Melani Sooriyaarachchi

Probing the coordination behavior of Hg2+, CH3Hg+, and Cd2+ towards mixtures of two biological thiols by HPLC-ICP-AES

Hepatocyte cytosol contains a multitude of proteins, but also comparatively high concentrations of l-glutathione (GSH, ~5.0 mM) and L-cysteine (Cys, ~0.5 mM). Since Hg(2+), CH(3)Hg(+) and Cd(2+) have a high affinity for thiols, their coordination to these thiols is likely involved in their intracellular transport. The comparative coordination behavior of these metal species towards mixtures of Cys and GSH, however, has not been studied under near physiological conditions. To probe these toxicologically relevant interactions, each metal species was separately injected onto a C(18)-HPLC column (37°C) that had been equilibrated with phosphate buffered saline (PBS) that contained 5.0 mM GSH (mobile phase) and detected with an inductively coupled plasma atomic emission spectrometer. The incremental increase of the Cys concentration in the mobile phase (in 0.5 or 1.0 mM steps) up to 10mM followed by the chromatography of each metal species decreased the retention of Hg(2+) and CH(3)Hg(+) albeit in a different manner. This behavior was rationalized in terms of the replacement of hydrophobic GS-moieties coordinated to each mercurial by less hydrophobic Cys-moieties. In contrast, a Cd-peak eluted close to the void volume with all investigated mobile phases. Using X-ray absorption spectroscopy, the Cd-compound that eluted with a PBS-buffer that contained 5.0 mM GSH was structurally characterized as tetrahedral (GS)(4)Cd. Thus, the in vivo formation of (GS)(4)Cd must be considered and HPLC-ICP-AES is identified as a useful tool to probe dynamic bioinorganic processes which involve the interaction of a metal ion with multiple ligands under physiologically relevant conditions.

Tuning the metabolism of the anticancer drug cisplatin with chemoprotective agents to improve its safety and efficacy

A metallomics approach can be used to probe the mechanisms by which the co-administration of sulfur-containing ‘chemoprotective agents’ can modulate the metabolism of cisplatin in the bloodstream.

Chemical basis for the detoxification of cisplatin-derived hydrolysis products by sodium thiosulfate

Cisplatin remains the most widely used platinum-based anti-cancer drug and is included on the World Health Organizations list of essential medicines. Cisplatin also exhibits severe toxic side-effects, in particular damage to both the kidney and the inner ear, which are thought to derive primarily from hydrolysis products that are more toxic than cisplatin itself. Selective inactivation of these hydrolysis products has emerged as a feasible strategy to mitigate side effects and transform cisplatin into a better medicinal drug. Sodium thiosulfate is one of the most promising of currently considered mitigation agents, and co-administration of large quantities with cisplatin has been shown to considerably reduce toxic side effects in animals without abolishing useful anti-cancer cytotoxicity. The structural basis of this antagonism has, however, remained uncertain. We report herein the structural characterization of the reaction product of hydrolyzed cisplatin and thiosulfate in aqueous solution using X-ray absorption spectroscopy. This reveals the formation of the four-coordinate Pt(II) species [Pt(S2O3)4]6- with Pt-S bond lengths of 2.30Å. Our structural conclusions are supported by density functional theory calculations. More generally speaking, the structural characterization of this Pt-thiosulfate complex reinvigorates the principle strategy to reduce the toxicity of cisplatin (and possibly other platinum-based anticancer drugs) by co-administering appropriate ameliorating agents for direct benefits to patients.

Advanced LC-analysis of human plasma for metallodrug metabolites

Understanding the fate of metallodrugs in the bloodstream is critical to assess if the parent drug has a reasonable probability to reach the intended target tissue and to predict toxic side-effects. To gain insight into these processes, we have added pharmacologically relevant doses of metallodrugs to blood plasma and applied an LC-method to directly analyze the latter for metallodrug metabolites. Using human or rabbit plasma, this LC-method was employed to gain insight into the metabolism of clinically used as well as emerging anticancer metallodrugs and to unravel the mechanisms by which small molecular weight compounds that - when co-administered with a metallodrug - decrease the toxic side-effects of the metallodrug by modulating its metabolism. The results suggest that the developed LC-method is useful to probe the fate of biologically active novel metal-complexes in plasma to help select those which may be advanced to animal/clinical studies to ultimately develop safer metallodrugs.