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Chiral aromatase and dual aromatase−steroid sulfatase inhibitors from the letrozole template : synthesis, absolute configuration, and in vitro activity


Reference:

Wood, P. M., Woo, L. W. L., Labrosse, J.-R., Trusselle, M. N., Abbate, S., Longhi, G., Castiglioni, E., Lebon, F., Purohit, A., Reed, M. J. and Potter, B. V. L., 2008. Chiral aromatase and dual aromatase−steroid sulfatase inhibitors from the letrozole template : synthesis, absolute configuration, and in vitro activity. Journal of Medicinal Chemistry, 51 (14), pp. 4226-4238.

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http://dx.doi.org/10.1021/jm800168s

Abstract

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.

Details

Item Type Articles
CreatorsWood, P. M., Woo, L. W. L., Labrosse, J.-R., Trusselle, M. N., Abbate, S., Longhi, G., Castiglioni, E., Lebon, F., Purohit, A., Reed, M. J. and Potter, B. V. L.
DOI10.1021/jm800168s
DepartmentsFaculty of Science > Pharmacy & Pharmacology
RefereedYes
StatusPublished
ID Code17625

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