Non-steroidal and steroidal sulfamates: new drugs for cancer therapy.
The development of inhibitors to block the formation of estrone and 5-androstenediol from sulfated precursors is an important new strategy for the treatment of breast cancer. In this study a series of tricyclic coumarin sulfamates (665-668 COUMATE) and a tricyclic oxepin sulfamate have been synthesised and tested for their ability to inhibit estrone sulfatase activity (E1-STS). In addition the effect of the steroid-based E1-STS inhibitor, 2-methoxyestrone-3-O-sulfamate (2-MeOEMATE) on the morphology of MDA-MB-231 cells and breast tumour-derived fibroblasts was also examined. The tricyclic coumarin sulfamates and oxepin sulfamate were potent inhibitors of E1-STS activity with IC(50)s ranging from 8 to 250 nM. Of this series 667 COUMATE was the most potent inhibitor (IC(50)=8 nM) and was three-times more potent than estrone-3-O-sulfamate (EMATE, IC(50)=25 nM). 667 COUMATE did not stimulate the growth of MCF-7 breast cancer cells and is therefore devoid of estrogenicity. 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 the morphology of MDA-MB-231 cells and breast tumour-derived fibroblasts causing a significant increase in the number of rounded cells. 667 COUMATE and 2-MeOEMATE therefore offer considerable potential for development for cancer therapy.
Purohit
A
A
Endocrinology and Metabolic Medicine, Imperial College School of Medicine, St. Mary's Hospital, Praed Street, W2 1NY, London, UK.
Woo
L W
LW
Barrow
D
D
Hejaz
H A
HA
Nicholson
R I
RI
Potter
B V
BV
Reed
M J
MJ
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D003374:Coumarins / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D004967:Estrogens / Q000494:pharmacology; D004970:Estrone / Q000031:analogs & derivatives* / Q000494:pharmacology; D005260:Female; D006801:Humans; D007700:Kinetics; D010082:Oxepins; D051381:Rats; D017208:Rats, Wistar; D013429:Sulfatases / Q000037:antagonists & inhibitors / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D013451:Sulfonic Acids / Q000737:chemistry* / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
C405442:2-methoxyoestrone-3-O-sulphamate; D000970:Antineoplastic Agents; D003374:Coumarins; D004791:Enzyme Inhibitors; D004967:Estrogens; D010082:Oxepins; D013449:Sulfonamides; D013451:Sulfonic Acids; D004970:Estrone; C520511:irosustat; C005741:sulfamic acid; D013429:Sulfatases; C020121:estrone sulfatase