Synthesis and Structure–Activity Relationship Studies of Derivatives of the Dual Aromatase–Sulfatase Inhibitor 4‐{[(4‐Cyanophenyl)(4H‐1,2,4‐triazol‐4‐yl)amino]methyl}phenyl sulfamate

Abstract

4-{[(4-Cyanophenyl)(4H-1,2,4-triazol-4-yl)amino]methyl}phenyl sulfamate and its ortho-halogenated (F, Cl, Br) derivatives are first-generation dual aromatase and sulfatase inhibitors (DASIs). Structure–activity relationship studies were performed on these compounds, and various modifications were made to their structures involving relocation of the halogen atom, introduction of more halogen atoms, replacement of the halogen with another group, replacement of the methylene linker with a difluoromethylene linker, replacement of the para-cyanophenyl ring with other ring structures, and replacement of the triazolyl group with an imidazolyl group. The most potent in vitro DASI discovered is an imidazole derivative with IC50 values against aromatase and steroid sulfatase in a JEG-3 cell preparation of 0.2 and 2.5 nm, respectively. The parent phenol of this compound inhibits aromatase with an IC50 value of 0.028 nm in the same assay.

Synthesis and Antiproliferative Evaluation of 5′‐Arylchalcogenyl‐3‐(phenylselanyl‐triazoyl)‐thymidine

“…For instance, compounds containing electron withdrawing groups attached to the aromatic ring in the selenium moiety demonstrated lower IC50 values and high antiproliferative capacity compared with an electron donating group (Table , compounds 11 d and 11 b, 11 k and 11 i , respectively). Structure‐activity relationship studies have shown that compounds containing halogen monosubstituents demonstrate more potent inhibitory activities in different cancer cell lines, including human lung adenocarcinoma cell line A549 . Woo et al.…”

Recent developments in steroidal and nonsteroidal aromatase inhibitors for the chemoprevention of estrogen-dependent breast cancer

“…) with IC 50 s of: aromatase = 0.0002 µM and STS = 0.0025 µM. [91] CONCLUSION: This is the first review in the last decade where both steroidal and nonsteroidal AIs reported in the literature have been summarized. Aromatase is an important target for breast cancer treatment and its inhibitors are very beneficial in this respect.…”

Synthesis and in vitro evaluation of piperazinyl-ureido sulfamates as steroid sulfatase inhibitors

“…Sulfamate analogs of Nacylated tyramine containing C-F bonds demonstrate that introduction of a fluorine atom into tyraminebased STS inhibitors remote from the aryl sulfamate moiety can enhance inhibitory activity, albeit in the micromolar range [29]. Recent work by some of us has shown that the introduction of halogens, particularly fluorine into the aryl sulfamate ring can appreciably improve the activity of STS inhibitors by lowering the pKa of the leaving phenol after transfer of the sulfamoyl moiety, thus increasing the "sulfamoyl-transfer potential" of the inhibitor [9,10,30].…”