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Antioxidant panaceas: Novel compounds protect cells from oxidative stress

Panacea, the Greek goddess of universal remedies, is also the name given to any chemical that can supposedly cure all ailments – for example, antioxidants. Since many diseases are either caused by or exacerbated by oxidative stress, the use of antioxidants as therapeutic agents is logical, and may well be successful. Swelling the ranks of known useful antioxidants, are several more compounds called diselenides and isoselenazoles (organic compounds containing one or more selenium atoms) that have been synthesised and characterised by a team of scientists from the Indian Institute of Science.

An inevitable result of breaking down our food for energy, walking out in the sun, or even just breathing, causes our bodies to create free radicals. These are chemical compounds, the most common of them known as ROS (reactive oxygen species) that ‘steal’ electrons from nearby molecules. The main outcome of this ‘theft’ is oxidative damage to cellular proteins, DNA and membranes, which, if unchecked, can lead to cell death. Oxidative damage is often touted as the main cause of ageing, and a whole host of illnesses ranging from diabetes, kidney failure, arthritis and Parkinson’s disease, to heart attacks and cancer. Thankfully, our bodies, which are constantly under fire from the relentless attacks of ROSes, have a host of free-radical fighters such as vitamin C, thioredoxins and peroxiredoxins that literally ‘quench’ them. Nevertheless, when free radical generation overwhelms these natural defences, antioxidants are useful drugs to have on hand.

Many of the antioxidant systems in our cells have proteins bonded to a selenium atom which is crucial to their antioxidant activities. Therefore, organoselenium compounds are a rational choice when looking for antioxidant therapeutics. Ebselen is a well-known previously reported artificial antioxidant that mimics the activity of glutathione peroxidase, a well-known enzyme of the cell’s antioxidant machinery. It is currently in the clinical trials for the treatment of oxidative stress disorders. “We wanted to synthesize a better and more potent analogue of ebselen”, say Profs G. Mugesh and Patrick D'Silva, who led the research team in this endeavour at IISc. In a paper published in Angewandte Chemie, they have shown that two classes of novel compounds called diselenides and isoselenazoles actually mimic two natural antioxidant enzymes and protect cells against oxidative stress. This report has been rated as being in the top 5% of articles in the journal, and has been catergorised as a ‘Very important Paper’ in the field.

The novel organoselenium compounds were synthesised by Dr. Debasish Bhowmick from Prof. Mugesh’s lab, and their effectiveness in protecting living cells from oxidative damage was tested by Shubhi Srivastava from Prof. D’Silva’s lab. Two human-derived cell lines, HEK293T and HeLaeKLaHe in artificial culture were first challenged with hydrogen peroxide (a potent ROS producing chemical), then different sets of these cells were then each treated with one of the new antioxidants or with ebselen. Not only were the new antioxidants significantly better than ebselen at reducing oxidative damage, they were also less toxic to the cells than ebselen. Although termed an excellent ROS ‘scavenger’, ebselen unfortunately inhibits the activity of glutathione reductase, a key player in the cell’s natural free-radical fighting system. This makes its usage as an antioxidant rather counterproductive. However, the novel oragnoselenium compounds in this study, especially the isoselenazoles do not seem to interfere with the cell’s usual antioxidant systems. “Based on the current positive results, the discovery needs further studies before its practical application as a better therapeutic drug than ebselen. Our plans for future studies involve testing the efficacy of selenazoles in animal models," say Profs Mugesh and Patrick D'Silva.

About the authors:

Dr. Debasish Bhowmick and Prof. G. Mugesh are at the Department of Inorganic and Physical Chemistry. Shubhi Srivastava and Prof. Patrick D’Silva are at the Department of Biochemistry.

The paper can be accessed at: http://onlinelibrary.wiley.com/doi/10.1002/anie.201502430

Contact:

Prof G. Mugesh: http://ipc.iisc.ernet.in/~mugesh/

Prof Patrick D'Silva: patrick@biochem.iisc.ernet.in, 080 - 2293 2821

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