| Autor: |
Kovács F; Department of Organic Chemistry, University of Szeged, Dóm tér 8, H-6720 Szeged, Hungary., Adamecz DI; Department of Biochemistry and Molecular Biology, Doctoral School of Biology, University of Szeged, Közép fasor 52, H-6726 Szeged, Hungary., Nagy FI; Department of Biochemistry and Molecular Biology, Doctoral School of Biology, University of Szeged, Közép fasor 52, H-6726 Szeged, Hungary., Papp B; Department of Biochemistry and Molecular Biology, Doctoral School of Biology, University of Szeged, Közép fasor 52, H-6726 Szeged, Hungary., Kiricsi M; Department of Biochemistry and Molecular Biology, Doctoral School of Biology, University of Szeged, Közép fasor 52, H-6726 Szeged, Hungary., Frank É; Department of Organic Chemistry, University of Szeged, Dóm tér 8, H-6720 Szeged, Hungary. |
| Abstrakt: |
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 IC 50 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. |
