Carborane-Based Tebufelone Analogs and Their Biological Evaluation In Vitro

Publikation: Beitrag in FachzeitschriftForschungsartikelBeigetragenBegutachtung

Beitragende

  • Sebastian Braun - , Universität Leipzig (Autor:in)
  • Svetlana Paskaš - , University of Belgrade (Autor:in)
  • Markus Laube - , Helmholtz-Zentrum Dresden-Rossendorf (HZDR) (Autor:in)
  • Sven George - , Johann Wolfgang Goethe-Universität Frankfurt am Main (Autor:in)
  • Bettina Hofmann - , Johann Wolfgang Goethe-Universität Frankfurt am Main (Autor:in)
  • Peter Lönnecke - , Universität Leipzig (Autor:in)
  • Dieter Steinhilber - , Johann Wolfgang Goethe-Universität Frankfurt am Main (Autor:in)
  • Jens Pietzsch - , Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Technische Universität Dresden (Autor:in)
  • Sanja Mijatović - , University of Belgrade (Autor:in)
  • Danijela Maksimović-Ivanić - , University of Belgrade (Autor:in)
  • Evamarie Hey-Hawkins - , Universität Leipzig (Autor:in)

Abstract

The presence of inflammatory mediators in the tumor microenvironment, such as cytokines, growth factors or eicosanoids, indicate cancer-related inflammatory processes. Targeting these inflammatory mediators and related signal pathways may offer a rational strategy for the treatment of cancer. This study focuses on the incorporation of metabolically stable, sterically demanding, and hydrophobic dicarba-closo-dodecaboranes (carboranes) into dual cyclooxygenase-2 (COX-2)/5-lipoxygenase (5-LO) inhibitors that are key enzymes in the biosynthesis of eicosanoids. The di-tert-butylphenol derivative tebufelone represents a selective dual COX-2/5-LO inhibitor. The incorporation of meta- or para-carborane into the tebufelone scaffold resulted in eight carborane-based tebufelone analogs that show no COX inhibition but 5-LO inhibitory activity in vitro. Cell viability studies on HT29 colon adenocarcinoma cells revealed that the observed antiproliferative effect of the para-carborane analogs of tebufelone is enhanced by structural modifications that include chain elongation in combination with introduction of a methylene spacer resulting in higher anticancer activity compared to tebufelone. Hence, this strategy proved to be a promising approach to design potent 5-LO inhibitors with potential application as cytostatic agents.

Details

OriginalspracheEnglisch
Aufsatznummere202300206
FachzeitschriftChemMedChem
Jahrgang18
Ausgabenummer14
PublikationsstatusVeröffentlicht - 17 Juli 2023
Peer-Review-StatusJa

Externe IDs

PubMed 37160667

Schlagworte

Ziele für nachhaltige Entwicklung

Schlagwörter

  • bioisosteric replacement, cancer, carboranes, cyclooxygenase, lipoxygenase, tebufelone