Synthesis of 2-aryl/alkylaminomethyl 17-sulfamate/17-methyl estratrienes and their in vitro cytotoxicity in human cancer cell cultures.

2-Methoxyestradiol (2-ME), a natural metabolite of 17β-estradiol, exhibits potent anticancer activity by inhibiting tubulin polymerization and modulating steroid sulfatase (STS). However, its rapid metabolism limits its clinical usefulness. To overcome these issues, we designed a new series of 2-aryl/alkylaminomethyl estratriene analogues with sulfamate groups at C‑3 and/or C‑17, serving as hybrid agents that disrupt microtubules and modulate STS, derived from the 2-ME pharmacophore. We used a stepwise transformation of estrone to access C‑2 aminomethyl frameworks, followed by regioselective sulfamoylation to create mono‑ (C‑17 or C‑3) and bis‑sulfamoylated derivatives, including 17‑sulfamates 8a-h, 3,17‑bis-sulfamates 11a-c, 3‑sulfamates 18a,b, and 25. These compounds were tested for their antiproliferative activity against HCT‑116 (colon) and MCF‑7 (breast) cancer cell lines. Notably, mono C‑17 sulfamoylated analogues with small lipophilic C‑2 amines, such as cyclopropyl 8a and 4‑chlorophenyl 8e, exhibited the most potent activity (GI < 3 μM), outperforming both 3‑sulfamates and 3,17‑bis-sulfamates. Structure-activity relationship analysis revealed that excessive polarity from bis‑sulfamoylation and bulky C‑2 amines reduces activity, while compact lipophilic or halogenated C‑2 substituents enhance the balance of electronic effects, steric compatibility, and permeability. Compared to literature on 2-ME sulfamates, our results show a distinct regioselectivity profile, with the 2‑aminomethyl scaffold favouring C‑17 sulfamoyation for maximum activity. This study offers the potential to develop estratriene-based anticancer agents with improved pharmacokinetic profiles.