Effect of a Bromo Substituent on the Glutathione Peroxidase Activity of a Pyridoxine-like Diselenide

In search for better mimics of the glutathioneperoxidase enzymes, pyridoxine-like diselenides 6 and 11,carrying a 6-bromo substituent, were prepared. Reaction of2,6-dibromo-3-pyridinol 5 with sodium diselenide provided 6via aromatic nucleophilic substitution of the 2-bromosubstituent. LiAlH4 caused reduction of all four ester groupsand returned 11 after acidic workup. The X-ray structure of 6showed that the dipyridyl diselenide moiety was kept in analmost planar, transoid conformation. According to NBOanalysis,this was due to weak intramolecular Se···O (1.1 kcal/mol) and Se···N-interactions (2.5 kcal/mol). That the 6-bromo substituent increased the positive charge on seleniumwas confirmed by NPA-analysis and seen in calculated andobserved 77Se NMR-shifts. Diselenide 6 showed a more than 3-fold higher reactivity than the corresponding des-bromocompound 3a and ebselen when evaluated in the coupled reductase assay. Experiments followed for longer time (2 h) confirmedthat diselenide 6 is a better GPx-catalyst than 11. On the basis of 77Se-NMR experiments, a catalytic mechanism for diselenide 6was proposed involving selenol, selenosulfide and seleninic acid intermediates. At low concentration (10 μM) where it showedonly minimal toxicity, it could scavenge ROS produced by MNC- and PMNC-cells more efficiently than Trolox.

Poon, Jia-feiUppsala universitet,Syntetisk organisk kemi(Swepub:uu)jiapo828 (författare)
Butcher, Ray J.Department of Chemistry, Howard University, USA. (författare)
Lu, XiUppsala universitet,Tillämpad materialvetenskap(Swepub:uu)xialu516 (författare)
Mestres, Gemma,1984-Uppsala universitet,Tillämpad materialvetenskap(Swepub:uu)gemme924 (författare)
Karlsson Ott, MarjamUppsala universitet,Tillämpad materialvetenskap(Swepub:uu)makar516 (författare)
Engman, LarsUppsala universitet,Syntetisk organisk kemi(Swepub:uu)len21181 (författare)
Uppsala universitetSyntetisk organisk kemi (creator_code:org_t)

Ingår i:The Journal of Organic Chemistry: American Chemical Society (ACS)50:15, s. 7385-73950022-32631520-6904

Av författaren/redakt...: Singh, Vijay P; Poon, Jia-fei; Butcher, Ray J.; Lu, Xi; Mestres, Gemma, ...; Karlsson Ott, Ma ...; visa fler...; Engman, Lars; visa färre...

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