Carborane‐Based Analogues of 5‐Lipoxygenase Inhibitors Co‐inhibit Heat Shock Protein 90 in HCT116 Cells

• Published in: ChemMedChem Vol. 14; no. 2; pp. 255 - 261
• Main Authors: Kuhnert, Robert, Sárosi, Menyhárt‐Botond, George, Sven, Lönnecke, Peter, Hofmann, Bettina, Steinhilber, Dieter, Steinmann, Sara, Schneider‐Stock, Regine, Murganić, Blagoje, Mijatović, Sanja, Maksimović‐Ivanić, Danijela, Hey‐Hawkins, Evamarie
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 22.01.2019
• Subjects: Angiogenesis; Arachidonic acid; Boranes - chemistry; Cancer; Carborane; carboranes; Colon; Colon cancer; Colonic Neoplasms - drug therapy; Colonic Neoplasms - metabolism; Colorectal cancer; Cytotoxicity; Drug Design; HCT116 Cells; Heat shock proteins; heat shock protein 90; HSP90 Heat-Shock Proteins - antagonists & inhibitors; Hsp90 protein; Humans; Inhibitors; Leukotrienes; Lipoxygenase; Lipoxygenase Inhibitors - chemistry; Lipoxygenase Inhibitors - pharmacology; Melanoma; Pharmacology; Toxicity; Tumor cell lines; inhibitors; lipoxygenase; cancer; heat shock protein 90; carboranes
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.201800651

5‐Lipoxygenase converts arachidonic acid into leukotrienes, which are involved in inflammation and angiogenesis. The introduction of carboranes can improve the pharmacokinetic behavior of metabolically less stable pharmaceutics. Herein we report the syntheses of several carborane‐based inhibitors of the 5‐lipoxygenase pathway. The isosteric replacement of phenyl rings by carboranes leads to improved cytotoxicity toward several melanoma and colon cancer cell lines. For the colon cancer cell line HCT116, the co‐inhibition of heat shock protein 90 was observed. A tale of two targets: The functionalization of carboranes with tetrahydropyranyl and quinolinyl substituents leads to less potent 5‐lipoxygenase (5‐LO) inhibitors with significantly increased and selective cytotoxicity toward melanoma and colon cancer cells. The increased cytotoxicity was shown to be related to the simultaneous inhibition of 5‐LO and heat shock protein 90 (Hsp90).