D-ring modified estrone derivatives as novel potent inhibitors of steroid sulfatase.
A series of novel D-ring modified derivatives of estrone was synthesized and tested as inhibitors of steroid sulfatase (STS). The steroidal D-ring was cleaved via an iodoform reaction and thermal condensation of the resulting marrianolic acid derivative gave 16,17-seco-estra-1,3,5(10)-triene-16,17-imide derivatives, where a piperidinedione moiety is in place of the D-ring. This synthetic approach was found to give a higher overall yield than the literature method of Beckmann rearrangement. A range of alkyl side chains have been introduced on the nitrogen atom of the imido-ring and the corresponding 3-O-sulfamates synthesized. The new D-ring modified estrone derivatives bearing a propyl (39) and a 1-pyridin-3-ylmethyl (46) moiety had IC(50) values of 1 nM when tested in placental microsomes for the inhibition of STS. These compounds are therefore up to 18-fold more potent than EMATE, the very first highly potent irreversible steroidal STS inhibitor.
Fischer
Delphine S
DS
Medicinal Chemistry, Department of Pharmacy and Pharmacology and Sterix Ltd., University of Bath, Claverton Down, Bath BA2 7AY, UK.
Woo
L W Lawrence
LW
Mahon
Mary F
MF
Purohit
Atul
A
Reed
Michael J
MJ
Potter
Barry V L
BV
D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D004970:Estrone / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology; D015394:Molecular Structure; D010920:Placenta / Q000378:metabolism; D012015:Reference Standards; D043266:Steryl-Sulfatase / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; C088768:estrone-3-O-sulfamate; D004970:Estrone; D043266:Steryl-Sulfatase