C-3- and C-4-Substituted Bicyclic CoumarinSulfamates as Potent Steroid Sulfatase Inhibitors

摘要

Synthetic routes to potent bicyclic nonsteroidal sulfamate-based active-site-directed inhibitors of the enzyme steroid sulfatase (STS), an emerging target in the treatment of postmenopausal hormone-dependent diseases, including breast cancer, are described. Sulfamate analogs >9–>27 and >28–>46 of the core in vivo active two-ring coumarin template, modified at the 4- and 3-positions, respectively, were synthesized to expand structure–activity relationships. α-Alkylacetoacetates were used to synthesize coumarin sulfamate derivatives with 3-position modifications, and the bicyclic ring of other parent coumarins was primarily constructed via the Pechmann synthesis of hydroxyl coumarins. Compounds were examined for STS inhibition in intact MCF-7 breast cancer cells and in placental microsomes. Low nanomolar potency STS inhibitors were achieved, and some were found to inhibit the enzyme in MCF-7 cells ca. 100–500 more potently than the parent 4-methylcoumarin-7-O-sulfamate >3, with the best compounds close in potency to the tricyclic clinical drug Irosustat. 3-Hexyl-4-methylcoumarin-7-O-sulfamate >29 and 3-benzyl-4-methylcoumarin-7-O-sulfamate >41 were particularly effective inhibitors with IC50 values of 0.68 and 1 nM in intact MCF-7 cells and 8 and 32 nM for placental microsomal STS, respectively.They were docked into the STS active site for comparison with estrone3-O-sulfamate and Irosustat, showing their sulfamategroup close to the catalytic hydrated formylglycine residue and theirpendant group lying between the hydrophobic sidechains of L103, F178,and F488. Such highly potent STS inhibitors expand the structure–activityrelationship for these coumarin sulfamate-based agents that possesstherapeutic potential and may be worthy of further development.