2-difluoromethoxy-substituted estratriene sulfamates: synthesis, antiproliferative SAR, antitubulin activity, and steroid sulfatase inhibition

Wolfgang Dohle, Hannah Asiki, Wojciech Gruchot, Paul Foster, Havreen Sahota, Ruoli Bai, Christensen Kirsten, Ernest Hamel, Barry V L Potter*

*Corresponding author for this work

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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 non-fluorinated 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 bis-sulfamate 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 nM.
Original languageEnglish
Article numbere202200408
Number of pages12
Early online date13 Oct 2022
Publication statusE-pub ahead of print - 13 Oct 2022

Bibliographical note

Print VoR not yet available as of 27/10/2022

Funding Information:
This research was supported in part by the Developmental Therapeutics Program in the Division of Cancer Treatment and Diagnosis of the National Cancer Institute, which includes federal funds under Contract No. HHSN261200800001E and in part by a summer studentship grant from the Lister Institute of Preventive Medicine and by bursaries from Merton and Somerville Colleges, Oxford (to H.A. and W.G.).

Publisher Copyright:
© 2022 Wiley-VCH GmbH.


  • colchicine binding
  • difluoromethoxy isosteres
  • microtubule disruptors
  • steroid sulfatase inhibition
  • tubulin assembly

ASJC Scopus subject areas

  • Drug Discovery
  • Molecular Medicine
  • Biochemistry
  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Pharmacology
  • Organic Chemistry


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