Synthesis, biological evaluation and docking studies of 13-epimeric 10-fluoro- And 10-chloroestra-1,4-dien-3-ones as potential aromatase inhibitors

Rebeka Jójárt, Péter Traj, Édua Kovács, Ágnes Horváth, Gyula Schneider, Mihály Szécsi, Attila Pál, Gábor Paragi, Erzsébet Mernyák

Research output: Contribution to journalArticle

Abstract

Fluorination of 13-epimeric estrones and their 17-deoxy counterparts was performed with Selectfluor as the reagent. In acetonitrile or trifluoroacetic acid (TFA), 10β-fluoroestra-1,4-dien-3-ones were formed exclusively. Mechanistic investigations suggest that fluorinations occurred via SET in acetonitrile, but another mechanism was operative in TFA. Simultaneous application of N-chlorosuccinimide (NCS) and Selectfluor in TFA led to a 1.3:1 mixture of 10β-fluoroestra-1,4-dien-3-one and 10β-chloroestra-1,4-dien-3-one as the main products. The potential inhibitory action of the 10-fluoro- or 10-chloroestra-1,4-dien-3-one products on human aromatase was investigated via in vitro radiosubstrate incubation. The classical estrane conformation with trans ring anellations and a 13β-methyl group seems to be crucial for the inhibition of the enzyme, while test compounds bearing the 13β-methyl group exclusively displayed potent inhibitory action with submicromolar or micromolar IC50 values. Concerning molecular level explanation of biological activity or inactivity, computational simulations were performed. Docking studies reinforced that besides the well-known Met374 H-bond connection, the stereocenter in the 13 position has an important role in the binding affinity. The configuration inversion at C-13 results in weaker binding of 13α-estrone derivatives to the aromatase enzyme.

Original languageEnglish
Article number1783
JournalMolecules
Volume24
Issue number9
DOIs
Publication statusPublished - 2019

Keywords

  • 13α-estrone
  • Aromatase
  • Docking
  • Selectfluor
  • Single electron transfer
  • TEMPO

ASJC Scopus subject areas

  • Analytical Chemistry
  • Chemistry (miscellaneous)
  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery
  • Physical and Theoretical Chemistry
  • Organic Chemistry

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