Microwave-assisted Phospha-Michael addition reactions in the 13α-oestrone series and in vitro antiproliferative properties

J Enzyme Inhib Med Chem. 2021 Dec;36(1):1931-1937. doi: 10.1080/14756366.2021.1963241.

Abstract

Microwave-assisted phospha-Michael addition reactions were carried out in the 13α-oestrone series. The exocyclic 16-methylene-17-ketones as α,β-unsaturated ketones were reacted with secondary phosphine oxides as nucleophilic partners. The addition reactions furnished the two tertiary phosphine oxide diastereomers in high yields. The main product was the 16α-isomer. The antiproliferative activities of the newly synthesised organophosphorus compounds against a panel of nine human cancer cell lines were investigated by means of MTT assays. The most potent compound, the diphenylphosphine oxide derivative in the 3-O-methyl-13α-oestrone series (9), exerted selective cell growth-inhibitory activity against UPCI-SCC-131 and T47D cell lines with low micromolar IC50 values. Moreover, it displayed good tumour selectivity property determined against non-cancerous mouse fibroblast cells.

Keywords: 13α-oestrone; Phospha-Michael addition; antiproliferative effect; tumour selectivity; α,β-unsaturated ketone.

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology
  • Cell Line
  • Cell Proliferation / drug effects
  • Drug Screening Assays, Antitumor
  • Estrone / chemical synthesis*
  • Estrone / pharmacology*
  • Fibroblasts / cytology
  • Humans
  • Mice
  • Microwaves
  • Models, Molecular
  • Organophosphorus Compounds / chemistry*
  • Phosphines / chemistry*
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • Organophosphorus Compounds
  • Phosphines
  • Estrone
  • phosphine
  • triphenylphosphine oxide

Grants and funding

The work of Renáta Minorics and Erzsébet Mernyák in this project was supported by the János Bolyai Research Scholarship of the Hungarian Academy of Sciences. This work was supported by National Research, Development and Innovation Office-NKFIH through project OTKA SNN 124329. Support from Ministry of Human Capacities, Hungary grant 20391–3/2018/FEKUSTRAT is acknowledged.