Journal of Gyansagar Science Foundation 2013 04 01

Author(s): Sanjeev Sogani, Vimal Jain
Publisher: Gyansagar Science Foundation

Page 46

Organoselenium compounds: A new generation of radio-protectors and mimics of glutathione
peroxidase
Abstract
This presentation aims to discuss our approach on design of low molecular-weight water-soluble organoselenium compounds as antioxidant and radio protectors. A variety of organoselenium compounds containing functional groups (e.g., OH, NH2, COOH) in the alkyl chain, 3, 5-dimethylpyrazole and 2-phenyl (3, 5-dimethylpyrazo-1-yl) groups have been synthesized and characterized by NMR (1H, 13C{1H}, "Se{H}) and in some cases by X-ray crystallography. Several of these compounds have been examined for GPx like activity, in -vitro antioxidant and radioprotecting activity. The results indicated that among aliphatic selenium compounds, those having functionalized propyl side chain showed maximum activity, diselenides were more active than monoselenides and among the functional groups, carboxylic acid group was the most effective. Based on these observations, diselenodipropionic acid ((HOOCCH,CH,Se),, DSEPA) was examined for in-vivo radioprotection in mice exposed to lethal and sub-lethal doses of gamma-radiation. At non-toxic dose of 2mg/kg body weight, DSEPA when administered prior to irradiation significantly increased the survival of the animals exposed to radiation. It was also effective in protecting radiosensitive organs like hematopoietic system and gastro-intestinal tract from radiation-induced damage.
Introduction
Ageing has been one of the major problems before the mankind. To defy aging we have been devising newer and innovative methods including extracts from plants of medicinal significance. Scientifically ageing is a complex process defined as progressive deterioration of physiological functions. There are several different mechanisms for ageing. Among them a mechanism involving reactive oxygen species (ROS) is widely accepted. Various free radicals (e.g., H., HO, O,-, R., etc) and oxidants (e.g., H2O,, singlet oxygen, HOCI, etc) generated in biological systems are collectively called as ROS. Excessive generation of ROS results in a state known as 'oxidative stress'. Excessive or misplaced ROS causes damage to cellular components like cell walls, lipid, membranes, DNA, etc which is manifested in the form of inflammatory, neurodegenerative and cardiovascular diseases.
The ROS are formed by two different routes, viz., (i) cellular metabolism of oxygen, and (ii) radiolysis of water (cells contain ~70% water) by high energy electromagnetic radiation (e.g. UV) or ionizing radiations (like y-rays) origin of which can be natural or manmade. In the first process a small amount (< 2%) of oxygen is inevitably converted to superoxide ion (0,-) during its metabolism in mitochondria. The superoxide ion is subsequently converted to hydrogen peroxide (H,O,), hydroxyl radicals (HO⚫) and eventually to other reactive species. In the second process, radiolysis of water takes
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place by ionizing radiation. Radiolysis of water results in to the formation of hydroxyl (HO) and hydrogen (H⚫) radicals which subsequently react with various other molecules affording peroxyl radicals.
Mother Nature has provided an elaborate defense mechanism to detoxify ROS. To protect against oxidations, cells possess different types of antioxidants ranging from vitamins C and E to enzymes like superoxide dismutase (SOD), catalase and glutathione peroxidase (GPX). These enzymes are capable of degrading ROS in to harmless compounds through a series of chemical reactions.
Oxygen (O), sulfur (S), selenium (Se) and tellurium (Te) constitue Group-VI of the Periodic Table. Besides oxygen, both sulfur and selenium are important elements in living organisms, although the importance of selenium as an essential micro-nutrient has been realized only recently12. It is a constituent of several redox active enzymes. Until now at least 25 selenium containing proteins have been identified in mammals. Among them, the most important and well studied seleno-protein is glutathione peroxidase. It is an antioxident enzyme playing a central role in combating oxidative stress. It detoxifies peroxides by reducing them to water or less reactive species. These enzymes contain selenocysteine (Scheme 1) at their active site, which is considered as the
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Vimal K. Jain
NH2
OH
HS
NH2
OH
HSe
Corresponding Auther: Vimal K. Jain, A.S. Hodage, C.P. Prabhu, P.P. Phadnis, A. Wadawale", L.B. Kumbhare, Beena Singh, Amit Kunwar and K. Indira Priyadarsinib
"Chemistry Division and "Radiation and Photo Chemistry Division, Bhabha Atomic Research Centre, Mumbai-400 085, e-mail; jainvk@barc.gov.in, Tel: (22)2559 5095;
NH2
OH