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 α. 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.