Design and synthesis of novel piperazine-based sulfamate derivatives as steroid sulfatase inhibitors

Steroid sulfatase (STS) is emerging as a promising target in the treatment of hormone receptor-positive (HR+)/HER2-negative breast cancer. In this study, a series of new sulfamate-based arylamido-adamantane derivatives (1a-p) with a piperazine linker were designed and synthesized to enhance their potential as STS inhibitors by improving their physicochemical and pharmacokinetic properties. The biological screening and solubility measurement were performed to assess the compounds properties. Among the 16 synthesized compounds, 11 compounds with ortho-halo-substitution exhibited 90% STS inhibitory activity due to enhanced hydrogen bonding and enzyme-inhibitor complex stabilization. Cell-free (JEG-3 placental cell lysate) and whole-cell assays (using intact monolayers of JEG-3 cells) revealed that 4-carboxamido phenyl sulfamate derivatives, particularly compounds 1f (IC₅₀ = 21.44 nM), 1b (IC₅₀ = 38.58 nM) and 1c (IC₅₀ = 44.08 nM) in cell free assay and 1b (IC₅₀ = 6.49 nM), 1c (IC₅₀ = 10.04 nM) and 1f (IC₅₀ = 21.44 nM) in whole cell assay exhibited potent STS inhibition. Notably, compound 1l showed poor cell-free potency (IC₅₀ = 202 nM) but significant whole-cell activity (IC₅₀ = 37.79 nM), highlighting improved lipid bilayer penetration. These findings validate the potential of piperazine-linked sulfamate derivatives as potent STS inhibitors that can offer new paths for hormone-dependent breast cancer therapy.