611-80-3Relevant academic research and scientific papers
Chiral aromatase and dual aromatase-steroid sulfatase inhibitors from the letrozole template: Synthesis, absolute configuration, and in vitro activity
Wood, Paul M.,Woo, L. W. Lawrence,Labrosse, Jean-Robert,Trusselle, Melanie N.,Abbate, Sergio,Longhi, Giovanna,Castiglioni, Ettore,Lebon, France,Purohit, Atul,Reed, Michael J.,Potter, Barry V. L.
scheme or table, p. 4226 - 4238 (2009/06/06)
To explore aromatase inhibition and to broaden the structural diversity of dual aromatase-sulfatase inhibitors (DASIs), we introduced the steroid sulfatase (STS) inhibitory pharmacophore to letrozole. Letrozole derivatives were prepared bearing bis-sulfamates or mono-sulfamates with or without adjacent substituents. The most potent of the achiral and racemic aromatase inhibitor was 40 (IC50 = 3.0 nM). Its phenolic precursor 39 was separated by chiral HPLC, and the absolute configuration of each enantiomer was determined using vibrational and electronic circular dichroism in tandem with calculations of the predicted spectra. Of the two enantiomers, (R)-phenol (39a) was the most potent aromatase inhibitor (IC50 = 0.6 nM, comparable to letrozole), whereas the (S)-sulfamate, (40b) inhibited STS most potently (IC50 = 553 nM). These results suggest that a new structural class of DASI for potential treatment of hormone-dependent breast cancer has been identified, and this is the first report of STS inhibition by an enantiopure nonsteroidal compound.
Synthesis, in vitro and in vivo activity of benzophenone-based inhibitors of steroid sulfatase
Hejaz, Hatem A. M.,Woo, L. W. Lawrence,Purohit, Atul,Reed, Michael J.,Potter, Barry V. L.
, p. 2759 - 2772 (2007/10/03)
Steroid sulfatase (STS) is an important new therapeutic target in oncology. Attempts to design nonsteroidal STS inhibitors, because of the oestrogenicity of the original lead oestrone 3-O-sulfamate in rodents, have led to the discovery of benzophenone-4,4′-O,O-bis-sulfamate (BENZOMATE, 3). The nonfused bicyclic BENZOMATE is a highly potent STS inhibitor in vitro, inhibiting STS activity in intact MCF-7 breast cancer cells by >70% at 0.1μM and in placental microsomes by >98% at 10μM. When MCF-7 cells were pre-treated with 3 at 1μM and then washed to remove unbound inhibitor, the initial 94% inhibition was reduced to 89% suggesting that 3, like other sulfamate-based STS inhibitors, inhibits the enzyme irreversibly. This agent also inhibits rat liver STS activity by 84% and 93% respectively 24h after a single dose of 1 or 10mg/kg, demonstrating that BENZOMATE possesses similar in vivo potency to the established potent nonsteroidal inhibitor 667COUMATE. Several modifications were made to BENZOMATE structurally and effects on in vitro activity were examined. These structure-activity relationship studies show that its carbonyl and bis-sulfamate groups are pivotal for activity, although conformational flexibility is not required. Two rigid anthraquinone-based sulfamate derivatives however showed inhibitory activity significantly better than BENZOMATE in the MCF-7 cell assay. BENZOMATE and related analogues therefore represent an important class of non-steroidal STS inhibitor and lead compounds for future drug design.
4,4′-Benzophenone-O,O′-disulfamate: A potent inhibitor of steroid sulfatase
Nussbaumer, Peter,Bilban, Melitta,Billich, Andreas
, p. 2093 - 2095 (2007/10/03)
We investigated whether the benzophenone moiety can be used as core element of steroid sulfatase (STS) inhibitors. While 4- and 3-benzophenone-O-sulfamates inhibit STS with IC50 values between 5 and 7 μM irrespective of additional hydroxy and m
