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

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) inhibitorsfor the treatment of breast cancer. Prompted by promisingbiological results and in silico analysis, the initial series of similarcompounds were extended, appending a variety of m-substituentsat the outer phenyl ring. The inhibition profiles of the newlysynthesized compounds were evaluated using a radioisotopeenzymatic assay and, together with the preceding reportedderivatives, using a radioisotope assay in MCF-7 cells. The mostactive compound,5l, demonstrated an extraordinary STSinhibitory potency in MCF-7 cells with an IC50value improved5-fold compared to that of the referenceIrosustat(0.21 vs 1.06nM). Thefive most potent compounds were assessed in vivo in a 67NR mouse mammary gland cancer model, with4bmeasured to induce up to 51% tumor growth inhibition at 50 mg/kg with no evidence of side effects and toxicity