Chromatography-free, Mitsunobu-triggered heterocyclizations of salicylhydroxamic acids to 3-hydroxybenzisoxazoles

Eker, Daniel Van; Chauhan, Jay; Murphy, William A.; Conlon, Ivie L.; Fletcher, Steven

doi:10.1016/j.tetlet.2016.10.045

Cited by 4 publications

(1 citation statement)

References 15 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This compound was next converted to a hydroxamic acid derivative of E2 ( 7 ) by a three-step sequence involving C-17 ketone reduction, methylester formation of the acid moiety [ 41 ] and the final nucleophilic acyl substitution with NH 2 OH [ 42 ]. Mitsunobu-triggered heterocyclization in anhydrous THF at RT [ 43 ] afforded 3′-hydroxybenzisoxazole 4h in 89% yield, whereas its O -methylation furnished 4i in 82% yield ( Scheme 2 ).…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2022

View full text Add to dashboard Cite

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.

show abstract

Section: Resultsmentioning

confidence: 99%