1. Academic Validation
  2. Design and synthesis of dansyl-labeled inhibitors of steroid sulfatase for optical imaging

Design and synthesis of dansyl-labeled inhibitors of steroid sulfatase for optical imaging

  • Bioorg Med Chem. 2020 Apr 1;28(7):115368. doi: 10.1016/j.bmc.2020.115368.
René Maltais 1 Adrien Ngueta Djiemeny 1 Jenny Roy 1 Xavier Barbeau 1 Jean-Philippe Lambert 2 Donald Poirier 3
Affiliations

Affiliations

  • 1 Laboratory of Medicinal Chemistry, Endocrinology and Nephrology Unit, CHU de Québec - Research Center, Québec, QC, Canada.
  • 2 Department of Molecular Medicine, Faculty of Medicine, Université Laval, Québec, QC, Canada.
  • 3 Laboratory of Medicinal Chemistry, Endocrinology and Nephrology Unit, CHU de Québec - Research Center, Québec, QC, Canada; Department of Molecular Medicine, Faculty of Medicine, Université Laval, Québec, QC, Canada. Electronic address: donald.poirier@crchul.ulaval.ca.
Abstract

Steroid Sulfatase (STS) is an important Enzyme regulating the conversion of sulfated Steroids into their active hydroxylated forms. Notably, the inhibition of STS has been shown to decrease the levels of active estrogens and was translated into clinical trials for the treatment of breast Cancer. Based on quantitative structure-activity relationship (QSAR) and molecular modeling studies, we herein report the design of fluorescent inhibitors of STS by adding a dansyl group on an estrane scaffold. Synthesis of 17α-dansylaminomethyl-estradiol (7) and its sulfamoylated analog 8 were achieved from estrone in 5 and 6 steps, respectively. Inhibition assays on HEK-293 cells expressing exogenous STS revealed a high level of inhibition for compound 7 (IC50 = 69 nM), a value close to the QSAR model prediction (IC50 = 46 nM). As an irreversible inhibitor, sulfamate 8 led to an even more potent inhibition in the low nanomolar value (IC50 = 2.1 nM). In addition, we show that the potent STS inhibitor 8 can be employed as an optical imaging tool to investigate intracellular Enzyme sub-localization as well as inhibitory behavior. As a result, confocal microscopy analysis confirmed good penetration of the STS fluorescent inhibitor 8 in cells and its localization in the endoplasmic reticulum where STS is localized.

Keywords

Danzyl derivative; Enzyme inhibitor; Fluorescent agent; Steroid; Steroid sulfatase.

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