Synthesis of antiproliferative 13α-d-homoestrones via Lewis acid-promoted one-pot Prins-Ritter reactions of d-secosteroidal δ-alkenyl-aldehydes

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Abstract

Abstract A simple one-pot Prins-Ritter route was developed for the synthesis of 16-acylamino-17a-hydroxy-d-homoestrone 3-benzyl and 3-methyl ethers in the 13α-estrone series. The d-secosteroidal δ-alkenyl-aldehydes were allowed to react with different nitriles in the presence of BF3·OEt2 as a Lewis acid catalyst. Prins cyclizations afforded 17a-hydroxy-16-carbenium ions, which underwent Ritter reactions with nitriles, leading to 16α- or 16β-acylamino derivatives. A side-product in which a dihydro-1,3-oxazine was bridged to six-membered ring D at positions 16α,17aα was formed in each reaction. The antiproliferative properties of the novel 13α-d-homosteroids were determined on a panel of human adherent cancer cell lines (HeLa, MCF-7, T47D, MDA-MB-231, MDA-MB-361, A2780 and A431) by means of MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) assays. Some compounds proved to be more effective (with submicromolar IC50 values) than the reference agent cisplatin. One of the most potent compounds substantially increased the rate of tubulin polymerization. Cell cycle analyses by flow cytometry indicated a concentration-dependent accumulation of the G2/M cell population.

Original languageEnglish
Article number7813
Pages (from-to)76-84
Number of pages9
JournalSteroids
Volume102
DOIs
Publication statusPublished - Dec 1 2015

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Keywords

  • Antiproliferative
  • Azabicyclononene
  • Dihydro-1,3-oxazine
  • One-pot
  • Prins-Ritter
  • d-Homoestrone

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Endocrinology
  • Pharmacology
  • Clinical Biochemistry
  • Organic Chemistry

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