Development of novel steroid sulfatase inhibitors. I. Synthesis and biological evaluation of biphenyl-4-O-sulfamates.

Abstract

Compounds which interfere with steroid sulfatase (STS) are expected as important novel therapeutic drugs for postmenopausal breast tumor. Therefore, a number of strategies have been adopted to design and synthesize potent, nonestrogenic STS inhibitors. We chose biphenyl as a scaffold for STS inhibitors and synthesized some biphenyl-4-O-sulfamate derivatives (29-43). Their inhibitory activity on STS and estrogenicity were evaluated. Substitution of electron-withdrawing groups (e.g., cyano, nitro) at the 2'- or 4'-position of biphenyl-4-O-sulfamate remarkably increased STS-inhibitory activity. Especially, 2',4'-dicyanobiphenyl-4-O-sulfamate (35, TZS-8478) showed very potent STS-inhibitory activity in vitro. The administration of TZS-8478 (0.5 mg/kg per day, p.o., for 5 days) completely inhibited rat liver and uterine STS similarly to EMATE (1). Furthermore, TZS-8478 (10 mg/kg per day, p.o., for 5 days) had no stimulative effect on uterine growth in ovariectomized rats, and its desulfamoylated compound (20) was little bound to the human estrogen receptor alpha. The identification of a potent steroid sulfatase inhibitor without estrogenicity, such as TZS-8478, should be of considerable value in evaluating the potential of steroid sulfatase inhibition for breast tumor therapy.

• Authors: Makoto Okada, Takayoshi Nakagawa, Shigeki Iwashita, Shigehiro Takegawa, Tomohito Fujii, Naoyuki Koizumi
• Journal: The Journal of steroid biochemistry and molecular biology (J Steroid Biochem Mol Biol) Vol. 87 Issue 2-3 Pg. 141-8 (Nov 2003) ISSN: 0960-0760 [Print] England
• PMID: 14672734 (Publication Type: Journal Article)

Chemical References

• Biphenyl Compounds
• Enzyme Inhibitors
• Estrogen Receptor alpha
• Receptors, Estrogen
• Sulfonic Acids
• estrone-3-O-sulfamate
• Estrone
• Estradiol
• sulfamic acid
• Steryl-Sulfatase
• estrone sulfate

Topics

• Animals
• Biphenyl Compounds (chemical synthesis, chemistry, metabolism, pharmacology)
• Breast Neoplasms (drug therapy, enzymology)
• Cell Line, Tumor
• Enzyme Inhibitors (chemical synthesis, pharmacology)
• Estradiol (metabolism)
• Estrogen Receptor alpha
• Estrone (analogs & derivatives, metabolism, pharmacology)
• Female
• Humans
• Liver (enzymology)
• Organ Size
• Rats
• Rats, Sprague-Dawley
• Receptors, Estrogen (metabolism)
• Steryl-Sulfatase (antagonists & inhibitors, metabolism)
• Structure-Activity Relationship
• Sulfonic Acids (chemical synthesis, chemistry, metabolism, pharmacology)
• Uterus (enzymology)