Journal
CHEMMEDCHEM
Volume 16, Issue 17, Pages 2650-2668Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cmdc.202100204
Keywords
Heck cross-coupling; 2-hydroxy-5-styrylbenzoic acid; SAR; xCT antiporter inhibitor; glioblastoma
Categories
Funding
- European Commission [675417]
- Department of Biomedicine at the University of Bergen
Ask authors/readers for more resources
The xCT antiporter plays a crucial role in glutathione biosynthesis and can be inhibited by the medication sulfasalazine. By designing and synthesizing styryl hydroxy-benzoic acid analogues, researchers discovered a promising candidate molecule with minimal toxicity in normal human astrocytes.
The xCT antiporter is a cell membrane protein involved in active counter-transportation of glutamate (outflux) with cystine (influx) over the human cell membrane. This feature makes the xCT antiporter a crucial element of the biosynthesis of the vital free radical scavenger glutathione. The prodrug sulfasalazine, a medication for the treatment of ulcerative colitis, was previously proven to inhibit the xCT antiporter. Starting from sulfasalazine, a molecular scaffold jumping followed by SAR-assisted design and synthesis provided a series of styryl hydroxy-benzoic acid analogues that were biologically tested in vitro for their ability to decrease intracellular glutathione levels using four different cancer cell lines: A172 (glioma), A375 (melanoma), U87 (glioma) and MCF7 (breast carcinoma). Depletion of glutathione levels varied among the compounds as well as among the cell lines. Flow cytometry using propidium iodide and the annexin V marker demonstrated minimal toxicity in normal human astrocytes for a promising candidate molecule (E)-5-(2-([1,1 '-biphenyl]-4-yl)vinyl)-2-hydroxybenzoic acid.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available