Synthesis and In Vitro Biological Evaluation of p -Carborane-Based Di- tert -butylphenol Analogs

Targeting inflammatory mediators and related signaling pathways may offer a rational strategy for the treatment of cancer. The incorporation of metabolically stable, sterically demanding, and hydrophobic carboranes in dual cycloxygenase-2 (COX-2)/5-lipoxygenase (5-LO) inhibitors that are key enzymes in the biosynthesis of eicosanoids is a promising approach. The di- tert -butylphenol derivatives R-830 , S-2474 , KME-4 , and E-5110 represent potent dual COX-2/5-LO inhibitors. The incorporation of p -carborane and further substitution of the p -position resulted in four carborane-based di- tert -butylphenol analogs that showed no or weak COX inhibition but high 5-LO inhibitory activities in vitro. Cell viability studies on five human cancer cell lines revealed that the p -carborane analogs R-830-Cb , S-2474-Cb , KME-4-Cb , and E-5110-Cb exhibited lower anticancer activity compared to the related di- tert -butylphenols. Interestingly, R-830-Cb did not affect the viability of primary cells and suppressed HCT116 cell proliferation more potently than its carbon-based R-830 counterpart. Considering all the advantages of boron cluster incorporation for enhancement of drug biostability, selectivity, and availability of drugs, R-830-Cb can be tested in further mechanistic and in vivo studies.