Synthesis and biological activity of the superestrogen (E)-17-oximino-3-O-sulfamoyl-1,3,5(10)-estratriene: x-ray crystal structure of (E)-17-oximino-3-hydroxy-1,3,5(10)-estratriene.
Steroid sulfatases regulate the formation of estrogenic steroids which can support the growth of endocrine-dependent breast tumors. Therefore, the development of potent steroid sulfatase inhibitors could have considerable therapeutic potential. Several such inhibitors have now been developed including estrone 3-O-sulfamate (EMATE, 1), which shows potent active site-directed inhibition. However, EMATE was subsequently shown to be also a potent estrogen. In an attempt to reduce the estrogenicity while retaining the potent sulfatase inhibitory properties associated with this type of molecule, (E)-17-oximino-3-O-sulfamoyl-1,3,5(10)-estratriene (5) (estrone oxime 3-O-sulfamate, OMATE) was synthesized. The X-ray crystal structure of (E)-17-oximino-3-hydroxy-1,3,5(10)-estratriene (4) (estrone oxime) demonstrated the presence of only one geometrical isomer [anti-isomer, (E)]. OMATE potently inhibited estrone sulfatase (E1-STS) activity and was similar to EMATE (>99% inhibition at 0.1 microM in MCF-7 breast cancer cells). It was also evaluated in vivo for its estrogenicity and ability to inhibit sulfatase activity. While it was equipotent with EMATE in vivo as a sulfatase inhibitor, it surprisingly had a stimulatory effect on uterine growth in ovariectomized rats about 1.5-fold greater than that of EMATE. Thus, OMATE possesses potential as a superestrogen and modification at C-17 is identified as a useful route for enhancement of estrogenicity in sulfamate-based estrogens.
Hejaz
H A
HA
Wolfson Laboratory of Medicinal Chemistry & Sterix Limited, Department of Pharmacy & Pharmacology, and Department of Chemistry, University of Bath, Claverton Down, Bath BA2 7AY, U.K.
Purohit
A
A
Mahon
M F
MF
Reed
M J
MJ
Potter
B V
BV
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001192:Arylsulfatases / Q000037:antagonists & inhibitors*; D001943:Breast Neoplasms; D018360:Crystallography, X-Ray; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004970:Estrone / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D009376:Neoplasms, Hormone-Dependent; D010052:Ovariectomy; D010091:Oximes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D043266:Steryl-Sulfatase; D014407:Tumor Cells, Cultured; D014599:Uterus / Q000187:drug effects / Q000201:enzymology
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D010091:Oximes; C120842:estrone oxime; C120843:estrone oxime 3-O-sulfamate; D004970:Estrone; D001192:Arylsulfatases; D043266:Steryl-Sulfatase