Non-steroidal and steroidal sulfamates: new drugs for cancer therapy

The development of inhibitors to block the formation of estrone and 5-andro stenediol from sulfated precursors is an important new strategy for the tre atment of breast cancer. In this study a series of tricyclic coumarin sulfa mates (665-668 COUMATE) and a tricyclic oxepin sulfamate have been synthesi sed and tested for their ability to inhibit estrone sulfatase activity (EI- STS). In addition the effect of the steroid-based E1-STS inhibitor, 2-metho xyestrone-3-O-sulfamate (2-McOEMATE) on the morphology of MDA-MB-231 cells acid breast tumour-derived fibroblasts was also examined. The tricyclic cou marin sulfamates and oxepin sulfamate were potent inhibitors of E1-STS acti vity with IC(50)s ranging from 8 to 250 nM. Of this series 667 COUMATE was the most potent inhibitor (IC50 = 8 nM) and was three-times more potent tha n estrone-3-O-sulfamate (EMATE. IC50 - 25 nM). 667 COUMATE did not stimulat e the growth of MCF-7 breast cancer cells and is therefore devoid of estrog enicity. In vivo, 667 COUMATE inhibited E1-STS activity in rat liver tissue to a similar extent to that of EMATE. 2-MeOEMATE had a marked effect on th e morphology of MDA-MB-231 cells and breast tumour-derived fibroblasts caus ing a significant increase in the number of rounded cells. 667 COUMATE and 2-MeOEMATE therefore offer considerable potential for development for cance r therapy. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.