Bioorganometallic chemistry-New vanadium complexes as optical probes to detect Cys sulfenic modifications in PTEN

摘要

Over the past few decades, a large number of proteins and enzymes have been identified wherein chemoselective oxidation of cysteine residues by reactive oxygen species (ROS) acts as a mechanism to alter or regulate normal cellular functions [1]. Generally, sulfenic acid (SOH) formation is the first event in the oxidative process and it has been widely reported as an important post-translational modification (PTM) found in several oxidative stress-related diseases, such as cancer and neurodegenerative disorders [2]. Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) is a member of the protein tyrosine phosphatase family known as an important tumor suppressor whose function includes significant roles in oxidative damage-associated pathologies [3]. According to recent studies, the switch-off nature of SOH modification functions as a reversible means to regulate PTEN function as well as a marker of initial protein damage. In this scenario, chemical probes for SOH detection could represent promising new tools for elucidating PTEN signaling pathways and regulatory mechanisms that involve thiol oxidation and redox regulation. This evidence led us to design, synthesize, and biologically evaluate a new series of vanadium complexes as optical probes towards modified PTEN (i.e. its sulfenic acid form), with the ultimate aim to detect and optically visualize the SOH oxidative modification on this enzyme by fluorescence methods. In previous studies we identified VO-OHpic, a vanadyl complex which displays remarkable affinity for PTEN inhibiting its activity in a dose dependent manner [4]. Thus, we have worked towards modifying VOOHpic by the introduction of coumarin- or naphthalenesulfonic-based fluorophores and dimedone (5,5-dimethyl-1,3-cyclohexane-dione) moiety, a cyclic ?-diketone which selectively reacts with sulfenic acids [1], in order to reach both optical visualization and SOH detection of oxidativeliy-damaged PTEN. Combining the three targeting modules (VO-OHpic + dimedone + fluorophore), a library of novel 'bridged-bipicolinic vanadyl complexes' has been synthesized and its biological evaluation is ongoing to confirm the success of our targeting strategy for the development of new complexes as versatile tools to be easily modified for structure–activity relationship (SAR) analysis towards PTEN sulfenic oxidative damage investigation. Financial support by the EPSRC (UK) through the Proxomics Project (http://www.proxomics.ac.uk/) is gratefully acknowledged.