2-difluoromethoxy-substituted estratriene sulfamates: synthesis, anti-proliferative sar, anti-tubulin activity and steroid sulfatase inhibition

Journal article

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 the corresponding nonfluorinated analogues. The fluorinated bis-sulfamate is a promising anti-proliferative 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 bissulfamate 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 Xray 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.

Authors: Dohle, W; Asiki, H; Gruchot, W; Foster, P; Sahota, HK

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Wiley
• Journal: CheMedChem
• Volume: 17
• Issue: 23
• Article number: e202200408
• Publication date: 2022-09-15
• Acceptance date: 2022-09-15
• DOI: 10.1002/cmdc.202200408
• EISSN: 1860-7187
• ISSN: 1860-7179
• Language: English
• Keywords: FFR