14β-(Isoxazol-3-yl)methylestrane Steroids: Chemoselective Synthesis and Transformations with Heterocyclic Ring Opening

Baranovsky, A. V.; Ladyko, Alesya; Shatskaya, V. A.; Scherbakov, Alexander M.

doi:10.1134/s107042801902012x

Cited by 6 publications

(1 citation statement)

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“…Chemical modification of natural steroids with different heterocycles provides a way to alter the function of the parent compound, and several derivatives have been demonstrated to be effective in the prevention and treatment of many types of cancers [ 11 ]. Although there are no examples in the literature for the synthesis of steroidal benzisoxazoles, the incorporation of the five-membered isoxazole ring into a sterane backbone in either a connected [ 12 , 13 , 14 ] or a condensed manner [ 15 ] led to some effective antiproliferative agents ( I – VIII , Figure 1 ). Nevertheless, the phenolic A-ring of estrogens offers the possibility to synthesize aromatic ring-integrated benzisoxazole hybrids and this modification may have beneficial outcomes in several aspects.…”

Section: Introductionmentioning

confidence: 99%

Substitutional Diversity-Oriented Synthesis and In Vitro Anticancer Activity of Framework-Integrated Estradiol-Benzisoxazole Chimeras

et al. 2022

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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.

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