2. Academic Validation
  3. Development of Sulfamoylated 4-(1-Phenyl-1 H-1,2,3-triazol-4-yl)phenol Derivatives as Potent Steroid Sulfatase Inhibitors for Efficient Treatment of Breast Cancer

Development of Sulfamoylated 4-(1-Phenyl-1 H-1,2,3-triazol-4-yl)phenol Derivatives as Potent Steroid Sulfatase Inhibitors for Efficient Treatment of Breast Cancer

  • J Med Chem. 2022 Mar 24;65(6):5044-5056. doi: 10.1021/acs.jmedchem.1c02220.
Karol Biernacki 1,  Olga Ciupak 1,  Mateusz Daśko 2,  Janusz Rachon 1,  Witold Kozak 3,  Janusz Rak 3,  Konrad Kubiński 4,  Maciej Masłyk 4,  Aleksandra Martyna 4,  Magdalena Śliwka-Kaszyńska 1,  Joanna Wietrzyk 5,  Marta Świtalska 5,  Alessio Nocentini 6,  Claudiu T Supuran 6,  Sebastian Demkowicz 1
Affiliations

Affiliations

  • 1 Department of Organic Chemistry, Faculty of Chemistry, Gdańsk University of Technology, Narutowicza 11/12, 80-233 Gdansk, Poland.
  • 2 Department of Inorganic Chemistry, Faculty of Chemistry, Gdańsk University of Technology, Narutowicza 11/12, 80-233 Gdansk, Poland.
  • 3 Department of Physical Chemistry, Faculty of Chemistry, University of Gdańsk, Wita Stwosza 63, 80-308 Gdansk, Poland.
  • 4 Department of Molecular Biology, Faculty of Biotechnology and Environment Sciences, The John Paul II Catholic University of Lublin, Konstantynów 1i, 20-708 Lublin, Poland.
  • 5 Department of Experimental Oncology, Hirszfeld Institute of Immunology and Experimental Therapy, Rudolfa Weigla 12, 53-114 Wrocław, Poland.
  • 6 Department of NEUROFARBA, Pharmaceutical and Nutraceutical Section, University of Florence, Via U. Schiff 6, Sesto Fiorentino, 50019 Firenze, Italy.
PMID: 35235747 DOI: 10.1021/acs.jmedchem.1c02220
Abstract

We present here the advances achieved in the development of new sulfamoylated 4-(1-phenyl-1H-1,2,3-triazol-4-yl)phenol derivatives as potent steroid sulfatase (STS) inhibitors for the treatment of breast Cancer. Prompted by promising biological results and in silico analysis, the initial series of similar compounds were extended, appending a variety of m-substituents at the outer phenyl ring. The inhibition profiles of the newly synthesized compounds were evaluated using a radioisotope enzymatic assay and, together with the preceding reported derivatives, using a radioisotope assay in MCF-7 cells. The most active compound, 5l, demonstrated an extraordinary STS inhibitory potency in MCF-7 cells with an IC50 value improved 5-fold compared to that of the reference Irosustat (0.21 vs 1.06 nM). The five most potent compounds were assessed in vivo in a 67NR mouse mammary gland Cancer model, with 4b measured to induce up to 51% tumor growth inhibition at 50 mg/kg with no evidence of side effects and toxicity.

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