Original article Synthesis and biological evaluation of novel spiro 6-methoxytetralin-1,3 0 -pyrrolidine based organoselenocyanates against cadmium-induced oxidative and hepatic damage in mice Ugir Hossain Sk b , Arun K. Sharma b , Sulekha Ghosh c , Sudin Bhattacharya a, * a Chittaranjan National Cancer Institute, Department of Cancer Chemoprevention, 37, S. P. Mukherjee Road, Kolkata 700 026, West Bengal, India b Department of Pharmacology, Chemical Carcinogenesis and Chemoprevention Program of Penn State Hershey Cancer Institute, CH72, Penn State College of Medicine, 500 University Drive, Hershey, PA 17033, USA c The Burdwan Medical College, Burdwan, 713104, West Bengal, India article info Article history: Received 29 December 2009 Received in revised form 31 March 2010 Accepted 1 April 2010 Available online 10 April 2010 Keywords: Organoselenocyanate Cadmium Hepatoprotective Oxidative stress abstract A series of novel organoselenocyanate compounds (6aed) having spiro[tetralin-1,3 0 -pyrrolidine] moiety were synthesized. The compounds were evaluated for their inhibitory activity against cadmium- (Cd) induced toxicity in Swiss Albino mice. All the compounds (6aed) inhibited the level of lipid peroxidation (LPO) and upregulated the activity of glutathione-S-transferase (GST), superoxide dismutase (SOD), catalase (CAT) and reduced glutathione (GSH) levels in treatment group in comparison to the untreated Cd control group. Serum transaminase activities, e.g., alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were also significantly lowered in the compound-treated mice. Elongation of the alkyl chain length bearing the selenocyanate (SeCN) active group enhanced the potency of the compounds, 6d being the most active one (6d > 6c > 6b > 6a). Ó 2010 Elsevier Masson SAS. All rights reserved. 1. Introduction Cadmium (Cd) is an important heavy metal widely used in batteries, metal plating, pigments, plastics, and alloys. In addition to occupational exposures, humans are exposed to environmental Cd through cigarette smoke and food items [1]. Literature reports have demonstrated that hepatic and testicular tissues are sensitive target for Cd toxicity. Cd-induced testicular pathogenicity includes severe hemorrhage, oedema, necrosis and atrophy as well as reduction in counts and motility of sperm [2,3]. However, the molecular mechanisms responsible for toxic effects of Cd are not being well understood. Various studies relate Cd to oxidative stress since this metal alters the antioxidant defense system in several tissues of different animals causing depletion in the levels of GSH, alteration in the activity of antioxidant enzymes, and change in the structure of the cellular membrane through process of lipid per- oxidation (LPO) [4,5]. In this way, studies on mammals have shown that Cd stimulated formation of reactive oxygen species (ROS), including oxygen free anion radical [6], hydrogen peroxide [7] and hydroxyl radical [8], causing enhanced LPO, DNA damage, altered calcium and sulfhydryl homeostasis as well as marked disturbances of antioxidant defense system [9e11]. Several reports in the liter- ature relate oxidative stress caused by Cd to its ability in depleting selenium (Se) from the body by the formation of CdeSe complex [12]. The depletion of Se content, during renal damage caused by Cd poisoning, could correlate with the increase of LPO, and abnormal subcellular distribution of Se [13]. Furthermore, Se deficiency has been reported to cause an overload of iron and unbalanced in vivo distributions of other elements, such as magnesium, calcium, copper and zinc [14]. On the other hand, the use of Se reduces the availability of metal ions including Cd, blocking them in insoluble compounds [15], and is often considered as an efficient therapy against metal toxicity in mammals [16]. In addition, there are evidences that Se compounds are capable of ameliorating the Cd- induced hepatotoxicity by increasing the antioxidative enzymes in animal tissue [17]. It has been observed that the chemical formulation of a Se- containing compound is critical for its biological activity [18]. Organoselenium compounds have been found to be less toxic than inorganic Se compounds such as sodium selenite. Therefore, there has been a growing interest in the synthesis of organo- selenium compounds. Recent studies have shown the efficacy of diphenyl diselenide (PhSe) 2 in reversal of acute testicular injury in male mice exposed to Cd. PhSe 2 acts through the formation of * Corresponding author. Tel.: þ91 33 2476 5101X316. E-mail address: sudinb19572004@yahoo.co.in (S. Bhattacharya). Contents lists available at ScienceDirect European Journal of Medicinal Chemistry journal homepage: http://www.elsevier.com/locate/ejmech 0223-5234/$ e see front matter Ó 2010 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.ejmech.2010.04.001 European Journal of Medicinal Chemistry 45 (2010) 3265e3273