{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Dohle W"],"funding":["CCR NIH HHS","Lister Institute of Preventive Medicine","NCI NIH HHS"],"pagination":["e202200408"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC9742152"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["17(23)"],"pubmed_abstract":["2-Difluoromethoxyestratriene derivatives were designed to improve potency and in vivo stability of the drug candidate 2-methoxyestradiol (2ME2). Compound evaluation in vitro against the proliferation of MCF-7 and MDA MB-231 breast cancer cells, as inhibitors of tubulin polymerisation and also steroid sulfatase (STS) both in cell lysates and in whole cells, showed promising activities. In antiproliferative assays 2-difluoromethoxyestradiol was less potent than 2ME2, but its sulfamates were often more potent than their corresponding non-fluorinated analogues. The fluorinated bis-sulfamate is a promising antiproliferative agent in MCF-7 cells (GI<sub>50</sub> 0.28 μM) vs the known 2-methoxyestradiol-3,17-O,O-bissulfamate (STX140, GI<sub>50</sub> 0.52 μM), confirming the utility of our approach. Compounds were also evaluated in the NCI 60-cell line panel and the fluorinated bis-sulfamate derivative displayed very good overall activities with a sub-micromolar average GI<sub>50</sub> . It was a very potent STS inhibitor in whole JEG-3 cells (IC<sub>50</sub> 3.7 nM) similar to STX140 (4.2 nM) and additionally interferes with tubulin assembly in vitro and colchicine binding to tubulin. An X-ray study of 2-difluoromethoxy-3-benzyloxyestra-1,3,5(10)-trien-17-one examined conformational aspects of the fluorinated substituent. The known related derivative 2-difluoromethyl-3-sulfamoyloxyestrone was evaluated for STS inhibition in whole JEG-3 cells and showed an excellent IC<sub>50</sub> of 55 pM."],"journal":["ChemMedChem"],"pubmed_title":["2-Difluoromethoxy-Substituted Estratriene Sulfamates: Synthesis, Antiproliferative SAR, Antitubulin Activity, and Steroid Sulfatase Inhibition."],"pmcid":["PMC9742152"],"funding_grant_id":["HHSN261200800001E","HHSN261200800001C"],"pubmed_authors":["Dohle W","Asiki H","Foster PA","Sahota HK","Bai R","Christensen KE","Hamel E","Gruchot W","Potter BVL"],"additional_accession":[]},"is_claimable":false,"name":"2-Difluoromethoxy-Substituted Estratriene Sulfamates: Synthesis, Antiproliferative SAR, Antitubulin Activity, and Steroid Sulfatase Inhibition.","description":"2-Difluoromethoxyestratriene derivatives were designed to improve potency and in vivo stability of the drug candidate 2-methoxyestradiol (2ME2). Compound evaluation in vitro against the proliferation of MCF-7 and MDA MB-231 breast cancer cells, as inhibitors of tubulin polymerisation and also steroid sulfatase (STS) both in cell lysates and in whole cells, showed promising activities. In antiproliferative assays 2-difluoromethoxyestradiol was less potent than 2ME2, but its sulfamates were often more potent than their corresponding non-fluorinated analogues. The fluorinated bis-sulfamate is a promising antiproliferative agent in MCF-7 cells (GI<sub>50</sub> 0.28 μM) vs the known 2-methoxyestradiol-3,17-O,O-bissulfamate (STX140, GI<sub>50</sub> 0.52 μM), confirming the utility of our approach. Compounds were also evaluated in the NCI 60-cell line panel and the fluorinated bis-sulfamate derivative displayed very good overall activities with a sub-micromolar average GI<sub>50</sub> . It was a very potent STS inhibitor in whole JEG-3 cells (IC<sub>50</sub> 3.7 nM) similar to STX140 (4.2 nM) and additionally interferes with tubulin assembly in vitro and colchicine binding to tubulin. An X-ray study of 2-difluoromethoxy-3-benzyloxyestra-1,3,5(10)-trien-17-one examined conformational aspects of the fluorinated substituent. The known related derivative 2-difluoromethyl-3-sulfamoyloxyestrone was evaluated for STS inhibition in whole JEG-3 cells and showed an excellent IC<sub>50</sub> of 55 pM.","dates":{"release":"2022-01-01T00:00:00Z","publication":"2022 Dec","modification":"2026-05-28T01:32:55.64Z","creation":"2025-02-19T04:25:32.341Z"},"accession":"S-EPMC9742152","cross_references":{"pubmed":["36109340"],"doi":["10.1002/cmdc.202200408"]}}