D-ring modified estrone derivatives as novel potent inhibitors of steroid sulfatase

Delpnine S. Fischer, L. W. Lawrence Woo, Mary F. Mahon, Atul Purohit, Michael J. Reed, Barry V. L. Potter

Research output: Contribution to journalArticlepeer-review

59 Citations (Scopus)

Abstract

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 IC50 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.
Original languageEnglish
Pages (from-to)1685-1700
JournalBioorganic and Medicinal Chemistry
Volume11
Issue number8
DOIs
Publication statusPublished - 2003

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