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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.
AuthorsL W Woo, N M Howarth, A Purohit, H A Hejaz, M J Reed, B V Potter
JournalJournal of medicinal chemistry (J Med Chem) Vol. 41 Issue 7 Pg. 1068-83 (Mar 26 1998) ISSN: 0022-2623 [Print] United States
PMID9544207 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • 4-methylcoumarin 7-O-sulfamate
  • Coumarins
  • Enzyme Inhibitors
  • Naphthalenes
  • Sulfonamides
  • Sulfatases
  • estrone sulfatase
  • Arylsulfatases
  • Steryl-Sulfatase
Topics
  • Arylsulfatases (antagonists & inhibitors, drug effects)
  • Coumarins (chemical synthesis, chemistry, pharmacology)
  • Enzyme Inhibitors (chemical synthesis, chemistry, pharmacology)
  • Female
  • Humans
  • Naphthalenes (chemical synthesis, pharmacology)
  • Steryl-Sulfatase
  • Sulfatases (antagonists & inhibitors, drug effects)
  • Sulfonamides (chemical synthesis, chemistry, pharmacology)
  • Tumor Cells, Cultured (drug effects)

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