biostudies-literatureDohle WCCR NIH HHSLister Institute of Preventive MedicineNCI NIH HHSe202200408https://www.ebi.ac.uk/biostudies/studies/S-EPMC9742152biostudies-literatureUnknown17(23)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 (GI₅₀ 0.28 μM) vs the known 2-methoxyestradiol-3,17-O,O-bissulfamate (STX140, GI₅₀ 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 GI₅₀ . It was a very potent STS inhibitor in whole JEG-3 cells (IC₅₀ 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 IC₅₀ of 55 pM.ChemMedChem2-Difluoromethoxy-Substituted Estratriene Sulfamates: Synthesis, Antiproliferative SAR, Antitubulin Activity, and Steroid Sulfatase Inhibition.PMC9742152HHSN261200800001EHHSN261200800001CDohle WAsiki HFoster PASahota HKBai RChristensen KEHamel EGruchot WPotter BVLfalse2-Difluoromethoxy-Substituted Estratriene Sulfamates: Synthesis, Antiproliferative SAR, Antitubulin Activity, and Steroid Sulfatase Inhibition.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 (GI₅₀ 0.28 μM) vs the known 2-methoxyestradiol-3,17-O,O-bissulfamate (STX140, GI₅₀ 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 GI₅₀ . It was a very potent STS inhibitor in whole JEG-3 cells (IC₅₀ 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 IC₅₀ of 55 pM.2022-01-01T00:00:00Z2022 Dec2026-05-28T01:32:55.64Z2025-02-19T04:25:32.341ZS-EPMC97421523610934010.1002/cmdc.202200408