Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.1.6.1 (sulfatase)
 3,205 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Steroid sulfatase (STS) catalyzes the hydrolyis of steroidal sulfates such as estrone sulfate (ES1) and is considered to be an attractive target in the treatment of steroid dependent cancers. A non-hydrolyzable estrone sulfate (ES1) analogue bearing an alpha,alpha-difluorosulfonamide moiety at the 3-position on the A-ring, compound , was synthesized. Key to the success of this synthesis was the first use of the allyl group as a sulfonamide protecting group. The pK(a) of this ES1 mimic in 0.1 M bis-tris propane, 10% DMSO was determined to be 8.05 using 19F NMR. Compound is a reversible inhibitor with a K(i) similar to that of its sulfonate analogue at pH 7.0. It is more potent than its non-fluorinated sulfonamide analogue and, its inhibitory potency increases with increasing pH, a trend opposite to that of other STS inhibitors. Possible reasons for this are presented.
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PMID:Synthesis of a non-hydrolyzable estrone sulfate analogue bearing the difluoromethanesulfonamide group and its evaluation as a steroid sulfatase inhibitor. 1613 94

Steroid sulfatase (STS) catalyzes the hydrolysis of steroidal sulfates such as estrone sulfate (ES1) to the corresponding steroids and inorganic sulfate. STS is considered to be a potential target for the development of therapeutics for the treatment of steroid-dependent cancers. Two steroidal and two coumarin- and chromenone-based boronic acids were synthesized and examined as inhibitors of purified STS. The boronic acid analog of estrone sulfate bearing a boronic acid moiety at the 3-position in place of the sulfate group was a good competitive STS inhibitor with a K(i) of 2.8microM at pH 7.0 and 6.8microM at pH 8.8. The inhibition was reversible and kinetic properties corresponding to the mechanism for slow-binding inhibitors were not observed. An estradiol derivative bearing a boronic acid group at the 3-position and a benzyl group at the 17-position was a potent reversible, non-competitive STS inhibitor with a K(i) of 250nM. However, its 3-OH analog, a known STS inhibitor, exhibited an almost identical affinity for STS and also bound in a non-competitive manner. It is suggested that these compounds prefer to bind in a hydrophobic tunnel close to the entrance to the active site. The coumarin and chromenone boronic acids were modest inhibitors of STS with IC(50)s of 86 and 171microM, respectively. Surprisingly, replacing the boronic acid group of the chromenone derivative with an OH group yielded a good reversible, mixed type inhibitor with a K(i) of 4.6microM. Overall, these results suggest that the boronic acid moiety must be attached to a platform very closely resembling a natural substrate in order for it to impart a beneficial effect on binding affinity compared to its phenolic analog.
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PMID:Boronic acids as inhibitors of steroid sulfatase. 1697 64