Synthesis of substituted 15β-alkoxy estrone derivatives and their cofactor-dependent inhibitory effect on 17β-HSD1

Bianka Edina Herman, Anita Kiss, J. Wölfling, E. Mernyák, Mihály Szécsi, G. Schneider

Research output: Contribution to journalArticle

Abstract

17β-Hydroxysteroid dehydrogenase type 1 (17β-HSD1) is a key enzyme in the biosynthesis of 17β-estradiol. Novel estrone-based compounds bearing various 15β-oxa-linked substituents and hydroxy, methoxy, benzyloxy, and sulfamate groups in position C3 as potential 17β-HSD1 inhibitors have been synthesized. In addition, in vitro inhibitory potentials measured in the presence of excess amount of NADPH or NADH were investigated. We observed substantial inhibitory potentials for several derivatives (IC50 < 1 µM) and increased binding affinities compared to unsubstituted core molecules. Binding and inhibition were found to be cofactor-dependent for some of the compounds and we propose structural explanations for this phenomenon. Our results may contribute to the development of new 17β-HSD1 inhibitors, potential drug candidates for antiestrogen therapy of hormone-dependent gynecological cancers.

Original languageEnglish
Pages (from-to)1271-1286
Number of pages16
JournalJournal of enzyme inhibition and medicinal chemistry
Volume34
Issue number1
DOIs
Publication statusPublished - Jan 1 2019

Fingerprint

Estrone
Estrogen Receptor Modulators
NADP
NAD
Inhibitory Concentration 50
Estradiol
Hormones
Enzymes
Pharmaceutical Preparations
3(17)-hydroxysteroid dehydrogenase
alkoxyl radical
Neoplasms
Therapeutics

Keywords

  • 17β-HSD1
  • estrogen biosynthesis
  • Michael addition
  • NADPH and NADH
  • substituted 15β-alkoxy-estrone derivatives

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery

Cite this

Synthesis of substituted 15β-alkoxy estrone derivatives and their cofactor-dependent inhibitory effect on 17β-HSD1. / Herman, Bianka Edina; Kiss, Anita; Wölfling, J.; Mernyák, E.; Szécsi, Mihály; Schneider, G.

In: Journal of enzyme inhibition and medicinal chemistry, Vol. 34, No. 1, 01.01.2019, p. 1271-1286.

Research output: Contribution to journalArticle

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