Design and synthesis of biphenyl and biphenyl ether inhibitors of sulfatases

Abstract

Two series of inhibitors of sulfatase 2, ARSA and ARSB were designed based on biphenyl and biphenyl ether scaffolds substituted with e.g. sulfamate and carboxylate groups.

Modified minimal-size fragments of heparan sulfate as inhibitors of endosulfatase-2 (Sulf-2)

“…Compounds were tested at a single concentration (500 mM) to compare inhibitory activity and the IC 50 value was determined for the most potent inhibitor. Biphenyl trichloroethylsulfamate 11 13 (Scheme 4), was included as a benchmark Sulf-2 inhibitor.…”

“…Compounds were tested at a single concentration (500 mM) to compare inhibitory activity and the IC 50 value was determined for the most potent inhibitor. Biphenyl trichloroethylsulfamate 11 13 (Scheme 4), was included as a benchmark Sulf-2 inhibitor. Inhibition of sulfatase from Aerobacter aerogenes, a bacterial sulfatase was used to assess selectivity of the compounds.…”

“…Trisulfated 5 was found to be superior to the other inhibitors investigated and is more potent against Sulf-2 and more selective for Sulf-2 vs. other sulfatases than a biphenyl trichloroethylsulfamate inhibitor reported in the literature. 13 We propose that compound 5, and consequently the disaccharide IdoA(2S)-GlcNS(6S), may represent the minimal-size fragment of HS required for effective inhibition of the endosulfatases. The disaccharide IdoA2S-GlcNS(6S) is not a substrate of the Sulfs, 14 however this fragment-size does efficiently bind to the active site (evidenced by inhibition in the 4-MUS assay), making it a good scaffold for inhibitor design.…”

Colorimetric Determination of Sulfate via an Enzyme Cascade for High-Throughput Detection of Sulfatase Activity

“…As they play an essential role in several diseases, their relevance in human health has been increasingly recognized . Given that the sulfation degree of their substrates is decisive for, e.g., ligand activity (which appears to be strongly related to certain types of cancer), the inhibition and modulation of sulfatases’ activity toward signaling molecules have been increasingly studied. , Furthermore, several technical applications of sulfatases have been developed, such as the enantioselective production of sec- alcohols from alkyl sulfates or the regioselective cleavage of sulfate groups from different types of carrageenan to control its gelling or texturizing properties . The increasing importance of this type of biocatalyst is reflected in the recent creation of a sulfatase classification database, which arranges enzymes according to their substrate specificity into alkyl or aryl sulfatases.…”