American Chemical Society
jm1c02220_si_003.pdb (343.17 kB)

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

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posted on 2022-03-02, 22:14 authored by Karol Biernacki, Olga Ciupak, Mateusz Daśko, Janusz Rachon, Witold Kozak, Janusz Rak, Konrad Kubiński, Maciej Masłyk, Aleksandra Martyna, Magdalena Śliwka-Kaszyńska, Joanna Wietrzyk, Marta Świtalska, Alessio Nocentini, Claudiu T. Supuran, Sebastian Demkowicz
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.