Design and synthesis of dansyl-labeled inhibitors of steroid sulfatase for optical imaging |
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| Affiliation: | 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;1. Department of Radiology CS2, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, Netherlands;2. Department of Bioorganic Synthesis, Leiden Institute of Chemistry, Leiden University, Leiden, Netherlands;3. Radionucleotide Laboratory, Free University, Amsterdam, Netherlands;4. Division of Drug Delivery Technology, Leiden Academic Center for Drug Research, Leiden University, Leiden, Netherlands;5. Department of Human Genetics, Leiden University Medical Center, Leiden, Netherlands;1. Laboratory of Medicinal Chemistry, Endocrinology and Nephrology Unit, CHU de Québec - Research Center (CHUL, T4), Québec, QC, G1V 4G2, Canada;2. Department of Molecular Medicine, Faculty of Medicine, Université Laval, Québec, QC, G1V 0A6, Canada;1. Laboratory of Medicinal Chemistry, Endocrinology and Nephrology Unit, CHU de Québec – Research Center (CHUL, T4), Québec, QC, Canada;2. Département de Chimie, Institut de Biologie Intégrative et Des Systèmes (IBIS), and Centre de Recherche sur la Fonction, la Structure et l’Ingénierie des Protéines (PROTEO), Université Laval, Québec, QC, Canada;3. Département de Biochimie Microbiologie et Bio-informatique, Institut de Biologie Intégrative et des Systèmes (IBIS), and Centre de Recherche sur la Fonction, la Structure et l’Ingénierie des Protéines (PROTEO), Université Laval, Québec, QC, Canada;4. Department of Molecular Medicine, Faculty of Medicine, Université Laval, Québec, QC, Canada;1. Pharmacognosy and Pharmaceutical Chemistry Department, College of Pharmacy Taibah University, Al Madinah Almunawarah, 30001, Saudi Arabia;2. Department of Pharmaceutical Analytical Chemistry, Faculty of Pharmacy, Assiut University, Assiut, 71526, Egypt;3. Experiments and Advanced Pharmaceutical Research Unit, Faculty of Pharmacy, Ain Shams University, Cairo, 1156, Egypt;1. Endocrinology and Nephrology Unit, CHU de Québec-Research Center (CHUL, T4), Québec City, QC, Canada;2. Department of Molecular Medicine, Faculty of Medicine, Université Laval, Québec City, QC, Canada;3. Département de chimie, Institut de biologie intégrative et des systèmes (IBIS), Québec City, QC, Canada;4. Centre de recherche sur la fonction, la structure et l''ingénierie des protéines (PROTEO),Université Laval, Québec City, QC, Canada;5. Département de biochimie microbiologie et bio-informatique, Institut de biologie intégrative et des systèmes (IBIS), Québec City, QC, Canada;1. Laboratory of Medicinal Chemistry, Endocrinology and Nephrology Unit, CHU de Québec – Research Center (CHUL, T4-42), Québec, QC, Canada;2. Faculty of Pharmacy, Endocrinology and Nephrology Unit, CHU de Québec − Research Center (CHUL, T4-13), Québec, QC, Canada;3. Department of Molecular Medicine, Faculty of Medicine, Université Laval, Québec, QC, Canada |
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| 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. |
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| Keywords: | Steroid Danzyl derivative Fluorescent agent Steroid sulfatase Enzyme inhibitor |
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