten–PtCl3 complex. Control experiments with ASA are negative. This is the first example of concomitant platination and acetylation of a peptide with an ASA metal complex.

Highlights

In the quest for novel anticancer agents, the combination of metallodrugs with biologically active compounds is gaining momentum
An Mass spectrometry (MS)-based study on the reaction products of Zeise’s salt with angiotensin 1 (AT) and UQ was published recently by our group [45], where we demonstrated that trans labilizing effects play a crucial role in the overall peptide metallation by P tII complexes
The details of the aquation of acetylsalicylic acid (ASA)–buten–PtCl3 remain elusive at this point due to inherent changes in the charge state of the P tII complex that pose a challenge for an observation by mass spectrometry

Summary

Introduction

In the quest for novel anticancer agents, the combination of metallodrugs with biologically active compounds is gaining momentum. Metal complexes of non-steroidal anti-inflammatory drugs (NSAIDs) show synergistic effects and promising anticancer activities. A recent review [1] discusses a vast number of metal complexes of NSAIDs and their antibacterial, antifungal, and antiproliferative activities as well as DNA-binding properties, highlighting the advantages and possibilities of these drug candidates. Overexpression of COX-2 in different types of tumors, such as prostate, colon, or breast cancer, makes this enzyme an interesting target for the development of novel anticancer drug candidates. Most NSAIDs non-selectively inhibit both COX enzymes. Coordination of NSAIDs to metal centers aims at obtaining antiproliferative activity through a dual mode of action: inhibition of COX and, e.g., ROS generation by the metal.

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