2. Academic Validation
  3. Synthesis and Biological Evaluation of 3,5-Diaryl-Substituted 1,2,4-Oxadiazole Sulfamates as Potent Steroid Sulfatase Inhibitors

Synthesis and Biological Evaluation of 3,5-Diaryl-Substituted 1,2,4-Oxadiazole Sulfamates as Potent Steroid Sulfatase Inhibitors

  • ACS Med Chem Lett. 2026 Jan 16;17(2):510-519. doi: 10.1021/acsmedchemlett.5c00706.
Karol Biernacki 1,  Olga Ciupak 2,  Mateusz Daśko 2,  Agata Grobelna 1,  Artur Mirocki 3,  Janusz Rak 3,  Paweł Czubak 4,  Aleksandra Martyna 4,  Konrad Kubiński 4,  Maciej Masłyk 4,  Katarzyna Szwarc-Karabyka 5,  Mateusz Kwaśnik 4,  Janusz Rachoń 1,  Sebastian Demkowicz 1
Affiliations

Affiliations

  • 1 Department of Organic Chemistry, Faculty of Chemistry, Gdańsk University of Technology, Narutowicza 11/12 Street, 80-233 Gdańsk, Poland.
  • 2 Department of Inorganic Chemistry, Faculty of Chemistry, Gdańsk University of Technology, Narutowicza 11/12 Street, 80-233 Gdańsk, Poland.
  • 3 Department of Physical Chemistry, Faculty of Chemistry, University of Gdańsk, Wita Stwosza 63 Street, 80-308 Gdańsk, Poland.
  • 4 Department of Molecular Biology, Faculty of Medicine, The John Paul II Catholic University of Lublin, Konstantynów 1i Street, 20-708, Lublin, Poland.
  • 5 Nuclear Magnetic Resonance Laboratory, Faculty of Chemistry, Gdańsk University of Technology, Narutowicza 11/12 Street, 80-233, Gdańsk, Poland.
PMID: 41704353 DOI: 10.1021/acsmedchemlett.5c00706
Abstract

A novel series of 3,5-disubstituted 1,2,4-oxadiazole sulfamates was synthesized and evaluated as Steroid Sulfatase (STS) inhibitors. Molecular docking predicted high affinity (binding energies of up to -8.9 kcal·mol-1), often surpassing the reference Irosustat. Biological evaluation confirmed potent inhibition; compound 9n reduced enzymatic STS activity to 3.5% at 10 μM. In JEG-3 cells, the most potent derivative, 9j, exhibited an IC50 of 6.64 nM, comparable to that of Irosustat (4.19 nM). Structure-activity relationship analysis revealed that the substitution pattern of the oxadiazole heterocycle plays a decisive role in determining biological activity. Shifting the aryl-sulphamate pharmacophore between positions 3- and 5- of the 1,2,4-oxadiazole heterocycle is crucial for maintaining high biological activity. These findings establish 3,5-disubstituted 1,2,4-oxadiazole sulfamates as promising leads for treating hormone-dependent cancers.

Keywords

1,2,4-oxadiazole; Steroid sulfatase; breast cancer; drug design; molecular modeling; structure−activity relationship.

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