Carborane-Based Tebufelone Analogs and Their Biological Evaluation In Vitro
2023
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Authors:
Braun, SebastianPaskaš, Svetlana
Laube, Markus
George, Sven
Hofmann, Bettina
Lönnecke, Peter
Steinhilber, Dieter
Pietzsch, Jens
Mijatović, Sanja
Maksimović-Ivanić, Danijela
Hey-Hawkins, Evamarie
Document Type:
Article (Published version)
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Show full item recordAbstract:
The presence of inflammatory mediators in the tumor microenvironment,
such as cytokines, growth factors or eicosanoids,
indicate cancer-related inflammatory processes. Targeting these
inflammatory mediators and related signal pathways may offer
a rational strategy for the treatment of cancer. This study
focuses on the incorporation of metabolically stable, sterically
demanding, and hydrophobic dicarba-closo-dodecaboranes
(carboranes) into dual cyclooxygenase-2 (COX-2)/5-lipoxygenase
(5-LO) inhibitors that are key enzymes in the biosynthesis
of eicosanoids. The di-tert-butylphenol derivative tebufelone
represents a selective dual COX-2/5-LO inhibitor. The incorporation
of meta- or para-carborane into the tebufelone scaffold
resulted in eight carborane-based tebufelone analogs that
show no COX inhibition but 5-LO inhibitory activity in vitro. Cell
viability studies on HT29 colon adenocarcinoma cells revealed
that the observed antiproliferative effect of the para-carborane
analogs of tebufelone is enhanced by structural modifications
that include chain elongation in combination with introduction
of a methylene spacer resulting in higher anticancer activity
compared to tebufelone. Hence, this strategy proved to be a
promising approach to design potent 5-LO inhibitors with
potential application as cytostatic agents.
Keywords:
bioisosteric replacement; cancer; carboranes; cyclooxygenase; lipoxygenase; tebufeloneSource:
ChemMedChem, 2023, 18, 14, e202300206-Funding / projects:
- The European Social Fund
- The German Research Foundation (Deutsche Forschungsgemeinschaft)
- The Graduate School Leipzig School of Natural Sciences – Building with Molecules and Nanoobjects (BuildMoNa)
- Ministry of Science, Technological Development and Innovation of the Republic of Serbia, institutional funding - 200007 (University of Belgrade, Institute for Biological Research 'Siniša Stanković') (RS-MESTD-inst-2020-200007)
DOI: 10.1002/cmdc.202300206
ISSN: 1860-7179
PubMed: 37160667