Synthesis and evaluation of general mechanism-based inhibitors of sulfatases based on (difluoro)methyl phenyl sulfate and cyclic phenyl sulfamate motifs

Abstract

Several model mechanism-based inhibitors (MbIs) were designed and evaluated for their ability to inhibit sulfatases. The MbI motifs were based on simple aromatic sulfates, which are known to be commonly accepted substrates across this highly conserved enzyme class, so that they might be generally useful for sulfatase labeling studies. (Difluoro)methyl phenol sulfate analogs, constructed to release a reactive quinone methide trap, were not capable of irreversibly inactivating the sulfatase active site. On the other hand, the cyclic sulfamates (CySAs) demonstrated inhibition profiles consistent with an active-site directed mode of action. These molecules represent a novel scaffold for labeling sulfatases and for probing their catalytic mechanism.

α‐Fluoro‐o‐cresols: The Key Role of Intramolecular Hydrogen Bonding in Conformational Preference and Hydrogen‐Bond Acidity

“…Experimental measurement of the cresol H-bond acidities was only possible for compounds 3a and 3d, given the known instability of -fluoro and ,-difluoro-o-cresols. 52,53 In the case of o-cresol 3a, the presence of the methyl group, an electrondonating substituent, slightly decreases the hydroxyl Hbond donating capacity in comparison with phenol (pK AHY = 1.92 and 2.06, 27 respectively). On the contrary, the strong electronwithdrawing effect of the CF 3 substituent yields to an expected strong increase of H-bond acidity (pK AHY = 2.59).…”

Multiple Pathways for the Irreversible Inhibition of Steroid Sulfatase with Quinone Methide‐Generating Suicide Inhibitors

“…[17,18] We also demonstrate that the inhibition of STS by compound 4 involves an unexpected process in which the main inactivation pathway does not involve reaction of a quinone methide with an active-site nucleophile; this has led to the discovery of 4-FE1 as a potent, slow-binding inhibitor of STS. Efforts to improve the potency of 4-FE1, such as by introducing benzylic moieties to the 17-position, [19] are in progress.…”

Improved Chiral Olefin Metathesis Catalysts: Increasing the Thermal and Solution Stability via Modification of a C1‐Symmetrical N‐Heterocyclic Carbene Ligand

“…In this model, the substrate is bound so that the olefin involved in the ring closure occupies a binding site cis to the NHC and the Cl atom has isomerized trans to the NHC (intermediate B, Figure 4). [18] The reaction between a triene such as 18 and the propagating species A could therefore afford two intermediates B or C (Figure 4). In these intermediates the alkylidene has moved from underneath the N-alkyl group to underneath the N-aryl group in accordance with recent work by Chen and co-workers.…”