title: Steroidal and nonsteroidal sulfamates as potent inhibitors of steroid sulfatase.
abstract: Synthetic routes to potent steroidal and nonsteroidal sulfamate-based active site-directed inhibitors of the enzyme steroid sulfatase, a topical target in the treatment of postmenopausal women with hormone-dependent breast cancer, are described. Novel compounds were examined for estrone sulfatase (E1-STS) inhibition in intact MCF-7 breast cancer cells and placental microsomes. Reaction of the sodium salt of estrone with sulfamoyl chloride gave estrone 3-O-sulfamate (EMATE, 2) which inhibits E1-STS activity potently (> 99% at 0.1 microM in intact MCF-7 cells, IC50 = 65 pM) in a time- and concentration-dependent manner, suggesting that EMATE is an active site-directed inhibitor. EMATE is also active in vivo orally. 5,6,7,8-Tetrahydronaphthalene 2-O-sulfamate (7) and its N-methylated derivatives (8 and 9) were synthesized, and 7 inhibits the E1-STS activity in intact MCF-7 cells by 79% at 10 microM. 4-Methylcoumarin 7-O-sulfamate (COUMATE) and its derivatives (14, 16, and 18) were prepared to extend this series of nonsteroidal inhibitors, and COUMATE reduces the E1-STS activity in placental microsomes by > 90% at 10 microM. Although the orally active COUMATE is less potent than EMATE as an active site-directed inhibitor, it has the important advantage of being nonestrogenic. Analogues (20, 22, 24, 26, 27, 31, 33, 39, and 44) of COUMATE were synthesized to study its structure-activity relationships, and sulfamates of tetralones (46 and 48) and indanones (49, 51, and 53) were also prepared. While most of these compounds were found to inhibit E1-STS activity less effectively than COUMATE, one analogue, 3,4-dimethylcoumarin 3-O-sulfamate (24), was found to be some 12-fold more potent than COUMATE as an E1-STS inhibitor in intact MCF-7 cells (IC50 = 30 nM for 24, cf. 380 nM for COUMATE). Hence, highly potent sulfamate-based inhibitors of steroid sulfatase, such as EMATE, COUMATE, and 24, possess therapeutic potential and will allow the importance of estrogen formation in breast tumors via the E1-STS pathway to be assessed. A pharmacophore for active site-directed sulfatase inhibition is proposed.
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy and Pharmacology, University of Bath, Claverton Down, U.K.
authors.forename: L W
authors.initials: LW
authors.lastname: Woo
authors.forename: N M
authors.initials: NM
authors.lastname: Howarth
authors.forename: A
authors.initials: A
authors.lastname: Purohit
authors.forename: H A
authors.initials: HA
authors.lastname: Hejaz
authors.forename: M J
authors.initials: MJ
authors.lastname: Reed
authors.forename: B V
authors.initials: BV
authors.lastname: Potter
mesh_terms: D001192:Arylsulfatases / Q000037:antagonists & inhibitors* / Q000187:drug effects; D003374:Coumarins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D006801:Humans; D009281:Naphthalenes / Q000138:chemical synthesis* / Q000494:pharmacology; D043266:Steryl-Sulfatase; D013429:Sulfatases / Q000037:antagonists & inhibitors / Q000187:drug effects; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects
chemical_list: C100463:4-methylcoumarin 7-O-sulfamate; D003374:Coumarins; D004791:Enzyme Inhibitors; D009281:Naphthalenes; D013449:Sulfonamides; D013429:Sulfatases; C020121:estrone sulfatase; D001192:Arylsulfatases; D043266:Steryl-Sulfatase