In Vitro Cytostatic Effect on Tumor Cells by Carborane‐Based Dual Cyclooxygenase‐2 and 5‐Lipoxygenase Inhibitors

The selective inhibition of enzymes that catalyze the conversion of arachidonic acid to inflammatory eicosanoids represents a promising approach for cancer therapy. This study, therefore, focuses on the incorporation of metabolically stable, sterically demanding, and hydrophobic carboranes into exis...

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Published in:Advanced therapeutics 2023-04, Vol.6 (4), p.n/a
Main Authors: Braun, Sebastian, Paskas, Svetlana, Laube, Markus, George, Sven, Hofmann, Bettina, Lönnecke, Peter, Steinhilber, Dieter, Pietzsch, Jens, Mijatović, Sanja S., Maksimović‐Ivanić, Danijela, Hey‐Hawkins, Evamarie
Format: Article
Language:English
Subjects:
bioisosteric replacement
cancer
carboranes
cyclooxygenases
dual inhibitors
lipoxygenases
multitarget drugs
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Summary:The selective inhibition of enzymes that catalyze the conversion of arachidonic acid to inflammatory eicosanoids represents a promising approach for cancer therapy. This study, therefore, focuses 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, the first carborane‐containing dual COX‐2/5‐LO inhibitors derived from RWJ‐63556 are presented. 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. The incorporation of metabolically stable and highly hydrophobic carboranes into RWJ‐63556, a dual inhibitor of cycloxygenase‐2 (COX‐2) and 5‐lipoxygenase (5‐LO), is investigated. Both enzymes are key mediators in the biosynthesis of pro‐inflammatory and tumor‐inducing eicosanoids. The replacement of the fluorophenyl moiety by meta‐ or para‐carborane results in the first group of carborane‐based dual COX‐2/5‐LO inhibitors as potent antitumor agents.
ISSN:2366-3987
2366-3987
DOI:10.1002/adtp.202200252