@article{dc5067595a904478aa9ffc9dac184241,
title = "Synthesis, biological evaluation, and stability studies of raloxifene mono- and bis-sulfamates as dual-targeting agents",
abstract = "All three possible sulfamate derivatives of the selective estrogen receptor modulator Raloxifene (bis-sulfamate 7 and two mono-sulfamates 8-9) were synthesized and evaluated as inhibitors of the clinical drug target steroid sulfatase (STS), both in cell-free and in cell-based assays, and also as estrogen receptor (ER) modulators. Bis-sulfamate 7 was the most potent STS inhibitor with an IC50 of 12.2 nM in a whole JEG3 cell-based assay, with the two mono-sulfamates significantly weaker. The estrogen receptor-modulating activities of 7-9 showed generally lower affinities compared to Raloxifene HCl, diethylstilbestrol and other known ligands, with mono-sulfamate 8 being the best ligand (Ki of 1.5 nM) for ERα binding, although 7 had a Ki of 13 nM and both showed desirable antagonist activity. The antiproliferative activities of the sulfamate derivatives against the T-47D breast cancer cell line showed 7 as most potent (GI50 = 7.12 µM), comparable to that of Raloxifene. Compound 7 also showed good antiproliferative potency in the NCI-60 cell line panel with a GI50 of 1.34 µM against MDA-MB-231 breast cancer cells. Stability testing of 7-9 showed that bis-sulfamate 7 hydrolyzed by desulfamoylation at a surprisingly rapid rate, initially leading selectively to 8 and finally to Raloxifene 3 without formation of 9. The mechanisms of these hydrolysis reactions could be extensively rationalized. Conversion of Raloxifene (3) into its bis-sulfamate (7) thus produced a promising drug lead with nanomolar dual activity as an STS inhibitor and ERα antagonist, as a potential candidate for treatment of estrogen-dependent breast cancer.",
keywords = "Enzyme inhibition, Estrogen receptor, Raloxifene, Steroid sulfatase, Sulfamate",
author = "Seyed-Omar Zaraei and Wolfgang Dohle and Anbar, {Hanan S.} and Randa El-Gama and Bertrand Leblond and Foster, {Paul A.} and Al-Tel, {Taleb H.} and Potter, {Barry V. L.} and El-Gamal, {Mohammed I.}",
year = "2024",
month = mar,
day = "1",
doi = "10.1016/j.bmc.2024.117645",
language = "English",
volume = "101",
journal = "Bioorganic & Medicinal Chemistry",
issn = "1464-3391",
publisher = "Elsevier",
}