Hybridization of steroids and other pharmacophores often modifies the bioactivity
of the parent compounds, improving selectivity and side effect profile. In this study,
estradiol and 3′-(un)substituted benzisoxazole moieties were combined into novel molecules
by structural integration of their aromatic rings. Simple estrogen starting materials,
such as estrone, estradiol and estradiol-3-methylether were used for the multistep
transformations. Some of the heterocyclic derivatives were prepared from the estrane
precursor by a formylation or Friedel–Crafts acylation—oximation—cyclization sequence,
whereas others were obtained by a functional group interconversion strategy. The antiproliferative
activities of the synthesized compounds were assessed on various human cervical, breast
and prostate cancer cell lines (HeLa, MCF-7, PC3, DU-145) and non-cancerous MRC-5
fibroblast cells. Based on the primary cytotoxicity screens, the most effective cancer-selective
compounds were selected, their IC50 values were determined and their apoptosis-inducing
potential was evaluated by quantitative real-time PCR. Pharmacological studies revealed
a strong structure–function relationship, where derivatives with a hydroxyl group
on C-17 exhibited stronger anticancer activity compared to the 17-acetylated counterparts.
The present study concludes that novel estradiol-benzisoxazole hybrids exert remarkable
cancer cell-specific antiproliferative activity and trigger apoptosis in cancer cells.
