Design and synthesis of dansyl-labeled inhibitors of steroid sulfatase for optical imaging. Issue 7 (1st April 2020) - Maltais, René
Graphical abstract: Highlights: Design of dansyl-labeled STS inhibitors assisted by QSAR and molecular docking. A short chemical synthesis led to phenolic and sulfamate dansyl-labeled inhibitors. Low nanomolar (IC50 ) inhibitors of steroid sulfatase (STS) were obtained. Confocal microscopy shows the STS inhibitor located in the endoplasmic reticulum. 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.