AbstractThe 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.