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Published on: February 15, 2016
1,2,3-Benzoxathiazine-2,2-Dioxides as Inhibitors of Thioredoxin Reductase
Jekaterīna Ivanova1, Ludmila Jackeviča1, Antons Sizovs1,2
1Latvian Institute of Organic Synthesis, Riga, Latvia.
None:
Thioredoxin reductase 1 (TrxR1) is a selenoenzyme central to cellular redox homeostasis. It is frequently upregulated in cancer and represents an attractive therapeutic target for covalent inhibition. 1,2,3-Benzoxathiazine-2,2-dioxides are bioisosteres of coumarin that have been investigated before as cancer-associated enzyme inhibitors but never as inhibitors of TrxR. In this study, 52 derivatives of 1,2,3-benzoxathiazine-2,2-dioxides were synthesized and evaluated for inhibition of recombinant rat TrxR1 using a DTNB (5,5'-Dithiobis-(2-nitrobenzoic acid)-based colorimetric assay. Although 4-methyl substituted derivatives expressed no activity, the TrxR inhibition effect was observed in the case of 4-unsubstituted 1,2,3-benzoxathiazine-2,2-dioxides, with some derivatives showing micromolar inhibition toward TrxR1. The most potent inhibitors were 8-aryl analogs 7k and 7l with IC50 = 19.3 and IC50 = 14.1, respectively. Compounds 7k and 7l also displayed cytotoxic effects in MDA-MB-231, MDA-MB-435, PANC-1, and U-118 human cancer cell lines after 48 h exposure with IC50 values ranging 30-62 µM. Covalent docking of 7k to TrxR1 (PDB: 3EAN) suggested binding under the mobile C-terminal arm and a geometry compatible with Michael addition to Sec498. Together, these results identify 1,2,3-benzoxathiazine-2,2-dioxides as a previously unexplored TrxR1 inhibitor scaffold and provide starting points for further optimization.
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