Synthesis and Biological Evaluation of 17 beta-Hydroxysteroid Dehydrogenase Type 1 (17 beta-HSD1) Inhibitors Based on a Thieno[2,3-d]pyrimidin-4(3H)-one Core

Annamaria Lilienkampf, Sampo Karkola, Sari Alho-Richmond, Pasi Koskimies, Nina Johansson, Kaisa Huhtinen, Kimmo Vihko, Kristiina Wahala*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Many breast tumors are hormone-dependent, and estrogens, especially estradiol (E2), have a pivotal role in their growth and development. 17 beta-Hydroxysteroid dehydrogenase type 1 (17 beta-HSD1) is a key enzyme in the biosynthesis of female sex steroids, catalyzing the NADPH-dependent reduction of estrone into biologically active estradiol. In this Study, a library of fused (di)cycloalkeno thieno[2,3-d]pyrimidin-4(3H)-one based compounds was synthesized, and the biological activities against 17 beta-HSD1 in a cell-free and in a cell-based Assay were evaluated. Several thieno[2,3-d]pyrimidin-4(3H)-one based compounds, at 0.1 and 1 mu M test concentrations, were found to be potent 17 beta-HSD1 inhibitors. For example, 4-(3-hydroxyphenylthio)-1,2,7,8,9,10,11,13-octahydro-13-oxo-[1]benzothieno[2',3':4,5]-pyrimido[1,2-a]azepine-3-carboxaldehyde (7f) is one of the most potent nonsteroidal 17 beta-HSD1 inhibitors reported to date with 94% inhibition of the recombinant enzyme at 0.1 mu M test concentration. Importantly, the majority of these compounds exhibited excellent selectivity over the oxidative isoform 17 beta-HSD2 and lacked estrogenic effects in an estrogen receptor (ER) binding assay.

Original languageEnglish
Pages (from-to)6660-6671
Number of pages12
JournalJournal of Medicinal Chemistry
Volume52
Issue number21
DOIs
Publication statusPublished - 12 Nov 2009

Keywords

  • SELECTIVE NONSTEROIDAL INHIBITORS
  • ESTROGEN-DEPENDENT DISEASES
  • SITE-DIRECTED MUTAGENESIS
  • HUMAN BREAST-CARCINOMA
  • POTENT INHIBITORS
  • ACTIVE-SITE
  • STEROID DEHYDROGENASE
  • AROMATASE INHIBITORS
  • CARBONYL-COMPOUNDS
  • ENZYME MODULATORS

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