Steroidal and nonsteroidal sulfamates as potent inhibitors of steroid sulfatase

Journal of Medicinal Chemistry
L W Lawrence WooB V Potter

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 th...Continue Reading

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Citations

Mar 30, 2004·Biochemical and Biophysical Research Communications·Julie E ReedBarry V L Potter
Jan 27, 2004·Bioorganic & Medicinal Chemistry Letters·Chirag K PatelSabbir Ahmed
Dec 16, 2003·The Journal of Steroid Biochemistry and Molecular Biology·Makoto OkadaNaoyuki Koizumi
May 3, 2005·The Journal of Steroid Biochemistry and Molecular Biology·Mathew P LeeseBarry V L Potter
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May 2, 2002·The Journal of Steroid Biochemistry and Molecular Biology·Sabbir AhmedLuther Sampson
May 2, 2002·The Journal of Steroid Biochemistry and Molecular Biology·Sabbir AhmedChirag K Patel
Feb 19, 2003·The Journal of Steroid Biochemistry and Molecular Biology·Sabbir AhmedCaroline P Owen
Apr 25, 2003·The Journal of Steroid Biochemistry and Molecular Biology·Bindumalini RaobaikadyMichael J Reed
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Jul 2, 2005·Expert Opinion on Emerging Drugs·Shigehira Saji, Masakazu Toi
Jan 18, 2011·Molecular and Cellular Endocrinology·L W Lawrence WooBarry V L Potter
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May 3, 2005·The Journal of Steroid Biochemistry and Molecular Biology·Paul M WoodBarry V L Potter
May 18, 2004·The Journal of Steroid Biochemistry and Molecular Biology·Georg WalterErwin von Angerer
Sep 21, 2013·Natural Product Research·Oue-artorn RajachanKwanjai Kanokmedhakul
Apr 28, 2004·Bioorganic & Medicinal Chemistry·Hatem A M HejazBarry V L Potter
Oct 20, 2004·Angewandte Chemie·Sarah R HansonChi-Huey Wong
May 10, 2005·International Journal of Cancer. Journal International Du Cancer·Bindumalini RaobaikadyAtul Purohit

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