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

Fingerprint

Lewis Acids
Nitriles
Aldehydes
Homosteroids
Cells
Methyl Ethers
Estrone
Cyclization
Tubulin
Oxazines
Polymerization
Cisplatin
Inhibitory Concentration 50
Cell Cycle
Flow Cytometry
Reference Values
Flow cytometry
Ions
Cell Line
Assays

Keywords

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

ASJC Scopus subject areas

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

Cite this

@article{04505b49c15444ab873b3fcfb81f9e7b,
title = "Synthesis of antiproliferative 13α-d-homoestrones via Lewis acid-promoted one-pot Prins-Ritter reactions of d-secosteroidal δ-alkenyl-aldehydes",
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.",
keywords = "Antiproliferative, Azabicyclononene, d-Homoestrone, Dihydro-1,3-oxazine, One-pot, Prins-Ritter",
author = "Judit Huber and J. W{\"o}lfling and G. Schneider and I. Ocsovszki and M{\'o}nika Varga and I. Zupk{\'o} and E. Merny{\'a}k",
year = "2015",
month = "12",
day = "1",
doi = "10.1016/j.steroids.2015.07.004",
language = "English",
volume = "102",
pages = "76--84",
journal = "Steroids",
issn = "0039-128X",
publisher = "Elsevier Inc.",

}

TY - JOUR

T1 - Synthesis of antiproliferative 13α-d-homoestrones via Lewis acid-promoted one-pot Prins-Ritter reactions of d-secosteroidal δ-alkenyl-aldehydes

AU - Huber, Judit

AU - Wölfling, J.

AU - Schneider, G.

AU - Ocsovszki, I.

AU - Varga, Mónika

AU - Zupkó, I.

AU - Mernyák, E.

PY - 2015/12/1

Y1 - 2015/12/1

N2 - 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.

AB - 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.

KW - Antiproliferative

KW - Azabicyclononene

KW - d-Homoestrone

KW - Dihydro-1,3-oxazine

KW - One-pot

KW - Prins-Ritter

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U2 - 10.1016/j.steroids.2015.07.004

DO - 10.1016/j.steroids.2015.07.004

M3 - Article

VL - 102

SP - 76

EP - 84

JO - Steroids

JF - Steroids

SN - 0039-128X

M1 - 7813

ER -