1. In Vitro Cytostatic Effect on Tumor Cells by Carborane‐Based Dual Cyclooxygenase‐2 and 5‐Lipoxygenase Inhibitors
- Author
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Sebastian Braun, Svetlana Paskas, Markus Laube, Sven George, Bettina Hofmann, Peter Lönnecke, Dieter Steinhilber, Jens Pietzsch, Sanja S. Mijatović, Danijela Maksimović‐Ivanić, and Evamarie Hey‐Hawkins
- Subjects
Pharmacology ,cyclooxygenases ,carboranes ,Biochemistry (medical) ,cancer ,Pharmaceutical Science ,Medicine (miscellaneous) ,Pharmacology (medical) ,bioisosteric replacement ,lipoxygenases ,dual inhibitors ,multi-target drugs ,Genetics (clinical) - Abstract
The selective inhibition of enzymes that catalyze the conversion of arachidonic acid to inflammatory eicosanoids represents a promising approach for cancer therapy. We, therefore, focus on the incorporation of metabolically stable, sterically demanding and hydrophobic carboranes into existing dual cycloxygenase-2 (COX-2)/5-lipoxygenase (5-LO) inhibitors that are key enzymes in the biosynthesis of eicosanoids. Here, we present the first carborane-containing dual COX-2/5-LO inhibitors derived from RWJ-63556. The replacement of the fluorophenyl moiety by meta- or para-carborane resulted in five carborane-containing derivatives 3, 6, 9, 13 and 17 that show high inhibitory activities toward COX-2 and 5-LO in vitro. Cell viability studies on the A375 melanoma cell line revealed that meta-carborane derivative 3 shows higher anticancer activity compared to RWJ-63556 based on accumulation of lipid droplets in the cells due to blockage of the COX-2 and 5-LO pathways, indicating a promising approach for the design of potent dual COX-2/5-LO inhibitors.
- Published
- 2023
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