Discovery of Estrogen Sulfotransferase Inhibitors from a Purine Library Screen

There is now substantial evidence that sulfated biomolecules (i.e., carbohydrates, proteins, and steroids) contribute to many disease states,1 including chronic inflammation,2 HIV-1 infection,3,4 and hormone-depend-ent breast tumor growth.5,6 The sulfate ester is often a key determinant of bioactivity, directing significant attention to the corresponding enzymes, the sulfotrans-ferases, as a new class of therapeutic targets. Estrogen sulfotransferase (EST) catalyzes the transfer of a sulfuryl group from 3′-phosphoadenosine 5′-phos-phosulfate (PAPS) to estrogen (3,17-â-estradiol) and estrogen-like compounds in the cytosol, solubilizing them to maintain hormone homeostasis (Figure 1). The delicate balance of sulfated and nonsulfated estrogens in vivo is dictated by EST and the desulfating enzyme,