Borcalein: a Carborane-Based Analogue of Baicalein with 12-Lipoxygenase-Independent Toxicity |
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Authors: | Dr. Robert Kuhnert Dr. Lydia Kuhnert Dr. Menyhárt-B. Sárosi Sven George Dr. Dijana Draca Dr. Svetlana Paskas Dr. Bettina Hofmann Prof. Dr. Dieter Steinhilber Prof. Dr. Walther Honscha Prof. Dr. Sanja Mijatović Prof. Dr. Danijela Maksimović-Ivanić Prof. Dr. Evamarie Hey-Hawkins |
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Affiliation: | 1. Institute of Inorganic Chemistry, Faculty of Chemistry and Mineralogy, Leipzig University, Johannisallee 29, 04103 Leipzig, Germany;2. Institute of Pharmacology, Pharmacy and Toxicology, Faculty of Veterinary Medicine, Leipzig University, An den Tierkliniken 15, 04103 Leipzig, Germany;3. Institute of Pharmaceutical Chemistry, University of Frankfurt, Max-von-Laue-Straße 9, 60438 Frankfurt, Germany;4. Department of Immunology, Institute for Biological Research “Sinisa Stankovic”, University of Belgrade, Bul. despota Stefana 142, 11060 Belgrade, Serbia |
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Abstract: | 12-Lipoxygenase is crucial for tumour angiogenesis. 5,6,7-Trihydroxy-2-phenyl-4H-1-benzopyran-4-one (baicalein) is a suitable inhibitor for this enzyme but is rapidly metabolised in vivo. Thus, an improvement of the metabolic stability is necessary to enhance the therapeutic efficiency. An emerging approach to enhance metabolic stability of carbon-based pharmaceuticals is the use of metabolically stable, non-toxic boron clusters, such as dicarba-closo-dodecaborane(12)s (carboranes) as phenyl mimetics. Therefore, the unsubstituted phenyl ring of baicalein was replaced by meta-carborane, resulting in borcalein, the carborane analogue of baicalein. This substitution resulted in a decreased inhibitory activity toward 12-lipoxygenase, but led to increased toxicity in melanoma (A375, B16, B16F10) and colon cancer cell lines (SW480, HCT116, CT26CL25) with decreased tumour selectivity in comparison to baicalein. Surprisingly, borcalein displays a different mechanism of cytotoxicity with increased intracellular production of reactive oxygen species (ROS), reactive nitrogen species (RNS) and nitric oxide (NO). |
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Keywords: | carboranes cancer lipoxygenase inflammation inhibitors |
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