DOI: 10.1002/chem.200900818 Synthesis and Structure–Activity Correlation Studies of Secondary- and Tertiary-Amine-Based Glutathione Peroxidase Mimics Krishna P. Bhabak and Govindasamy Mugesh* [a] Introduction Glutathione peroxidase (GPx) is a mammalian selenoen- zyme, which catalyzes the reduction of harmful peroxides by using glutathione (GSH) as a cofactor. [1] The catalytic cycle involves the reaction of peroxides with the selenol form of the enzyme (E-SeH) to produce the corresponding selenenic acid (E-SeOH), which upon reaction with GSH generates the enzyme-bound selenenyl sulfide (E-Se-SG). The nucleo- philic attack of a second GSH molecule at the Se S bond regenerates the active-site selenol, with release of the cofac- tor in its oxidized form (GSSG; Figure 1). [1e–g] At high con- centrations of peroxide, the selenenic acid generated in the reaction may undergo further oxidation to produce the cor- responding seleninic acid (E-SeO 2 H) or selenonic acid (E- SeO 3 H); these reactions reduce the catalytic efficiency of GPx. Therefore, rapid reactions of the selenenic acid (E- SeOH) with GSH and of the resulting selenenyl sulfide (E- Se-SG) with a second GSH molecule to produce the selenol are crucial for good catalytic activity. As selenium redox chemistry at the active site of GPx plays an important role in oxidative damage, [2] several groups have worked toward the design and synthesis of low- molecular-weight organoselenium compounds that function- ally mimic GPx activity in the presence of thiols. [3] These mimics include the well-known anti-inflammatory com- pound ebselen (1) [4] and its analogues, [5, 6] camphor-based se- lenenyl amide 2, [7] tert-amino-substituted diselenides 3–7, [8] Abstract: In this study, a series of sec- ondary- and tertiary-amino-substituted diaryl diselenides were synthesized and studied for their glutathione peroxidase (GPx) like antioxidant activities with H 2 O 2 , cumene hydroperoxide, or tBuOOH as substrates and with PhSH or glutathione (GSH) as thiol cosub- strates. This study reveals that replace- ment of the tert-amino groups in ben- zylamine-based diselenides by sec- amino moieties drastically enhances the catalytic activities in both the aro- matic thiol (PhSH) and GSH assay sys- tems. Particularly, the N-propyl- and N-isopropylamino-substituted disele- nides are 8–18 times more active than the corresponding N,N-dipropyl- and N,N-diisopropylamine-based com- pounds in all three peroxide systems when GSH is used as the thiol cosub- strate. Although the catalytic mecha- nism of sec-amino-substituted disele- nides is similar to that of the tert- amine-based compounds, differences in the stability and reactivity of some of the key intermediates account for the differences in the GPx-like activities. It is observed that the sec-amino groups are better than the tert-amino moieties for generating the catalytically active selenols. This is due to the absence of any significant thiol-exchange reactions in the selenenyl sulfides derived from sec-amine-based diselenides. Further- more, the seleninic acids (RSeO 2 H) de- rived from the sec-amine-based com- pounds are more stable toward further reactions with peroxides than their tert- amine-based analogues. Keywords: amines · antioxidant activity · enzyme mimics · per- ACHTUNGTRENNUNGoxidases · selenium · thiol exchange [a] K.P. Bhabak, Prof. G. Mugesh Department of Inorganic and Physical Chemistry Indian Institute of Science, Bangalore 560 012 (India) Fax: (+ 91) 80-2360-1552/0683 E-mail : mugesh@ipc.iisc.ernet.in Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.200900818. Figure 1. Proposed catalytic mechanism for the reduction of hydroperox- ides by GPx.  2009 Wiley-VCH Verlag GmbH&Co. KGaA, Weinheim Chem. Eur. J. 2009, 15, 9846 – 9854 9846