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C-3- and C-4-Substituted Bicyclic Coumarin Sulfamates as Potent Steroid Sulfatase Inhibitors

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Title: C-3- and C-4-Substituted Bicyclic Coumarin Sulfamates as Potent Steroid Sulfatase Inhibitors
Authors: Ganeshapillai, D
Woo, LWL
Thomas, MP
Purohit, A
Potter, BVL
Item Type: Journal Article
Abstract: Synthetic routes to potent bicyclic nonsteroidal sulfamate-based active-site-directed inhibitors of the enzyme steroid sulfatase (STS), an emerging target in the treatment of postmenopausal hormone-dependent diseases, including breast cancer, are described. Sulfamate analogs 9–27 and 28–46 of the core in vivo active two-ring coumarin template, modified at the 4- and 3-positions, respectively, were synthesized to expand structure–activity relationships. α-Alkylacetoacetates were used to synthesize coumarin sulfamate derivatives with 3-position modifications, and the bicyclic ring of other parent coumarins was primarily constructed via the Pechmann synthesis of hydroxyl coumarins. Compounds were examined for STS inhibition in intact MCF-7 breast cancer cells and in placental microsomes. Low nanomolar potency STS inhibitors were achieved, and some were found to inhibit the enzyme in MCF-7 cells ca. 100–500 more potently than the parent 4-methylcoumarin-7-O-sulfamate 3, with the best compounds close in potency to the tricyclic clinical drug Irosustat. 3-Hexyl-4-methylcoumarin-7-O-sulfamate 29 and 3-benzyl-4-methylcoumarin-7-O-sulfamate 41 were particularly effective inhibitors with IC50 values of 0.68 and 1 nM in intact MCF-7 cells and 8 and 32 nM for placental microsomal STS, respectively. They were docked into the STS active site for comparison with estrone 3-O-sulfamate and Irosustat, showing their sulfamate group close to the catalytic hydrated formylglycine residue and their pendant group lying between the hydrophobic sidechains of L103, F178, and F488. Such highly potent STS inhibitors expand the structure–activity relationship for these coumarin sulfamate-based agents that possess therapeutic potential and may be worthy of further development.
Issue Date: 30-Sep-2018
Date of Acceptance: 16-Aug-2018
URI: http://hdl.handle.net/10044/1/63831
DOI: https://dx.doi.org/10.1021/acsomega.8b01383
ISSN: 2470-1343
Publisher: American Chemical Society
Start Page: 10748
End Page: 10772
Journal / Book Title: ACS OMEGA
Volume: 3
Issue: 9
Copyright Statement: © 2018 American Chemical Society. This is an open access article published under a Creative Commons Attribution (CC-BY) License (https://pubs.acs.org/page/policy/authorchoice_ccby_termsofuse.html), which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.
Keywords: Science & Technology
Physical Sciences
Chemistry, Multidisciplinary
Chemistry
BREAST-CANCER PATIENTS
SITE-DIRECTED INHIBITION
BETA-KETO-ESTERS
ESTRONE SULFATASE
BIOLOGICAL EVALUATION
(P-O-SULFAMOYL)-N-ALKANOYL TYRAMINES
AROMATASE INHIBITOR
ETHYL ACETOACETATE
ENDOCRINE THERAPY
DIETHYL MALONATE
Publication Status: Published
Online Publication Date: 2018-09-06
Appears in Collections:Department of Medicine (up to 2019)