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

Abstract

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.

Carborane‐Based Tebufelone Analogs and Their Biological Evaluation In Vitro

“…Additionally, there was no lipid accumulation detected in the cytoplasm of viable cells (data not shown), and overall, the cell morphology upon 72 h treatment with 8 was not remarkably changed (see Supporting Information, Figure S6). This work gives evidence that the carborane‐based tebufelone derivatives have a different mode of action compared to recently presented carborane‐based RWJ‐63556 derivatives [52] …”

“…The anticancer activity of compounds 2 , 4 , 6 , 8 , 10 , 12 , 14 , and 16 was screened on different human carcinoma cell lines. Based on COX‐2 and 5‐LO expression, the melanoma cell line A375, three colon cancer cell lines HT29, SW480, and SW620, as well as a lung cancer cell line A549 were selected [26,52,57] . Tebufelone ( 17 ) was used as a reference compound.…”

“…Based on COX-2 and 5-LO expression, the melanoma cell line A375, three colon cancer cell lines HT29, SW480, and SW620, as well as a lung cancer cell line A549 were selected. [26,52,57] Tebufelone (17) was used as a reference compound. The influence of the incorporated carborane moieties on cancer cell viability was examined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and crystal violet (CV) assays (Table 2, see Supporting Information, Table S3).…”

“…However, the quinoline‐containing analog, CarbZDChin, showed increased cytotoxicity on colon carcinoma in vitro and in vivo [51] . We have recently reported the first carborane‐based dual COX‐2/5‐LO inhibitors that are derived from RWJ‐63556 showing excellent inhibitory potential toward COX‐2 and 5‐LO, accompanied by high anticancer activity on the A357 melanoma cell line [52] …”

“…[51] We have recently reported the first carborane-based dual COX-2/5-LO inhibitors that are derived from RWJ-63556 showing excellent inhibitory potential toward COX-2 and 5-LO, accompanied by high anticancer activity on the A357 melanoma cell line. [52] Herein, we report the synthesis of eight carborane-containing tebufelone analogs, their inhibitory potential toward COX-1, COX-2, and 5-LO, as well as their cytotoxicity on five human cancer cell lines.…”