title: 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.affiliation: Organic Chemistry Research Department, Teikoku Hormone Mfg. Co. Ltd., 1604 Shimosakunobe, Takatsu-ku, Kawasaki 213-8522, Japan. okada-m1@kw.teikoku-hormone.co.jp
authors.forename: Makoto
authors.initials: M
authors.lastname: Okada
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Nakagawa
authors.forename: Shigeki
authors.initials: S
authors.lastname: Iwashita
authors.forename: Shigehiro
authors.initials: S
authors.lastname: Takegawa
authors.forename: Tomohito
authors.initials: T
authors.lastname: Fujii
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Koizumi
mesh_terms: D000818:Animals; D001713:Biphenyl Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D004958:Estradiol / Q000378:metabolism; D047628:Estrogen Receptor alpha; D004970:Estrone / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D005260:Female; D006801:Humans; D008099:Liver / Q000201:enzymology; D009929:Organ Size; D051381:Rats; D017207:Rats, Sprague-Dawley; D011960:Receptors, Estrogen / Q000378:metabolism; D043266:Steryl-Sulfatase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013451:Sulfonic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D014599:Uterus / Q000201:enzymology
chemical_list: D001713:Biphenyl Compounds; D004791:Enzyme Inhibitors; D047628:Estrogen Receptor alpha; D011960:Receptors, Estrogen; D013451:Sulfonic Acids; C088768:estrone-3-O-sulfamate; D004970:Estrone; D004958:Estradiol; C005741:sulfamic acid; D043266:Steryl-Sulfatase; C017296:estrone sulfate